Inhibitors of vap-1

Abstract

Provided herein are compounds and methods of using the same to modulate VAP-1 activity.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 738,933, filed September 28, 2018, the disclosure of which is considered part of the disclosure of this application and is incorporated herein by reference in its entirety. Background Technology

[0003] The medical field needs compounds that can effectively treat diseases and conditions mediated by VAP-1 protein activity, such as uveitis. This article discloses solutions to this and other problems in the field. Summary of the Invention

[0004] On the one hand, this article provides compounds having structural formula (IV):

[0005]

[0006] Or its olefin isomers, tautomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs;

[0007] in:

[0008] X 1 and X 4 Independently, it can be either =N– or =CH–;

[0009] X 5 =N– or –CR 5 –;

[0010] X 6 =N– or –CR 6 –;

[0011] Y represents the bond, –O–, –S–, –NR. 7 –、–OCX2–、–(CH2) z2 W–, -C(O)O- or -C(O)NH-;

[0012] W represents a bond, –O–, –S–, or –NH–;

[0013] z1 and z2 are independent integers from 0 to 3;

[0014] n1, n2, n5, n6, and n7 are independent integers from 0 to 4;

[0015] m1, m2, m5, m6, m7, v1, v2, v5, v6, and v7 are independently 1 or 2;

[0016] L 1 For key, –O–, –S–, –NR1L – substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0017] R 1L It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0018] R 1 Independently hydrogen, halogen, –CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 -CN, -SO n1 R 1A –SO v1 NR 1B R 1C -NHNR 1B R 1C -ONR 1B R 1C -NHC(O)NHNR 1B R 1C -NHC(O)NR 1B R 1C –N(O) m1 –NR 1B R 1C –C(O)R 1D –C(O)OR 1D –C(O)NR 1B R 1C –OR 1A -NR 1B SO2R 1A -NR 1B C(O)R 1D -NR 1B C(O)OR 1D –NR 1B OR 1D –OCX 1.1 3. –OCHX 1.1 2. R 12 -Substituted or unsubstituted alkyl groups, R 12 -Substituted or unsubstituted heteroalkyl, R 12 -substituted or unsubstituted cycloalkyl, R 12 -Substituted or unsubstituted heterocyclic alkyl groups, R 12 -substituted or unsubstituted aryl, or R 12-Substituted or unsubstituted heteroaryl groups or at least one amino acid;

[0019] R 2 Hydrogen, halogen, -CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 -CN, -SO n2 R 2A –SO v2 NR 2B R 2C –NR 2B R 2C –C(O)R 2D –C(O)OR 2D –C(O)NR 2B R 2C –OR 2A –OCX 2.1 3. –OCHX 2.1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0020] R 3 and R 4 Independently hydrogen or –F;

[0021] R 5 Hydrogen, halogen, -CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 –CN, –N3, –SO n5 R 5A –SO v5 NR 5B R 5C -NHNR 5B R 5C -ONR 5B R 5C -NHC(O)NHNR 5B R 5C -NHC(O)NR 5B R 5C –N(O) m5 –NR 5B R 5C –C(O)R 5D –C(O)OR 5D –C(O)NR 5B R 5C –OR 5A -NR 5B SO2R 5A-NR 5B C(O)R 5D -NR 5B C(O)OR 5D –NR 5B OR 5D –OCX 5.1 3. –OCHX 5.1 2. Substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0022] R 6 Hydrogen, halogen, -CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 –CN, –N3, –SO n6 R 6A –SO v6 NR 6B R 6C -NHNR 6B R 6C -ONR 6B R 6C -NHC(O)NHNR 6B R 6C -NHC(O)NR 6B R 6C –N(O) m6 –NR 6B R 6C –C(O)R 6D –C(O)OR 6D –C(O)NR 6B R 6C –OR 6A -NR 6B SO2R 6A -NR 6B C(O)R 6D -NR 6B C(O)OR 6D –NR 6B OR 6D –OCX 6.1 3. –OCHX 6.1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0023] R 7 Hydrogen, halogen, –CX 7.1 3. -CHX 7.12. -CH2X 7.1 -CN, -SO n7 R 7A –SO v7 NR 7B R 7C –NR 7B R 7C –C(O)R 7D –C(O)OR 7D –C(O)NR 7B R 7C –OR 7A –OCX 7.1 3. –OCHX 7.1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0024] R 12 Hydrogen, halogen, –CX 12.1 3. -CHX 12.1 2. -CH2X 12.1 -CN, -SO n12 R 12A –SO v12 NR 12B R 12C –NR 12B R 12C –C(O)R 12D –C(O)OR 12D –C(O)NR 12B R 12C –OR 12A –OCX 12.1 3. –OCHX 12.1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0025] R 1A For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12A -Substituted or unsubstituted alkyl groups, R 12A -Substituted or unsubstituted heteroalkyl, R 12A -substituted or unsubstituted cycloalkyl, R 12A -Substituted or unsubstituted heterocyclic alkyl groups, R 12A -substituted or unsubstituted aryl, or R 12A -Substituted or unsubstituted heteroaryl groups;

[0026] R 1B For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12B -Substituted or unsubstituted alkyl groups, R 12B -Substituted or unsubstituted heteroalkyl, R 12B -substituted or unsubstituted cycloalkyl, R 12B -Substituted or unsubstituted heterocyclic alkyl groups, R 12B -substituted or unsubstituted aryl, or R 12B -Substituted or unsubstituted heteroaryl groups;

[0027] R 1C For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12C -Substituted or unsubstituted alkyl groups, R 12C -Substituted or unsubstituted heteroalkyl, R 12C -substituted or unsubstituted cycloalkyl, R 12C -Substituted or unsubstituted heterocyclic alkyl groups, R 12C -substituted or unsubstituted aryl, or R 12C -Substituted or unsubstituted heteroaryl groups; or R groups bonded to the same nitrogen atom 1B and R 1C The substituents may optionally be joined to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups;

[0028] R 1D For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12D -Substituted or unsubstituted alkyl groups, R 12D -Substituted or unsubstituted heteroalkyl, R 12D -substituted or unsubstituted cycloalkyl, R 12D -Substituted or unsubstituted heterocyclic alkyl groups, R 12D -substituted or unsubstituted aryl, or R 12D -Substituted or unsubstituted heteroaryl groups;

[0029] R 2A R 2B R 2C R 2D R 5A R 5B R 5C R 5D R 6A R 6B R 6C R 6D R 7A R7B R 7C R 7D R 12A R 12B R 12C and R 12D Independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R bonded to the same nitrogen atom. 2B and R 2C ;R 5B and R 5C ;R 6B and R 6C ;R 7B and R 7C ;R 8B and R 8C ; or R 12B and R 12C The substituents may optionally be joined to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; and

[0030] X, X 1.1 X 2.1 X 5.1 X 6.1 X 7.1 and X 12.1 It can be independently –Cl, –Br, –I, or –F.

[0031] In another aspect, a pharmaceutical composition is provided comprising a compound of the structural formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and at least one pharmaceutically acceptable excipient.

[0032] One aspect provides a method for inhibiting vascular adhesion protein-1 (VAP-1) using compounds of the structural formulas (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or olefinic isomers, tautomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

[0033] One aspect provides a method for treating or preventing an ophthalmic disease or condition in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of the structural formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0034] In another aspect, a method for treating or preventing uveitis in a subject in need is provided, comprising administering to the subject a therapeutically effective amount of a compound of the structural formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0035] Incorporation

[0036] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually cited and incorporated herein by reference. Detailed Implementation

[0037] This article provides, for example, compounds and compositions for inhibiting vascular adhesion protein-1 (VAP-1), and pharmaceutical compositions comprising such compounds and compositions. This article also provides, for example, methods for treating or preventing diseases, conditions, or symptoms thereof by modulating (e.g., inhibiting) VAP-1-mediated processes.

[0038] I. Definition

[0039] The abbreviations used in this article have their conventional meanings in the fields of chemistry and biology. The chemical structures and general formulas described in this article are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0040] When substituents are represented by their conventional chemical formula written from left to right, they also encompass chemically identical substituents obtained from structures written from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0041] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, means a straight (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and may include monovalent, divalent, and polyvalent groups having a specified number of carbon atoms (i.e., C1-C1). 10 (This refers to one to ten carbon atoms). An alkyl group is an uncyclic chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, and homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Unsaturated alkyl groups are groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers. An alkoxy group is an alkyl group that is attached to the rest of the molecule via an oxygen linker (-O-).

[0042] Unless otherwise stated, the term "alkylene" itself, or as part of another substituent, refers to a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, alkyl (or alkylene) groups have 1 to 24 carbon atoms, with those having 10 or fewer carbon atoms being preferred herein. "Lower alkyl" or "lower alkylene" refers to a shorter-chain alkyl or alkylene group, typically having eight or fewer carbon atoms. Unless otherwise stated, the term "alkenyl" itself, or as part of another substituent, refers to a divalent group derived from an olefin.

[0043] Unless otherwise stated, the term "heteroalkyl" on its own, or in combination with another term, means a stable straight or branched chain, or a combination thereof, comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom (e.g., N, S, Si, or P) may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is attached to the remainder of the molecule. Heteroalkyl groups are uncyclic chains. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. At most two or three heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may include up to eight optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0044] Similarly, unless otherwise stated, the term "heteroalkylene" itself, or as part of another substituent, refers to a divalent group derived from a heteroalkylene group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom can also occupy either end or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the general formula of the linking group is written does not imply the orientation of that linking group. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As stated above, heteroalkyl as used herein includes those groups that are attached to the rest of the molecule via heteroatoms, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO2R'. When "heteroalkyl" is referred to, followed by a specific heteroalkyl group such as -NR'R", it should be understood that the terms heteroalkyl and -NR'R are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are listed for clarity. Therefore, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups such as -NR'R".

[0045] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl" on their own or in combination with other terms refer to "alkyl" and "heteroalkyl" in cyclic form, respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, the heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, etc. "Cycloalkylene" and "heterocycloalkylene" alone or as part of another substituent refer to divalent groups derived from cycloalkylene and heterocycloalkylene, respectively. "Cycloalkylene" also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, etc.

[0046] Unless otherwise stated, the terms "halogenated" or "halogen" on their own or as part of another substituent refer to a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "halogenated alkyl" are intended to include both monohalogenated and polyhalogenated alkyl groups. For example, the term "halogenated (C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0047] Unless otherwise stated, the term "acyl" means -C(O)R, where R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0048] Unless otherwise stated, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which can be a monocyclic or fused together (i.e., fused-ring aryl) or a plurality of covalently linked rings (preferably 1-3 rings). A fused-ring aryl refers to a plurality of fused rings, wherein at least one ring in the fused ring is an aryl ring. The term "heteroaryl" refers to an aryl (or ring) containing at least one heteroatom such as N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl (i.e., a plurality of fused rings, wherein at least one ring in the fused ring is a heteroaromatic ring). A 5,6-fused heteroaryl refers to two fused rings, one of which is a 5-membered ring and the other a 6-membered ring, and at least one of which is a heteroaryl ring. Similarly, a 6,6-fused heteroaryl refers to two fused rings, one of which is a 6-membered ring and the other a 6-membered ring, and at least one of which is a heteroaryl ring. Furthermore, a 6,5-fused heteroaryl group refers to two rings fused together, one of which is a 6-membered ring and the other a 5-membered ring, and at least one of the rings is a heteroaryl ring. The heteroaryl group can be attached to the rest of the molecule via a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thiopheneyl, pyridinyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indoleyl, isoindoleyl, benzothiapheneyl, isoquinolinyl, quinoxalinyl, quinolinyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl The substituents in each of the above-described aryl and heteroaryl ring systems are selected from the acceptable substituents described below. "Arylidene" and "heteroarylidene" alone or as part of another substituent refer to divalent groups derived from aryl and heteroaryl groups, respectively. Heteroaryl substituents can be bonded to cyclic heteroatoms via an -O- bond.

[0049] A spirocycle is two or more rings in which adjacent rings are connected by a single atom. The individual rings within a spirocycle can be identical or different. The individual rings within a spirocycle can be substituted or unsubstituted and can have different substituents than the other individual rings within a group of spirocycles. Possible substituents for the individual rings within a spirocycle are possible substituents for the same ring when it is not part of the spirocycle (e.g., substituents for cycloalkyl or heteroalkyl rings). A spirocycle can be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heteroalkyl, or a substituted or unsubstituted heteroalkylene, and the individual rings within the spirocycle group can be any of those immediately preceding in the list, including all rings of one type (e.g., all rings are substituted heteroalkylene, where each ring can be the same or different substituted heteroalkylene). When referring to spirocycle systems, heterocyclic spirocycle means a spirocycle in which at least one ring is heterocyclic and each ring can be different. When referring to spirocycle systems, substituted spirocycle means that at least one ring is substituted and each substituent can optionally be different.

[0050] symbol This indicates the connection point between the chemical part and the rest of the molecular chemical formula.

[0051] As used in this article, the term "oxo" refers to oxygen bonded to a carbon atom by a double bond.

[0052] The term "alkylene aryl" refers to the aryl moiety covalently bonded to the alkylene portion (also referred to herein as the alkylene linker). In some embodiments, the alkylene aryl group has the following formula:

[0053]

[0054] The alkylene aryl moiety may be substituted (e.g., substituted with a substituent) on the alkylene moiety or the aryl linker (e.g., at carbons 2, 3, 4, or 6) by a halogen, oxo, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3-SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl groups, or substituted or unsubstituted 2- to 5-membered heteroalkyl groups. In some embodiments, the alkylene aryl group is unsubstituted.

[0055] Each of the above terms (e.g., "alkyl", "heteroalkyl", "cycloalkyl", "heterocycloalkyl", "aryl", and "heteroaryl") includes both substituted and unsubstituted forms of the indicated group. Some substituents for each type of group are provided below.

[0056] Substituents in alkyl and heteroalkyl groups (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, ynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be one or more selected from, but not limited to, a variety of groups including: -OR', =O, =NR', =N-OR', -NR'R”, -SR', -halogen, -SiR'R”R”', -OC(O)R', -C(O)R', -CO2R', -CONR'R ", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R"')=NR"", -NR-C(NR 'R")=NR"', -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NR'NR"R"', -ONR'R", -NR'C(O)NR"NR"' R””, -CN, -NO2, -NR'SO2R”, -NR'C(O)R”, -NR'C(O)-OR”, -NR'OR”, the numerical range is from zero to (2m'+1), where m' is the total number of carbon atoms in this group. R, R', R”, R”’ and R”” each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., substituted with...). 1-3 halogen-substituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When the compounds described herein contain more than one R group, for example, each R group is chosen independently; when more than one of these groups is present, each R', R”, R”', and R”” group is also chosen independently. When R' and R” are attached to the same nitrogen atom, they can combine with that nitrogen atom to form a 4, 5, 6, or 7-membered ring. For example, -NR'R” includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Those skilled in the art will understand from the above discussion of substituents that the term "alkyl" is intended to include groups comprising a carbon atom bonded to a group other than a hydrogen group, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0057] Similar to the substituents described for alkyl groups, the substituents for aryl and heteroaryl groups are varied and selected from, for example: -OR', -NR'R”, -SR', -halogen, -SiR'R”R”', -OC(O)R', -C(O)R', -CO2R', -CONR'R”, -OC(O)NR'R”, -NR”C(O)R', -NR'-C(O)NR”R”', -NR”C(O)2R', -NR-C(NR'R”R”')=NR””, -NR-C(NR'R”)=NR”', -S(O)R', -S(O)2R', -S(O)2NR'R”, -NRSO2R', -NR'NR”R”', -ONR'R”, -NR'C(O)NR”NR”'R””, -CN The values ​​of -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy and fluoro(C1-C4)alkyl, -NR'SO2R”, -NR'C(O)R”, -NR'C(O)-OR”, and -NR'OR” range from zero to the total number of open valences on the aromatic ring system; and wherein R', R”, R”' and R”” are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When the compound described herein contains more than one R group, for example, each R group is selected independently; when more than one of these groups is present, each R', R”, R”' and R”” group is also selected independently.

[0058] Substituents in the ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be described as substituents on the ring, rather than on a specific atom of the ring (often referred to as floating substituents). In such cases, the substituent can be attached to any ring atom (obeying the rules of valence), and in the case of fused or spirocyclic rings, the substituent is described as associated with one member of the fused or spirocyclic ring (floating substituent on a monocyclic ring), and can be a substituent on any fused or spirocyclic ring (floating substituent on a polycyclic ring). When a substituent is attached to the ring rather than a specific atom (floating substituent), and the substituent's subscript is an integer greater than 1, multiple substituents can be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent can optionally be different. Where the connection point between the ring and the rest of the molecule is not limited to a single atom (floating substituent), the connection point can be any atom of the ring, and in the case of fused or spirocyclic rings, it can be any atom of any fused or spirocyclic ring, but obeying the rules of valence. When a ring, fused ring, or spirocyclic ring contains one or more cyclic heteroatoms, and the ring, fused ring, or spirocyclic ring exhibits more than one floating substituent (including, but not limited to, connection points with the rest of the molecule), the floating substituent can be bonded to the heteroatom. In cases where the cyclic heteroatom is bonded to one or more hydrogen atoms in a structure or formula with a floating substituent (e.g., a cyclic nitrogen with two bonds bonded to the ring atom and a third bond bonded to a hydrogen atom), when the heteroatom is bonded to the floating substituent, the substituent is understood to replace the hydrogen atom, while adhering to the rules of valence.

[0059] Two or more substituents may optionally join to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Although not mandatory, such so-called cyclizing substituents are commonly found to be attached to a cyclic base structure. In one embodiment, the cyclizing substituent is attached to an adjacent member of the base structure. For example, two cyclizing substituents attached to an adjacent member of a cyclic base structure produce a fused ring structure. In another embodiment, the cyclizing substituent is attached to a single member of the base structure. For example, two cyclizing substituents attached to a single member of a cyclic base structure produce a spirocyclic structure. In yet another embodiment, the cyclizing substituent is attached to a non-adjacent member of the base structure.

[0060] The two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form the formula -TC(O)-(CRR'). q A -U- ring, wherein T and U are independently -NR-, -O-, -CRR'-, or single bonds, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with the formula -A-(CH2). rThe substituents of -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 4. One of the single bonds in the newly formed ring may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by the formula -(CRR'). s -X'-(C”R”R”') d - substituents, wherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2- or -S(O)2NR'-. Substituents R, R', R” and R”' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

[0061] As used herein, the term “heteroatom” or “cyclic heteroatom” is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0062] As used in this article, "substituent" refers to a group selected from the following:

[0063] (A) Oxygenation, halogenation

[0064] The following are listed: -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and...

[0065] (B) Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, which are substituted by at least one substituent selected from the following:

[0066] (i) Oxygenated, halogenated

[0067] The following are listed: -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and...

[0068] (ii) Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, which are substituted by at least one substituent selected from the following:

[0069] (a) Oxygenation, halogenation

[0070] The following are listed: -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and...

[0071] (b) Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, which are substituted by at least one substituent selected from the following: oxo, halogen

[0072] Unsubstituted alkyl, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl.

[0073] As used herein, “size-restricted substituent” or “size-restricted substituent group” refers to a group selected from all the substituents described above for “substituent”, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C2 group. 20Alkyl groups, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 20-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C8 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10-membered heteroaryl.

[0074] As used herein, “lower substituent” or “lower substituent group” refers to a group selected from all the substituents described above for “substituent”, wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 Aryl, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5 to 9-membered heteroaryl group.

[0075] In some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-restricted substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0076] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl group may be a substituted or unsubstituted C1-C2. 20 Alkyl groups, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 20-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C8 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 10-membered heteroaryl group. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C 20Alkylenes, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 3- to 8-membered heteroalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 A aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5 to 10 heteroaryl group.

[0077] In some embodiments, each substituted or unsubstituted alkyl group is a substituted or unsubstituted C1-C8 alkyl group, each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2- to 8-membered heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C7 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 cycloalkyl group. 10 The aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group. In some embodiments, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C1-C8 alkylene group, each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 2- to 8-membered heteroaryl group, each substituted or unsubstituted cycloalkylene group is a substituted or unsubstituted C3-C7 cycloalkylene group, each substituted or unsubstituted heterocycloalkylene group is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C8 alkylene group. 10 The compound is an aryl group, and / or each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5 to 9-membered heteroaryl group. In some embodiments, the compound is a chemical substance listed in the following Examples section, figures, or tables.

[0078] Certain compounds disclosed herein have asymmetric carbon atoms (optical or chiral centers) or double bonds. Enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers, and single isomers of amino acids, which can be defined in absolute stereochemistry, are included within the scope of this disclosure. The compounds disclosed herein do not include those known in the art that are too unstable to be synthesized and / or isolated. This disclosure is intended to include compounds in racemic and optically pure forms; optically active (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain an alkene bond or other geometrically asymmetric center, and unless otherwise specified, the compounds are intended to include E and Z geometric isomers.

[0079] As used herein, the term "isomer" refers to a compound that has the same number and type of atoms and therefore the same molecular weight, but differs in the arrangement or configuration of the atoms.

[0080] As used in this paper, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another.

[0081] It will be apparent to those skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of this disclosure.

[0082] Unless otherwise stated, the structures described herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations of each asymmetric center. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers and diastereomers, are within the scope of this disclosure.

[0083] Unless otherwise stated, the structures shown herein are also intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is... 13 C- or 14 Compounds with this structure other than C-enriched carbon substitutions are also within the scope of this disclosure.

[0084] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds may contain radioactive isotopes such as tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radioactive labeling. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure.

[0085] The term "isotope variant" refers to a compound that contains an isotope in a non-natural proportion at one or more atoms constituting the compound. In some embodiments, the "isotope variant" of the compound contains one or more isotopes in a non-natural proportion, including but not limited to hydrogen (…). 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), Carbon-12 ( 12 C), Carbon-13 ( 13 C), Carbon-14 ( 14 C) Nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 (15 N), Oxygen-14 ( 14 O), Oxygen-15 ( 15 O), Oxygen-16 ( 16 O), Oxygen-17 ( 17 O), Oxygen-18 ( 18 O), Fluorine-17 ( 17 F), Fluorine-18 ( 18 F), Phosphorus-31 ( 31 P), Phosphorus-32 ( 32 P), Phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), Chlorine-35 ( 35 Cl), Chlorine-36 ( 36 Cl), Chlorine-37 ( 37 Cl), Bromine-79 ( 79 Br), bromine-81 ( 81 Br), Iodine-123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and Iodine-131 131 I). In some embodiments, the "isotopic variant" of the compound is in a stable form, i.e., non-radioactive. In some embodiments, the "isotopic variant" of the compound contains one or more isotopes in non-natural proportions, including but not limited to hydrogen (I). 1 H), deuterium ( 2 H), carbon-12 ( 12 C), Carbon-13 ( 13 C) Nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), Oxygen-16 ( 16 O), Oxygen-17 ( 17 O), Oxygen-18 ( 18 O), Fluorine-17 ( 17 F), Phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), Chlorine-35 ( 35 Cl), Chlorine-37 ( 37 Cl), Bromine-79 ( 79Br), bromine-81 ( 81 Br) and iodine-127 127 I). In some embodiments, the "isotopic variant" of the compound is in an unstable form, i.e., radioactive. In some embodiments, the "isotopic variant" of the compound contains one or more isotopes in non-natural proportions, including but not limited to tritium (I). 3 H), carbon-11 ( 11 C), Carbon-14 ( 14 C) Nitrogen-13 ( 13 N), Oxygen-14 ( 14 O), Oxygen-15 ( 15 O), Fluorine-18 ( 18 F), Phosphorus-32 ( 32 P), Phosphorus-33 ( 33 P), sulfur-35 ( 35 S), Chlorine-36 ( 36 Cl), Iodine-123 ( 123 I), iodine-125( 125 I), iodine-129( 129 I) and Iodine-131 131 I). It should be understood that in the compounds provided herein, for example, any hydrogen can be... 2 H, or for example any carbon, can be 13 C, or any nitrogen, for example, can be 15 N, or any oxygen, can be 18 O, provided that it is feasible to the judgment of someone skilled in the art. In some embodiments, the "isotopic variant" of the compound contains a non-natural proportion of deuterium (D).

[0086] It should be noted that throughout the application, the alternatives are written in the Markush group, for example, each amino acid position contains more than one possible amino acid. In particular, it is conceivable that each member of the Markush group should be considered separately, thereby including another embodiment, and the Markush group should not be understood as a single unit.

[0087] The term "analogue," used in its common sense in chemistry and biology, refers to a compound that is structurally similar to another compound (the so-called "reference" compound) but has a different composition. This is achieved, for example, by substituting an atom of a different element for another atom, or by having a specific functional group present, or by substituting one functional group for another, or by having absolute stereochemistry of one or more chiral centers of the reference compound. Therefore, an analogue is a compound that is functionally or physically similar to or equivalent to a reference compound, but not structurally or physically similar to it.

[0088] As used herein, the terms “an” or “a” mean one or more (or a combination of substituents). Additionally, as used herein, the phrase “replaced by” means that the specified group can be replaced by one or more of any or all of the said substituents. For example, in the case of a group such as an alkyl or heteroaryl group, “replaced by an unsubstituted C1-C…” 20 When "alkyl or unsubstituted 2 to 20 heteroalkyl" is substituted, the group may contain one or more unsubstituted C1-C1 groups. 20 Alkyl and / or one or more unsubstituted 2 to 20 heteroalkyl groups.

[0089] Furthermore, when a group is partially substituted by an R substituent, it can be referred to as "R-substituted". When partially R-substituted, the portion is substituted by at least one R substituent, and each R substituent is optionally different. When a specific R group is present in the description of a chemical genus (e.g., formula (I)), Roman numeral symbols can be used to distinguish each appearance of that specific R group. For example, in the presence of multiple R groups... 13 In the case of substituents, each R can be 13 Substituents are classified as R 13A R 13B R 13C R 13D etc., where R 13A R 13B R 13C R 13D Each of them in R 13 Defined within the scope of the definition, and optionally defined differently.

[0090] The description of the compounds disclosed herein is limited by principles of chemical bonding known to those skilled in the art. Therefore, in cases where a group can be substituted with one or more of a plurality of substituents, such substituents are chosen to conform to the principles of chemical bonding, resulting in compounds that are not inherently unstable and / or that are known to those skilled in the art to be unstable under ambient conditions (such as aqueous, neutral, and several known physiological conditions). For example, according to principles of chemical bonding known to those skilled in the art, heterocyclic alkyl or heteroaryl groups are linked to the remainder of the molecule via cyclic heteroatoms, thereby avoiding inherently unstable compounds.

[0091] The term "pharmaceutically acceptable salt" is intended to include salts of active compounds prepared with pharmaceutically acceptable acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of this disclosure contain relatively acidic functionality, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds of this disclosure contain relatively basic functionality, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of the desired acid, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. Also included are salts of amino acids, such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of this disclosure simultaneously possess basic and acidic functionalities, which allows the compound to be converted into either a basic addition salt or an acid addition salt.

[0092] Therefore, the compounds of this disclosure can exist in the form of salts, such as salts formed with pharmaceutically acceptable acids. This disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts formed with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., iodomethane, iodoethane, etc.). These salts can be prepared by methods known to those skilled in the art.

[0093] Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner.

[0094] In addition to the salt form, this disclosure also provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of this disclosure. The prodrugs of the compounds described herein can be converted in vivo after administration.

[0095] Some of the compounds disclosed herein can exist in non-solventized forms as well as in solvated forms, including hydrated forms.

[0096] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate the administration and absorption of a compound to a subject and can be included in the compositions of this disclosure without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and colorants. Such articles may be sterile and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, and / or aromatic substances that do not react adversely with the compounds of this disclosure. Those skilled in the art will recognize that other pharmaceutical excipients may be used in this disclosure.

[0097] The term "article" is intended to include formulations of active compounds carried by an encapsulating material, which provides capsules in which the active component, with or without another carrier, is surrounded by and thus associated with the carrier. Similarly, it includes capsules and tablets. Tablets, powders, capsules, pills, capsules, and tablets can be used as solid dosage forms suitable for oral administration.

[0098] "VAP-1 inhibitor" refers to a compound that reduces the activity of VAP-1 compared to a control, such as a compound that is not present or has known activity (e.g., the compound described herein).

[0099] Vascular adhesion protein-1 (VAP-1) is a member of the copper-containing amine oxidase / aminourea-sensitive amine oxidase (AOC / SSAO) family, existing in the human body in both membrane-bound and soluble forms. The membrane-bound form of VAP-1 is primarily expressed in endothelial cells, smooth muscle cells, and adipocytes, while soluble VAP-1 is mainly released from vascular endothelial cells into the plasma. VAP-1 possesses a distal adhesion domain and an enzymatically active amine oxidase site on the extracellular membrane. As an adhesion molecule, VAP-1 participates in leukocyte rolling, adhesion, and migration, which is crucial for leukocyte extravasation into sites of inflammation. VAP-1 also acts as an amine oxidase. It possesses dopaquinone (TPQ) as a cofactor at its active site and catalyzes the conversion of primary amines (e.g., methylamine and aminoacetone) into their corresponding aldehydes (e.g., formaldehyde and methylglyoxal), releasing ammonia and hydrogen peroxide simultaneously.

[0100] RCH2NH2+O2+H2O→RCHO+H2O2+NH3

[0101] "Contact" is used in its ordinary sense and refers to the process of bringing at least two different substances (e.g., chemical compounds including biomolecules or cells) into sufficiently close proximity to react, interact, or physically contact. However, it should be understood that the resulting reaction products can be produced directly from the reaction between the added reagents, or from intermediates of one or more added reagents that can be produced in the reaction mixture.

[0102] The term “contact” can include causing two substances to react, interact, or come into physical contact, wherein the two substances can be the compounds and proteins or enzymes described herein (e.g., VAP-1).

[0103] As defined herein, the terms “activation” and / or “activation” in relation to proteins refer to the transformation of a protein from an initially inactive or inactive state into a biologically active derivative. These terms refer to the activation or reactivation, sensitization, or upregulation of signal transduction or enzyme activity or the amount of protein that is reduced in a disease.

[0104] The terms "agonist," "activator," "upregulator," etc., refer to substances that can detectably increase the expression or activity of a given gene or protein. An agonist can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control without an agonist. In some cases, the expression or activity is 1.5, 2, 3, 4, 5, 10, or higher than that without an agonist. In some embodiments, an agonist is a molecule that interacts with a target to cause or promote an increase in target activation. In some embodiments, an activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell.

[0105] As defined herein, the term "inhibition" in relation to protein-inhibitor interactions refers to a negative impact (e.g., reduction) on the activity or function of a protein relative to the activity or function of the protein in the absence of an inhibitor. In some embodiments, inhibition refers to a negative effect (e.g., reduction) on the concentration or level of a protein relative to the concentration or level of the protein in the absence of an inhibitor. In some embodiments, inhibition refers to the reduction of disease or disease symptoms. In some embodiments, inhibition refers to a reduction in the activity of a specific protein target. Thus, inhibition includes at least partially, partially, or completely blocking stimulation, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating the activity of signal transduction or enzymes or the amount of protein. In some embodiments, inhibition refers to a reduction in the activity of a target protein due to a direct interaction (e.g., the inhibitor binding to the target protein). In some embodiments, inhibition refers to a reduction in the activity of a target protein due to an indirect interaction (e.g., the inhibitor binding to a protein that activates the target protein, thereby preventing the activation of the target protein).

[0106] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” are used interchangeably to refer to a substance capable of detectably reducing the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to a control without an antagonist. In some cases, expression or activity may be 1.5, 2, 3, 4, 5, 10, or less than in the absence of an antagonist. Antagonists prevent, reduce, inhibit, or neutralize the activity of agonists, and even in the absence of a defined agonist, antagonists can prevent, inhibit, or reduce the constitutive activity of a target, such as a target receptor. In some embodiments, an inhibitor is a molecule that reduces, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor can also be defined as a molecule that reduces, blocks, or inactivates constitutive activity. "Antagonists" are molecules that have the opposite effect to agonists.

[0107] The terms "disease" or "condition" refer to the state or health status of a patient or subject who can be treated with the compounds or methods provided herein. The disease can be an autoimmune disease. The disease can be an inflammatory disease.

[0108] As used herein, the term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation (e.g., an increased level of inflammation compared to a control group, such as a healthy person without the disease). Examples of inflammatory diseases include autoimmune diseases and uveitis (e.g., anterior uveitis, including iridocyclitis and iritis, intermediate uveitis or pars plana cyclitis, posterior uveitis or chorioretinitis, and panuveitis). Such conditions are often inextricably linked to other diseases, symptoms, and conditions. The non-restricted list of inflammatory diseases, symptoms, and conditions includes Behcet's disease, Crohn's disease, Fuchs' heterochromia iridocyclitis, granulomatous polyangiitis, HLA-B27-associated uveitis, arthritis (e.g., juvenile idiopathic arthritis), sarcoidosis, spondyloarthritis, sympathetic ophthalmia, tubulointerstitial nephritis, uveitis syndrome, ankylosing spondylitis, chronic granulomatous disease, enteritis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, polyarteritis nodosa, psoriatic arthritis, reactive arthritis, sarcoidosis, systemic lupus erythematosus, Vogt-Koyanagi-Harada disease, Whipple's disease, white spot syndrome, and masquerade syndrome. Uveitis can also be associated with infectious diseases such as brucellosis, herpes simplex virus, varicella-zoster virus, leptospirosis, Lyme disease, hypothetical ocular histoplasmosis syndrome, syphilis, toxocariasis, toxoplasmosis chorioretinitis, tuberculosis, and Zika fever.

[0109] White spot syndrome includes, but is not limited to, acute posterior pole multifocal squamous pigment epithelial lesions, shotgun choroidal retinal lesions, multifocal choroiditis and panuveitis, multiple transient white spot syndrome, punctate inner choroiditis, creeping choroiditis, and acute band-like occult outer retinal lesions.

[0110] Mummy syndromes are classified into non-neoplastic and neoplastic diseases. Non-limiting examples of non-neoplastic masquerade syndromes include retinitis pigmentosa, intraocular foreign bodies, juvenile xanthogranuloma, and retinal detachment. Non-limiting examples of neoplastic masquerade syndromes include retinoblastoma, lymphoma, malignant melanoma, leukemia, and reticulum cell sarcoma.

[0111] The term "treatment" or "management" refers to any sign of success in the treatment or improvement of an injury, disease, pathology, or condition, including any objective or subjective parameters such as symptom reduction, relief, decrease, or increased patient tolerance to the injury, pathology, or condition; slowing the rate of degeneration or decline; making the endpoint of degeneration less debilitating; or improving the patient's physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "management" and its variations may include prevention of an injury, pathology, condition, or disease. In some implementations, treatment is prevention. In some implementations, treatment does not include prevention.

[0112] As used herein (and as is known in the art), “treatment” or “treatment” also broadly includes any method used to obtain a beneficial or desired outcome (including clinical outcome) with respect to the condition of a subject. Beneficial or desired clinical outcome may include, but is not limited to, relief or improvement of one or more symptoms or conditions, reduction of disease severity, stabilization (i.e., non-deterioration) of the disease state, prevention of disease spread or diffusion, delay or slowing of disease progression, improvement or relief of the disease state, reduction of disease recurrence, and remission, whether partial or complete, and whether detectable or undetectable. In other words, “treatment” as used herein includes any cure, improvement, or prevention of disease. Treatment may prevent the onset of disease; inhibit the spread of disease; relieve symptoms of disease (e.g., eye pain, seeing halos around lights, red eyes, extremely high intraocular pressure), completely or partially eliminate the underlying cause of disease, shorten the duration of disease, or a combination of the above.

[0113] As used herein, “treatment” and “management” include prophylactic treatment. Treatment methods include administering a therapeutically effective amount of the compound described herein to a subject. Administration may consist of a single administration or may include a series of administrations. The length of treatment depends on a variety of factors, such as the severity of the condition, the patient’s age, the concentration of the compound, the activity of the composition used for treatment, or a combination thereof. It should also be understood that the effective dose of the agent used for treatment or prevention may be increased or decreased during a particular treatment or prevention regimen. Changes in dose can be determined and become apparent through standard diagnostic tests known in the art. In some cases, prolonged administration may be necessary. For example, administering the composition to a subject in an amount and duration sufficient to treat the patient.

[0114] The term "prevention" refers to reducing the occurrence of disease symptoms in patients. As mentioned above, prevention can be complete (no detectable symptoms) or partial, resulting in fewer observed symptoms than would be possible without treatment. In some implementations, prevention refers to slowing the progression of a disease, symptom, or condition, or inhibiting its progression into a harmful or otherwise undesirable state.

[0115] "Patient" or "subject in need" means a living organism that suffers from or is susceptible to a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human.

[0116] "Effective amount" is the amount of a compound sufficient to achieve its stated purpose (e.g., to achieve the effect it is administered, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce enzyme signaling pathways, or to alleviate one or more symptoms of a disease or condition) in the absence of the compound. An example of an "effective amount" is an amount sufficient to help treat, prevent, or alleviate one or more symptoms of a disease; it may also be referred to as a "therapeutic effective amount." "Ameliorate" one or more symptoms (and its grammatical equivalents) means to reduce the severity or frequency of one or more symptoms, or to eliminate one or more symptoms. A "preventive effective amount" of a drug is the amount of drug that, when administered to a subject, has the expected preventive effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition or its symptoms. A complete preventive effect does not necessarily occur with the administration of a single dose; it may occur only after the administration of a series of doses. Therefore, a preventive effective amount can be administered by one or more administrations. As used herein, "activity reduction amount" refers to the amount of antagonist required to reduce enzyme activity in the absence of an antagonist. As used herein, “functionally disruptive dose” refers to the amount of antagonist required to disrupt the function of an enzyme or protein in the absence of an antagonist. The exact dose will depend on the therapeutic purpose and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Vols. 1–3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, edited by Gennaro, Lippincott, Williams & Wilkins). Therapeuticly effective doses can be determined by measuring the relevant physiological effects and can be adjusted based on the dosing regimen and diagnostic analysis of the subject's condition. For example, measuring serum levels of a VAP-1 inhibitor at a specific time after administration can indicate whether a therapeutically effective dose has been administered.

[0117] For any of the compounds described herein, the therapeutically effective amount can first be determined from cell culture assays. The target concentration will be the concentration of the active compound capable of achieving the methods described herein, as measured using methods described herein or known in the art.

[0118] As is known in the art, therapeutically effective doses for humans can also be determined from animal models. For example, human doses can be formulated to achieve concentrations found to be effective in animals. As described above, the human dose can be adjusted by monitoring the effectiveness of the compound and adjusting the dose upward or downward. Adjusting the dose based on the methods described above and others to obtain maximum efficacy in humans is entirely within the capabilities of a person skilled in the art. Adjusting the dose based on the methods described above and others to obtain maximum therapeutic window efficacy or toxicity in humans is entirely within the capabilities of a person skilled in the art.

[0119] As used herein, the term "therapeutic effective dose" refers to an amount of therapeutic agent sufficient to alleviate the condition as described above. For example, for a given parameter, a therapeutic effective dose will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as an increase or decrease "multiple." For example, a therapeutic effective dose may have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times, or more relative to a control.

[0120] Dosage may vary depending on the patient and the needs of the compound used. In the context of this disclosure, the dose administered to the patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The magnitude of the dose will also be determined by the presence, nature, and extent of any adverse side effects. The determination of the appropriate dose for a particular situation is within the skill of a technician. Typically, treatment begins with a smaller dose than the optimal dose of the compound. The dose is then increased in small increments until the optimal effect is achieved in these situations. Dosage and intervals can be individually adjusted to provide the level of the compound administered that is effective for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

[0121] As used herein, the term "application" means oral or topical application. The compositions of this disclosure can be delivered via a topical route and formulated as solutions, suspensions, emulsions, gels, and ointments. Oral products include tablets, pills, and capsules suitable for patient ingestion.

[0122] For any of the compounds described herein, the therapeutically effective amount can first be determined from cell culture assays. The target concentration will be the concentration of the active compound capable of achieving the methods described herein, as measured using methods described herein or known in the art.

[0123] Dosage and intervals can be individually adjusted to provide levels of the applied compound that are effective for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

[0124] Using the teachings provided herein, effective prophylactic or therapeutic treatment regimens can be planned that do not cause substantial toxicity but effectively treat clinical symptoms exhibited by a particular patient. This planning should involve careful selection of the active compound by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, preferred route of administration, and the toxicity profile of the chosen agent.

[0125] As used herein, “cell” means a cell that performs metabolic or other functions sufficient to maintain or replicate its genomic DNA. Cells can be identified by methods known in the art, including, for example, the presence of an intact membrane, staining with a specific dye, the ability to produce offspring, or, in the case of gametes, the ability to produce viable offspring by combining with a second gamete. Cells can include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammals, insects (e.g., the beet armyworm), and human cells. Cells can be useful when they are naturally non-adhesive or have been treated to be non-adhesive to surfaces (e.g., by trypsin digestion).

[0126] "Control" or "controlled experiment," used in its ordinary sense, refers to an experiment in which the subjects or reagents are treated in the same way as in a parallel experiment, except that the procedures, reagents, or variables are omitted. In some cases, a control is used as a comparative standard for evaluating the effectiveness of an experiment. In some embodiments, a control is a measurement of protein activity in the absence of the compounds described herein (including embodiments and examples).

[0127] In the context of a substance or its activity or function that is associated with a disease (e.g., a VAP-1-related disease (e.g., uveitis)), the term “associated” or “related to” means that the disease (e.g., uveitis) is (wholly or partially) caused by that substance or its activity or function, or is a symptom of a disease caused by it. For example, uveitis associated with VAP-1 activity or function can be uveitis (wholly or partially) caused by abnormal VAP-1 function (e.g., enzyme activity, protein-protein interactions, signal transduction pathways), or uveitis in which a specific symptom of the disease is (wholly or partially) caused by abnormal VAP-1 activity or function. As used herein, if it is a causative factor, it is described as those that are associated with the disease and can serve as targets for disease treatment. For example, in cases where increased VAP-1 activity or function (e.g., signal transduction pathway activity) causes a disease (e.g., uveitis), uveitis associated with VAP-1 activity or function or a VAP-1-related disease (e.g., uveitis) can be treated with compounds described herein (e.g., VAP-1 modulators or VAP-1 inhibitors). For example, in cases where increased VAP-1 activity or function (e.g., signaling pathway activity) causes disease, inflammatory diseases associated with or related to VAP-1 activity or function can be treated with VAP-1 modulators or VAP-1 inhibitors.

[0128] As used herein, the term “abnormal” means different from normal. When used to describe enzyme activity or protein function, abnormality refers to activity or function that is greater than or less than the average value of a normal control or normal disease-free control sample. Abnormal activity can refer to an amount of activity that causes disease, wherein an amount that restores abnormal activity to normal or is disease-independent (e.g., by administering a compound or using the methods described herein) results in the disease or a reduction in one or more disease symptoms.

[0129] As used herein, the terms “VAP-1 inhibitor,” “VAP-1 antagonist,” “vascular adhesion protein-1 inhibitor,” “vascular adhesion protein-1 antagonist,” and all other related terms accepted in the art (many of which are set forth below) refer to compounds capable of directly or indirectly modulating the VAP-1 receptor in in vitro assays, in vivo models, and / or other means of indicating therapeutic effect. These terms also refer to compounds that have demonstrated at least some therapeutic benefit in human subjects.

[0130] The phrase "in a quantity sufficient to achieve change" refers to a detectable difference between the levels of an indicator measured before (e.g., baseline levels) and after the administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., subject's sense of well-being).

[0131] The "activity" of a molecule can describe or refer to the binding of a molecule to a ligand or receptor; catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation, or maturation; antigenic activity; the ability to regulate the activity of other molecules; and so on.

[0132] "Substantially pure" means that the component constitutes more than 50% of the total content of the composition, and typically more than 60% of the total content of the composition. More typically, "substantially pure" refers to a composition in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. In some cases, the polypeptide will constitute more than about 90% or more than about 95% of the total content of the composition (by weight).

[0133] The term "uveitis" is used because the disease typically affects a part of the eye called the uvea. However, uveitis is not limited to the uvea. These conditions can also affect the lens, retina, optic nerve, and vitreous humor, leading to decreased vision or blindness. Common symptoms of uveitis include decreased vision, pain, light sensitivity, and increased floaters. Uveitis is a general term describing a group of inflammatory diseases that cause swelling and damage to the tissues of the eye.

[0134] II.Compounds

[0135] In some embodiments, the compounds described herein may include substituents (e.g., R...). 3 R 5 or R 6 Multiple cases (and / or other variables). In such an implementation, each variable may optionally be different and appropriately labeled to more clearly distinguish each group. For example, in each R 3 R 5 or R 6 In different situations, they can be referred to as, for example, R 3.1 R 3.2 R 3.3 R 3.4 R 3.5 R 5.1 R 5.2 R 5.3 R 5.4 or R 6.1 R 6.2 R 6.3 R 6.4 R 6.5 R 6.6 R 6.7 R 6.8 R 6.9 or R 6.10 , where R 3 The definition is (independently assigned) to R3.1 R 3.2 R 3.3 R 3.4 R 3.5 Let's assume; R 5 Assigned (independently) to R 5.1 R 5.2 R 5.3 R 5.4 To assume; or R 6 Assigned (independently) to R 6.1 R 6.2 R 6.3 R 6.4 R 6.5 R 6.6 R 6.7 R 6.8 R 6.9 or R 6.10 Let's assume. In R 3 R 5 or R 6 The variables and / or other variables used in the definition that appear in multiple situations and are different can be similarly and appropriately labeled in order to more clearly distinguish each group.

[0136] In some embodiments, unless otherwise stated, the compound described herein is a racemic mixture of all stereoisomers. In some embodiments, unless otherwise stated, the compound described herein is a racemic mixture of all enantiomers. In some embodiments, unless otherwise stated, the compound described herein is a racemic mixture of two opposite stereoisomers. In some embodiments, unless otherwise stated, the compound described herein is a racemic mixture of two opposite enantiomers. In some embodiments, unless otherwise stated, the compound described herein is a single stereoisomer. In some embodiments, unless otherwise stated, the compound described herein is a single enantiomer. In some embodiments, the compound is the compound described herein (e.g., in an aspect, embodiment, example, figure, table, scheme, or claim).

[0137] On the one hand, this article provides compounds having structural formula (IV):

[0138]

[0139] Or its olefin isomers, tautomers or isotopic variants; or pharmaceutically acceptable thereof.

[0140] Salt, solvate, hydrate, or prodrug;

[0141] in:

[0142] X1 and X 4 Independently, it can be either =N– or =CH–;

[0143] X 5 =N– or –CR 5 –;

[0144] X 6 =N– or –CR 6 –;

[0145] Y represents the bond, –O–, –S–, –NR. 7 –、–OCX2–、–(CH2) z2 W–, -C(O)O- or -C(O)NH-;

[0146] W represents a bond, –O–, –S–, or –NH–;

[0147] z1 and z2 are independent integers from 0 to 3;

[0148] n1, n2, n5, n6, and n7 are independent integers from 0 to 4;

[0149] m1, m2, m5, m6, m7, v1, v2, v5, v6, and v7 are independently 1 or 2;

[0150] L 1 For key, –O–, –S–, –NR 1L – substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

[0151] R 1L It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0152] R 1 Independently hydrogen, halogen, –CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 -CN, -SO n1 R 1A –SO v1 NR 1B R 1C -NHNR 1B R 1C -ONR 1B R 1C -NHC(O)NHNR 1B R1C -NHC(O)NR 1B R 1C –N(O) m1 –NR 1B R 1C –C(O)R 1D –C(O)OR 1D –C(O)NR 1B R 1C –OR 1A -NR 1B SO2R 1A -NR 1B C(O)R 1D -NR 1B C(O)OR 1D –NR 1B OR 1D –OCX 1.1 3. –OCHX 1.1 2. R 12 -Substituted or unsubstituted alkyl groups, R 12 -Substituted or unsubstituted heteroalkyl, R 12 -substituted or unsubstituted cycloalkyl, R 12 -Substituted or unsubstituted heterocyclic alkyl groups, R 12 -substituted or unsubstituted aryl, or R 12 -Substituted or unsubstituted heteroaryl groups or at least one amino acid;

[0153] R 2 Hydrogen, halogen, -CX 2.1 3. -CHX 2.1 2. -CH2X 2.1 -CN, -SO n2 R 2A –SO v2 NR 2B R 2C –NR 2B R 2C –C(O)R 2D –C(O)OR 2D –C(O)NR 2B R 2C –OR 2A –OCX 2.1 3. –OCHX 2.1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0154] R 3 and R 4Independently hydrogen or –F;

[0155] R 5 Hydrogen, halogen, -CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 –CN, –N3, –SO n5 R 5A –SO v5 NR 5B R 5C -NHNR 5B R 5C -ONR 5B R 5C -NHC(O)NHNR 5B R 5C -NHC(O)NR 5B R 5C –N(O) m5 –NR 5B R 5C –C(O)R 5D –C(O)OR 5D –C(O)NR 5B R 5C –OR 5A -NR 5B SO2R 5A -NR 5B C(O)R 5D -NR 5B C(O)OR 5D –NR 5B OR 5D –OCX 5.1 3. –OCHX 5.1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0156] R 6 Hydrogen, halogen, -CX 6.1 3. -CHX 6.1 2. -CH2X 6.1 –CN, –N3, –SO n6 R 6A –SO v6 NR 6B R 6C -NHNR 6B R 6C -ONR 6B R 6C -NHC(O)NHNR 6B R6C -NHC(O)NR 6B R 6C –N(O) m6 –NR 6B R 6C –C(O)R 6D –C(O)OR 6D –C(O)NR 6B R 6C –OR 6A -NR 6B SO2R 6A -NR 6B C(O)R 6D -NR 6B C(O)OR 6D –NR 6B OR 6D –OCX 6.1 3. –OCHX 6.1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0157] R 7 Hydrogen, halogen, –CX 7.1 3. -CHX 7.1 2. -CH2X 7.1 -CN, -SO n7 R 7A –SO v7 NR 7B R 7C –NR 7B R 7C –C(O)R 7D –C(O)OR 7D –C(O)NR 7B R 7C –OR 7A –OCX 7.1 3. –OCHX 7.1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0158] R 12 Hydrogen, halogen, –CX 12.1 3. -CHX 12.1 2. -CH2X 12.1 -CN, -SO n12 R 12A –SO v12NR 12B R 12C –NR 12B R 12C –C(O)R 12D –C(O)OR 12D –C(O)NR 12B R 12C –OR 12A –OCX 12.1 3. –OCHX 12.1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0159] R 1A For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12A -Substituted or unsubstituted alkyl groups, R 12A -Substituted or unsubstituted heteroalkyl, R 12A -substituted or unsubstituted cycloalkyl, R 12A -Substituted or unsubstituted heterocyclic alkyl groups, R 12A -substituted or unsubstituted aryl, or R 12A -Substituted or unsubstituted heteroaryl groups;

[0160] R 1B For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12B -Substituted or unsubstituted alkyl groups, R 12B -Substituted or unsubstituted heteroalkyl, R 12B -substituted or unsubstituted cycloalkyl, R 12B -Substituted or unsubstituted heterocyclic alkyl groups, R 12B -substituted or unsubstituted aryl, or R 12B -Substituted or unsubstituted heteroaryl groups;

[0161] R 1C For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12C -Substituted or unsubstituted alkyl groups, R 12C -Substituted or unsubstituted heteroalkyl, R 12C -substituted or unsubstituted cycloalkyl, R 12C -Substituted or unsubstituted heterocyclic alkyl groups, R 12C -substituted or unsubstituted aryl, or R 12C -Substituted or unsubstituted heteroaryl groups; or R groups bonded to the same nitrogen atom 1Band R 1C The substituents may optionally be joined to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups;

[0162] R 1D For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12D -Substituted or unsubstituted alkyl groups, R 12D -Substituted or unsubstituted heteroalkyl, R 12D -substituted or unsubstituted cycloalkyl, R 12D -Substituted or unsubstituted heterocyclic alkyl groups, R 12D -substituted or unsubstituted aryl, or R 12D -Substituted or unsubstituted heteroaryl groups;

[0163] R 2A R 2B R 2C R 2D R 5A R 5B R 5C R 5D R 6A R 6B R 6C R 6D R 7A R 7B R 7C R 7D R 12A R 12B R 12C and R 12D Independently hydrogen, halogen, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R bonded to the same nitrogen atom. 2B and R 2C ;R 5B and R 5C ;R 6B and R 6C ;R 7B and R 7C ;R 8B and R 8C ; or R 12B and R 12C The substituents may optionally be joined to form substituted or unsubstituted heterocyclic alkyl groups or substituted or unsubstituted heteroaryl groups; and

[0164] X, X 1.1 X2.1 X 5.1 X 6.1 X 7.1 and X 12.1 It can be independently –Cl, –Br, –I, or –F.

[0165] In some embodiments, the compound of formula (IV) has the structural formula (IV-A):

[0166]

[0167] Or its olefinic isomers, tautomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

[0168] In some embodiments, the compound of formula (IV) has the structural formula (IV-B):

[0169]

[0170] Or its olefinic isomers, tautomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

[0171] In some embodiments, the compound of formula (IV) has the structural formula (VA):

[0172]

[0173] Or its olefinic isomers, tautomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

[0174] In some embodiments, the compound of formula (IV) has the structural formula (VB):

[0175]

[0176] Or its olefinic isomers, tautomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

[0177] In some embodiments, the compound of formula (IV) has structural formulas (VI-A):

[0178]

[0179] Or its olefinic isomers, tautomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

[0180] In some embodiments, the compound of formula (IV) has the structural formula (VI-B):

[0181]

[0182] Or its olefinic isomers, tautomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

[0183] In some embodiments, the compound of formula (IV) has the structural formula (VII-A):

[0184]

[0185] Or its olefinic isomers, tautomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

[0186] In some embodiments, the compound of formula (IV) has the structural formula (VII-B):

[0187]

[0188] Or its olefinic isomers, tautomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

[0189] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, X 1 =N–.

[0190] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, X 1 =CH–.

[0191] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, X 4 =N–.

[0192] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, X 4 =CH–.

[0193] In some embodiments of compounds of formula (IV) and / or (VA), a portion of the structure is represented as

[0194] for

[0195]

[0196] In some embodiments of compounds of formula (IV) and / or (VB), a portion of the structure is represented as

[0197] for

[0198] In some embodiments of compounds of formula (IV) and / or (VI-A), a portion of the structure is represented as follows for

[0199] In some embodiments of compounds of formula (IV) and / or (VII-A), a portion of the structure is represented as

[0200] for

[0201] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, Y is a bond.

[0202] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, Y is –OCF2–.

[0203] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, Y is –O–.

[0204] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, Y is –S–.

[0205] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, Y is –NH–.

[0206] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, Y is –CH2O–.

[0207] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, Y is -C(O)NH-.

[0208] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or olefin isomers, tautomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, z1 is 0. In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or olefin isomers, tautomers or isotopic variants thereof; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, z1 is 1. In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, z1 is 2.

[0209] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 5 and R 6 It is independently hydrogen, halogen, or an unsubstituted alkyl group.

[0210] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 5 and R 6 It can be hydrogen –F, –Br or –CH3 independently.

[0211] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 3 For –F.

[0212] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 3 It is hydrogen.

[0213] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 4 For –F.

[0214] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 4 It is hydrogen.

[0215] In some embodiments, the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is a mixture of compounds having the following limitations:

[0216] R 3 For –F and R 4 It is hydrogen; and

[0217] R 3 It is hydrogen and R 4 For –F.

[0218] In some embodiments, the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefin isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, comprises a mixture of (E)- and (Z)-olefin isomers.

[0219] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, the ratio of the (E)-isomer or tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to the (Z)-isomer or tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is from about 10:1 to about 1:10.

[0220] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, the ratio of the (E)-isomer or tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to the (Z)-isomer or tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is from about 5:1 to about 1:5.

[0221] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, the ratio of the (E)-isomer or tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof to the (Z)-isomer or tautomer, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof is approximately 1:1.

[0222] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 2 It is hydrogen.

[0223] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, L 1 For key, –NR 1L – substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heteroalkylene.

[0224] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, L 1 For key.

[0225] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, L 1 For –NR 1L –

[0226] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 1L It is hydrogen or a substituted or unsubstituted alkyl group.

[0227] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, L 1 It is a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted heteroalkylene.

[0228] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 1 For –NR 1B R 1C –C(O)NR 1B R 1C –OR 1A R 12 -Substituted or unsubstituted alkyl groups, R 12 -Substituted or unsubstituted heteroalkyl, R 12 -substituted or unsubstituted cycloalkyl, R 12 -Substituted or unsubstituted heterocyclic alkyl groups, R 12 -substituted or unsubstituted aryl, or R 12 -Substituted or unsubstituted heteroaryl groups.

[0229] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 1 For R 12 -Substituted or unsubstituted C1-C6 alkyl groups.

[0230] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 1 It is –(CH2)3CH3.

[0231] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 12 -Substituted or unsubstituted cycloalkyl groups.

[0232] In some embodiments of the compound of formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, R 12 It is a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group.

[0233] In one respect, this article provides a compound, wherein the compound is:

[0234]

[0235] Or its olefinic isomers, tautomers or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

[0236] In some implementations, L 1 For key, –O–, –S–, –NR 1L – substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0237] In some implementations, L 1 For R 9 -Substituted or unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In some embodiments, L 1 For R 9 -Substituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene). In some embodiments, L 1 It is an unsubstituted alkylene (e.g., C1-C8 alkylene, C1-C6 alkylene, or C1-C4 alkylene).

[0238] In some implementations, L 1 For R 9 -Substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene). In some embodiments, L 1 For R 9 -Substituted heteroalkylene (e.g., 2- to 8-membered heteroalkylene, 2- to 6-membered heteroalkylene, or 2- to 4-membered heteroalkylene). In some embodiments, L 1 It is an unsubstituted heteroalkylene (e.g., 2 to 8-membered heteroalkylene, 2 to 6-membered heteroalkylene, or 2 to 4-membered heteroalkylene).

[0239] In some implementations, L 1 For R 9 -Substituted or unsubstituted cycloalkylene groups (e.g., C3-C8 cycloalkylene groups, C3-C6 cycloalkylene groups, or C5-C6 cycloalkylene groups). In some embodiments, L 1 For R 9 -Substituted cycloalkylene groups (e.g., C3-C8 cycloalkylene groups, C3-C6 cycloalkylene groups, or C5-C6 cycloalkylene groups). In some embodiments, L 1 It is an unsubstituted cycloalkylene group (e.g., C3-C8 cycloalkylene group, C3-C6 cycloalkylene group, or C5-C6 cycloalkylene group).

[0240] In some implementations, L 1 For R 9 -Substituted or unsubstituted heterocyclic alkylene groups (e.g., 3- to 8-membered heterocyclic alkylene groups, 3- to 6-membered heterocyclic alkylene groups, or 5- to 6-membered heterocyclic alkylene groups). In some embodiments, L 1 For R 9 -Substituted heterocyclic alkylene groups (e.g., 3- to 8-membered heterocyclic alkylene groups, 3- to 6-membered heterocyclic alkylene groups, or 5- to 6-membered heterocyclic alkylene groups). In some embodiments, L 1 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl group, 3- to 6-membered heterocyclic alkyl group, or 5- to 6-membered heterocyclic alkyl group).

[0241] In some implementations, L 1 For R 9 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Alpha-aryl, C 10 (arylene or phenylene). In some embodiments, L 1 For R 9 -Substituted aryl groups (e.g., C6-C) 10 Alpha-aryl, C 10 (arylene or phenylene). In some embodiments, L 1 For unsubstituted aryl groups (e.g., C6-C) 10 Alpha-aryl, C 10 (arylene or phenylene).

[0242] In some implementations, L 1 For R 9 -Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In some embodiments, L 1 For R 9 -Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In some embodiments, L 1It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0243] In some implementations, R 1 Independently hydrogen, halogen, –CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 -CN, -SO n1 R 1A –SO v1 NR 1B R 1C -NHNR 1B R 1C -ONR 1B R 1C -NHC(O)NHNR 1B R 1C -NHC(O)NR 1B R 1C –N(O) m1 –NR 1B R 1C –C(O)R 1D –C(O)OR 1D –C(O)NR 1B R 1C –OR 1A -NR 1B SO2R 1A -NR 1B C(O)R 1D -NR 1B C(O)OR 1D –NR 1B OR 1D –OCX 1.1 3. –OCHX 1.1 2. R 12 -Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 12 -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 12 -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 12 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 12 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 aryl or phenyl), or R12 -Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0244] In some implementations, R 1 For R 12 - Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 1 For R 12 -Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 1 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0245] In some implementations, R 1 For R 12 -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In some embodiments, R 1 For R 12 -Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In some embodiments, R 1 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0246] In some implementations, R 1 For R 12 -Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In some embodiments, R 1 For R 12 -Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In some embodiments, R 1 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0247] In some implementations, R 1 For R 12 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In some embodiments, R 1 For R 12 -Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In some embodiments, R 1It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0248] In some implementations, R 1 For R 12 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (Aryl or phenyl). In some embodiments, R 1 For R 12 -Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (Aryl or phenyl). In some embodiments, R 1 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0249] In some implementations, R 1 For R 12 -Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In some embodiments, R 1 For R 12 -Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In some embodiments, R 1 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0250] In some implementations, R 1A For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12A -Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 12A -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 12A -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 12A -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 12A -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 aryl or phenyl), or R 12A-Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0251] In some implementations, R 1B For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12B -Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 12B -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 12B -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 12B -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 12B -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 aryl or phenyl), or R 12B -Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In some embodiments, R is bonded to the same nitrogen atom. 1B and R 1C Substituents may optionally join to form R 12B - substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), or R 12B -Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0252] In some implementations, R 1C For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12C -Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 12C -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 12C -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 12C -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 12C -Substituted or unsubstituted aryl groups (e.g., C6-C)10 Aryl, C 10 aryl or phenyl), or R 12C -Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In some embodiments, R is bonded to the same nitrogen atom. 1B and R 1C Substituents may optionally join to form R 12C -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups) or R 12C -Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0253] In some implementations, R 1D For hydrogen, halogens, –CF3, –CCl3, –CBr3, –CI3, –COOH, –CONH2, R 12D -Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 12D -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 12D -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 12D -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 12D -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 aryl or phenyl), or R 12D -Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0254] R 9 Independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R 10-Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 10 -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 10 -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 10 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 10 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 aryl or phenyl), or R 10 -Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0255] In the implementation plan, R 9 For R 10 -Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 9 For R 10 -Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 9 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0256] In the implementation plan, R 9 For R 10 -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 9 For R 10 -Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 9 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0257] In the implementation plan, R 9 For R 10 -Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 9 For R 10 -Substituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 9It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0258] In the implementation plan, R 9 For R 10 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 9 For R 10 -Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 9 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0259] In the implementation plan, R 9 For R 10 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 9 For R 10 -Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 9 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0260] In the implementation plan, R 9 For R 10 -Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 9 For R 10 -Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 9 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0261] R 10Independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R 11 -Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 11 -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 11 -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 11 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 11 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 aryl or phenyl), or R 11 -Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0262] In the implementation plan, R 10 For R 11 -Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 10 For R 11 -Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In the embodiments, R 10 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0263] In the implementation plan, R 10 For R 11 -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 10 For R 11 -Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In the embodiments, R 10It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0264] In the implementation plan, R 10 For R 11 -Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 10 For R 11 -Substituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In the embodiments, R 10 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0265] In the implementation plan, R 10 For R 11 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 10 For R 11 -Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In the embodiments, R 10 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0266] In the implementation plan, R 10 For R 11 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 10 For R 11 -Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl). In the implementation scheme, R 10 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0267] In the implementation plan, R 10 For R 11 -Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 10 For R 11 -Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In the embodiments, R 10It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0268] R 12 Independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R 13 -Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 13 -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 13 -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 13 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 13 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 aryl or phenyl), or R 13 -Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0269] In some implementations, R 12 For R 13 - Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 12 For R 13 -Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 12 It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0270] In some implementations, R 12 For R 13 -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In some embodiments, R 12For R 13 -Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In some embodiments, R 12 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0271] In some implementations, R 12 For R 13 -Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In some embodiments, R 12 For R 13 -Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In some embodiments, R 12 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0272] In some implementations, R 12 For R 13 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In some embodiments, R 12 For R 13 -Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In some embodiments, R 12 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0273] In some implementations, R 12 For R 13 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (Aryl or phenyl). In some embodiments, R 12 For R 13 -Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (Aryl or phenyl). In some embodiments, R 12 For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0274] In some implementations, R 12 For R 13-Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In some embodiments, R 12 For R 13 -Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In some embodiments, R 12 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0275] R 13 Independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, R 14 -Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), R 14 -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups), R 14 -substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), R 14 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups), R 14 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 aryl or phenyl), or R 14 -Substituted or unsubstituted heteroaryl groups (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0276] In some implementations, R 13 For R 14 - Substituted or unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 13 For R 14 -Substituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl). In some embodiments, R 13It is an unsubstituted alkyl group (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl).

[0277] In some implementations, R 13 For R 14 -Substituted or unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl). In some embodiments, R 13 For R 14 -Substituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl groups, 2- to 6-membered heteroalkyl groups, or 2- to 4-membered heteroalkyl groups). In some embodiments, R 13 It is an unsubstituted heteroalkyl group (e.g., 2 to 8-membered heteroalkyl, 2 to 6-membered heteroalkyl, or 2 to 4-membered heteroalkyl).

[0278] In some implementations, R 13 For R 14 -Substituted or unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In some embodiments, R 13 For R 14 -Substituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl). In some embodiments, R 13 It is an unsubstituted cycloalkyl group (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl).

[0279] In some implementations, R 13 For R 14 -Substituted or unsubstituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In some embodiments, R 13 For R 14 -Substituted heterocyclic alkyl groups (e.g., 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups, or 5- to 6-membered heterocyclic alkyl groups). In some embodiments, R 13 It is an unsubstituted heterocyclic alkyl group (e.g., 3- to 8-membered heterocyclic alkyl, 3- to 6-membered heterocyclic alkyl, or 5- to 6-membered heterocyclic alkyl).

[0280] In some implementations, R 13 For R 14 -Substituted or unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (Aryl or phenyl). In some embodiments, R 13 For R 14 -Substituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (Aryl or phenyl). In some embodiments, R 13For unsubstituted aryl groups (e.g., C6-C) 10 Aryl, C 10 (aryl or phenyl).

[0281] In some implementations, R 13 For R 14 -Substituted or unsubstituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In some embodiments, R 13 For R 14 -Substituted heteroaryl groups (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl). In some embodiments, R 13 It is an unsubstituted heteroaryl group (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, or 5 to 6-membered heteroaryl).

[0282] R 11 R 12A R 12B R 12C R 12D and R 14 Independently, it can be hydrogen, oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCH Cl2, -OCHBr2, -OCHI2, -OCHF2, unsubstituted alkyl groups (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl groups (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl groups (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl groups (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl groups (e.g., C6-C... 10 Aryl, C 10 Aryl or phenyl) or unsubstituted heteroaryl (e.g., 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl or 5 to 6-membered heteroaryl).

[0283] III. Pharmaceutical Composition

[0284] One aspect provides a pharmaceutical composition comprising the structural formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and at least one pharmaceutically acceptable excipient.

[0285] In one respect, this article provides a pharmaceutical composition comprising a compound, wherein said compound is:

[0286]

[0287] Or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient.

[0288] In some embodiments, the at least one pharmaceutically acceptable excipient is a pharmaceutically acceptable ophthalmic carrier.

[0289] The compounds disclosed herein (e.g., VAP-1 inhibitors) may be in the form of compositions suitable for administration to a subject. Typically, such compositions are “pharmaceutical compositions” comprising a compound (e.g., a VAP-1 inhibitor) and one or more pharmaceutically or physiologically acceptable diluents, carriers, or excipients. In some embodiments, the compound (e.g., a VAP-1 inhibitor) is present in a therapeutically acceptable amount. The pharmaceutical compositions may be used in the methods of this disclosure; thus, for example, the pharmaceutical compositions may be administered to a subject ex vivo or in vivo to achieve the therapeutic and prophylactic methods and uses described herein.

[0290] The pharmaceutical compositions disclosed herein can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are described herein.

[0291] Pharmaceutical compositions containing an active ingredient (e.g., an inhibitor of VAP-1 function) may be in forms suitable for oral administration, such as tablets or capsules (e.g., hard or soft capsules). Pharmaceutical compositions intended for oral administration may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically refined and palatable product. Tablets, capsules, etc., contain an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for their preparation. These excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0292] Tablets, capsules, etc., suitable for oral administration can be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated using techniques known in the art to form permeable therapeutic tablets for controlled release. Other agents include biodegradable or biocompatible particulates or polymeric materials such as polyesters, polyamines, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide / glycolic acid copolymers, polylactide / glycolic acid copolymers, or ethylene-vinyl acetate copolymers to control the delivery of the administered composition. For example, oral pharmaceutical agents can be encapsulated in microcapsules or colloidal drug delivery systems, which are prepared by using hydroxymethylcellulose or gelatin-microcapsules or poly(methyl methacrylate) microcapsules, respectively, by coagulation techniques or by interfacial polymerization. Colloidal dispersions include macromolecular complexes, nanocapsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the above formulations will be readily apparent to those skilled in the art.

[0293] Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium such as peanut oil, liquid paraffin, or olive oil.

[0294] Aqueous suspensions contain an active substance mixed with excipients suitable for their preparation. Such excipients can be suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), or condensation products of alkyl esters and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethene-oxoctetrol), or condensation products of ethylene oxide and esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and esters derived from fatty acids and hexitol anhydrides (e.g., polyvinyl sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0295] The pharmaceutical compositions typically comprise a therapeutically effective amount of the VAP-1 inhibitor described herein and one or more pharmaceutically and physiologically acceptable formulation agents. Suitable pharmaceutically or physiologically acceptable diluents, carriers, or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethylparaben), emulsifiers, suspending agents, dispersants, solvents, fillers, loosening agents, detergents, buffers, mediators, diluents, and / or adjuvants. For example, suitable mediators may be physiological saline solutions or citrate-buffered saline solutions, possibly supplemented with other substances commonly found in pharmaceutical compositions intended for parenteral administration. Neutral buffered saline solutions or saline solutions mixed with serum albumin are further exemplary mediators. Those skilled in the art will readily recognize the various buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, the buffer components can be water-soluble materials such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and their salts. Acceptable buffers include, for example, Tris buffer; N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES); 2-(N-morpholino)ethanesulfonic acid (MES); sodium 2-(N-morpholino)ethanesulfonate (MES); 3-(N-morpholino)propanesulfonic acid (MOPS); and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0296] Formulations may also include carriers to protect the composition from rapid degradation or clearance from the body, such as controlled-dilution formulations, including liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, time-delayed materials, such as glyceryl monostearate or glyceryl stearate alone or in combination with waxes, may be employed. Any drug delivery device can be used to deliver VAP-1 inhibitors, including implants (e.g., implantable pumps) and catheter systems, slow-infusion pumps, and devices, all of which are well known to those skilled in the art.

[0297] Pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions. Such suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned herein, according to known techniques. Sterile injectable articles may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, etc. EL (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile, non-volatile oils are routinely used as solvents or suspension media; for this purpose, any non-irritating non-volatile oil can be used, including synthetic mono- or diglycerides of glycerol. Furthermore, fatty acids such as oleic acid can be used in the preparation of injectable formulations. Prolonged absorption of specific injectable formulations can be achieved by including agents that delay absorption (e.g., aluminum monostearate or gelatin).

[0298] Preparations intended for oral use may be in the form of hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin. They may also be in the form of soft gelatin capsules, in which the active ingredient is mixed with an aqueous or oily medium such as peanut oil, liquid paraffin, or olive oil.

[0299] In some cases, the VAP-1 compound used in the methods described herein is in the form of a sterile, injectable aqueous or oily suspension. This suspension can be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known methods. The sterile injectable product can also be formulated as a suspension in a non-toxic, parenteral-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable mediators and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can be used in the preparation of the injectable product.

[0300] In some embodiments, the composition is in the form of a solution (e.g., an aqueous solution).

[0301] In some cases, the compositions described herein further comprise preservatives. In some cases, preservatives are added to the compositions described herein at a concentration to prevent the growth of microorganisms introduced into the composition or to destroy such microorganisms.

[0302] In some embodiments, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, stabilized oxychloride complex, SofZia (Alcon), polyquaternium-1, chlorobutanol, disodium edetate, and polyhexamethylene biguanide.

[0303] In some cases, the compositions described herein further comprise disinfectants. In some cases, disinfectants include polymeric biguanides, polymeric quaternary ammonium compounds, chlorites, diguanidines, chlorite compounds (e.g., potassium chlorite, sodium chlorite, calcium chlorite, magnesium chlorite, or mixtures thereof), and combinations thereof.

[0304] In some embodiments, the ophthalmic composition further comprises a buffer. In some embodiments, the buffer is selected from borates, borate-polyol complexes, phosphate buffers, citrate buffers, acetate buffers, carbonate buffers, organic buffers, amino acid buffers, or combinations thereof.

[0305] In some cases, borates include boric acid, salts of boric acid, other pharmaceutically acceptable borates, and combinations thereof. In other cases, borates include boric acid, sodium borate, potassium borate, calcium borate, magnesium borate, manganese borate, and other such borates.

[0306] As used herein, the term polyol includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms that are not trans-configured with each other. In some embodiments, the polyol is chain or cyclic, substituted or unsubstituted, or a mixture thereof, provided that the resulting complex is water-soluble and pharmaceutically acceptable. In some cases, examples of polyols include sugars, sugar alcohols, sugar acids, and uronic acids. In some cases, polyols include, but are not limited to, mannitol, glycerol, xylitol, and sorbitol.

[0307] In some embodiments, the phosphate buffer comprises phosphoric acid; alkali metal phosphates, such as disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and tripotassium phosphate; alkaline earth metal phosphates, such as calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, magnesium dihydrogen phosphate, magnesium dihydrogen phosphate (magnesium hydrogen phosphate), and magnesium trihydrogen phosphate; ammonium phosphate, such as diammonium hydrogen phosphate and ammonium dihydrogen phosphate; or combinations thereof. In some cases, the phosphate buffer is an anhydride. In some cases, the phosphate buffer is a hydrate.

[0308] In some embodiments, the borate-polyol complex includes those described in U.S. Patent 6,503,497. In some cases, the borate-polyol complex comprises a borate in an amount of about 0.01% w / v to about 2.0% w / v and one or more polyols in an amount of about 0.01% w / v to about 5.0% w / v.

[0309] In some cases, citrate buffers include citric acid and sodium citrate.

[0310] In some cases, acetate buffers include acetic acid, potassium acetate, and sodium acetate.

[0311] In some cases, carbonate buffers include sodium bicarbonate and sodium carbonate.

[0312] In some cases, organic buffers include Good buffers, such as 2-(N-morpholino)ethanesulfonic acid (MES), N-(2-acetamido)iminodiacetic acid, N-(carbamoylmethyl)iminodiacetic acid (ADA), piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES), N-(2-acetamido)-2-aminoethanesulfonic acid (ACES), β-hydroxy-4-morpholinopropanesulfonic acid, 3-morpholino-2-hydroxypropanesulfonic acid (MOPSO), choline chloride, 3-(N-morpholino)propanesulfonic acid (MOPS), N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPE) S), 3-(N,N-bis[2-hydroxyethyl]amino)-2-hydroxypropanesulfonic acid (DIPSO), acetamylglycine, 3-{[1,3-dihydroxy-2-(hydroxymethyl)-2-propyl]amino}-2-hydroxy-1-propanesulfonic acid (TAPSO), piperazine-1,4-bis(2-hydroxypropanesulfonic acid) (POPSO), 4-(2-hydroxyethyl)piperazine-1-(2-hydroxypropanesulfonic acid) hydrate (HEPPSO), 3-[4-(2-hydroxyethyl)-1-piperazinyl]propanesulfonic acid (HEPPS), N-tris(hydroxymethyl)methylglycine (tricine), glycineamide, N,N-dihydroxyethylglycine (bicine) or N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid sodium salt (TAPS); glycine; and diethanolamine (DEA).

[0313] In some cases, amino acid buffers include taurine, aspartic acid and its salts (such as potassium salts), E-aminocaproic acid, etc.

[0314] In some cases, the compositions described herein further comprise a tension modifier. A tension modifier is an agent introduced into articles such as ophthalmic compositions to reduce local irritation by preventing osmotic shock at the site of application. In some cases, buffer solutions and / or pD modifiers that broadly maintain ophthalmic solutions at specific ion concentrations and pDs are considered tension modifiers. In some cases, tension modifiers include various salts, such as halide salts of monovalent cations. In some cases, tension modifiers include mannitol, sorbitol, dextrose, sucrose, urea, and glycerin. In some cases, suitable tension modifiers include sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, glucose, sucrose, urea, propylene glycol, glycerin, or combinations thereof.

[0315] In some cases, the concentration of the tension modifier in the compositions described herein is from about 0.5% to about 10.0%. In some cases, the percentage is a weight percentage.

[0316] In some cases, the compositions described herein further comprise a pD modifier. In some embodiments, the pD modifier used is an acid or a base. In some embodiments, the base is an oxide, hydroxide, carbonate, bicarbonate, etc. In some cases, the oxide is a metal oxide, such as calcium oxide, magnesium oxide, etc.; the hydroxide is an alkali metal and alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, etc., or their deuterated equivalents; and the carbonate is sodium carbonate, sodium bicarbonate, potassium bicarbonate, etc. In some cases, the acid is an inorganic acid and an organic acid, such as hydrochloric acid, nitric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, malic acid, tartaric acid, etc., or their deuterated equivalents. In some cases, the pD modifier includes, but is not limited to, acetates, bicarbonates, ammonium chloride, citrates, phosphates, pharmaceutically acceptable salts thereof, and combinations or mixtures thereof.

[0317] In some cases, the compositions described herein further comprise disinfectants. In some cases, disinfectants include polymeric biguanides, polymeric quaternary ammonium compounds, chlorites, diguanidines, chlorite compounds (e.g., potassium chlorite, sodium chlorite, calcium chlorite, magnesium chlorite, or mixtures thereof), and combinations thereof.

[0318] In some cases, the compositions described herein further comprise stabilizers. Stabilizers useful in ophthalmologically acceptable formulations disclosed herein include, for example, fatty acids, fatty alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ether, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, and combinations thereof. In some embodiments, amide analogs of stabilizers are also used. In other embodiments, the selected stabilizer alters the hydrophobicity of the formulation, improves the mixability of the various components in the formulation, controls the moisture content in the formulation, or controls the flowability of the phase.

[0319] In other embodiments, the stabilizer is present in an amount sufficient to inhibit the degradation of the ophthalmic agent. Examples of such stabilizers include, but are not limited to: glycerol, methionine, thioglycerol, EDTA, ascorbic acid, polysorbate 80, polysorbate 20, arginine, heparin, dextran sulfate, cyclodextrin, pentosan polysulfate and other heparin-like substances, divalent cations such as magnesium and zinc, or combinations thereof.

[0320] Other stabilizers useful for ophthalmologically acceptable formulations include one or more anti-aggregation additives to enhance the stability of ophthalmic formulations by reducing protein aggregation rates. The choice of anti-aggregation additive depends on the nature of the conditions under which the ophthalmic agent, such as a VAP-1 inhibitor, is exposed. For example, some formulations subjected to agitation and thermal stress require different anti-aggregation additives than those subjected to lyophilization and reconstitution. Useful anti-aggregation additives, by way of example only, include urea, guanidine chloride, simple amino acids such as glycine or arginine, sugars, polyols, polysorbates, polymers such as polyethylene glycol and dextran, alkyl sugars such as alkyl glycosides, and surfactants.

[0321] Where necessary, other useful formulations may optionally contain one or more ophthalmologically acceptable antioxidants to enhance chemical stability. Suitable antioxidants, by way of example only, include ascorbic acid, methionine, sodium thiosulfate, and sodium metabisulfite. In one embodiment, the antioxidant is selected from metal chelators, thiol-containing compounds, and other general stabilizers.

[0322] Other useful compositions contain one or more ophthalmologically acceptable surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10 and octoxynol 40.

[0323] In other embodiments, additional surfactants (co-surfactants) and / or buffers are combined with one or more pharmaceutically acceptable mediators described above to maintain the product at its optimal pD with respect to stability. Suitable cosurfactants include, but are not limited to: a) natural and synthetic lipophiles, such as phospholipids, cholesterol and cholesterol fatty acid esters and their derivatives; b) nonionic surfactants, including, for example, polyoxyethylene fatty alcohol esters, sorbitan fatty acid esters (Span), polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate (Tween 60), polyoxyethylene (20) sorbitan monolaurate (Tween 20) and other Tweens), sorbitan esters, glycerides (e.g., Myrj and triacetylglycerol), polyethylene glycol, hexadecyl alcohol, cetostearyl alcohol, octadecyl alcohol, polysorbate 80, poloxamer, poloxamine, polyoxyethylene castor oil derivatives (e.g. RH40, Cremphor A25, Cremphor A20, EL) and other Cremophor, sulfosuccinates, alkyl sulfates (SLS); PEG glycerol fatty acid esters, such as PEG-8 glycerol caprylate / decanoate (Labrasol), PEG-4 glycerol caprylate / decanoate (Labrafac Hydro WL 1219), PEG-32 glycerol laurate (Gelucire 444 / 14), PEG-6 glycerol monooleate (Labrafil M 1944CS), PEG-6 glycerol linoleate (Labrafil M 2125CS); propylene glycol monooleate and propylene glycol dioleate, such as propylene glycol laurate, propylene glycol caprylate / decanoate; 700, ascorbic acid-6-palmitate, octadecylamine, sodium lauryl sulfate, polyoxyethylene glycerol triricinoleate and any combination or mixture thereof; c) anionic surfactants, including but not limited to calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium sulfosuccinate, dioctyl, sodium alginate, alkyl polyoxyethylene sulfate, sodium lauryl sulfate, triethanolamine stearate, potassium laurate, bile salts and any combination or mixture thereof; and d) cationic surfactants, such as hexadecyltrimethylammonium bromide and dodecyl dimethyl benzyl ammonium chloride.

[0324] pD

[0325] In some embodiments, the pD of the compositions described herein is adjusted (e.g., by using a buffer and / or a pD adjuster) to an ophthalmic compatible pD range of about 4 to about 8, about 4.5 to about 7.5, or about 5 to about 7. In some embodiments, the pD of the ophthalmic composition is about 5.0 to about 7.0. In some embodiments, the pD of the ophthalmic composition is about 5.5 to about 7.0. In some embodiments, the pD of the ophthalmic composition is about 6.0 to about 7.0.

[0326] In some implementations, useful formulations contain one or more pD modifiers or buffers. Suitable pD modifiers or buffers include, but are not limited to, acetates, bicarbonates, ammonium chlorides, citrates, phosphates, deuterated forms of acetates, bicarbonates, ammonium chlorides, citrates, phosphates, their pharmaceutically acceptable salts, and combinations or mixtures thereof.

[0327] In one embodiment, when one or more buffer solutions are used in the formulations of this disclosure, they are combined with, for example, a pharmaceutically acceptable medium and are present in the final formulation in amounts ranging from, for example, from about 0.1% to about 20%, from about 0.5% to about 10%. In some embodiments of this disclosure, the amount of buffer solution contained in the gel formulation is such that the pD of the gel formulation does not interfere with the body's natural buffering system.

[0328] In one embodiment, diluents are also used to stabilize the compound because they provide a more stable environment. In some cases, salts dissolved in buffered solutions (which also provide pD control or maintenance) are used as diluents in the art, including but not limited to phosphate-buffered saline solutions.

[0329] In some implementations, pD is calculated according to the formula published in Glaso et al., “Use of glass electrodes to measure acids in deuterium oxide,” J. Physical Chem. 64(1):188-190 (1960).

[0330] Uniformity between aqueous solution dosages

[0331] Typical ophthalmic aqueous solutions are packaged in eye drop bottles and administered as drops. For example, a single administration (i.e., a single dose) of an ophthalmic aqueous solution includes administering one, two, three, or more drops into the eye of a patient or subject. In some embodiments, a dose of the ophthalmic aqueous solution described herein is one drop of an aqueous solution composition from an eye drop bottle.

[0332] In some cases, the description herein includes aqueous ophthalmic compositions that provide a uniform concentration between doses. In some cases, the uniform concentration between doses does not present a significant variation in drug content between doses. In some cases, the uniform concentration between doses provides a consistent drug content between doses.

[0333] In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 50%. In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 40%. In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 30%. In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 20%. In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 10%. In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 5%.

[0334] In some embodiments, the dose-interval ophthalmic concentration variation is based on 10 consecutive doses. In some embodiments, the dose-interval ophthalmic concentration variation is based on 8 consecutive doses. In some embodiments, the dose-interval ophthalmic concentration variation is based on 5 consecutive doses. In some embodiments, the dose-interval ophthalmic concentration variation is based on 3 consecutive doses. In some embodiments, the dose-interval ophthalmic concentration variation is based on 2 consecutive doses.

[0335] Non-settling formulations should not require shaking to achieve uniform drug dispersion. "No-shake" formulations are potentially advantageous over shaken formulations because patient shaking behavior is a major source of variability in drug dosage. It has been reported that, despite clear shaking instructions on the label, patients often fail to shake or forget to shake their ophthalmic compositions before administering the dose. On the other hand, even for those patients who do shake the product, it is often impossible to determine whether the intensity and / or duration of shaking is sufficient to homogenize the product. In some embodiments, the ophthalmic gel and ophthalmic ointment compositions described herein are "no-shake" formulations that maintain the uniformity between doses described herein.

[0336] viscosity of aqueous solution

[0337] In some embodiments, the composition has a Brookfield RVDV viscosity of about 10 cp to about 40,000 cp at about 20°C and a viscosity of 1s. -1 The shear rate. In some embodiments, the composition has a Brookfield RVDV viscosity of about 100 cp to about 40,000 cp at about 20°C and a shear rate of 1s. -1The shear rate. In some embodiments, the composition has a Brookfield RVDV viscosity of about 500 cp to about 30,000 cp at about 20°C and a shear rate of 1s. -1 The shear rate. In some embodiments, the composition has a Brookfield RVDV viscosity of about 1000 cp to about 20,000 cp at about 20°C, and a shear rate of 1s. -1 The shear rate. In some embodiments, the composition has a Brookfield RVDV viscosity of about 2000 cp to about 10,000 cp at about 20°C, and a shear rate of 1s. -1 The shear rate. In some embodiments, the composition has a Brookfield RVDV viscosity of about 4000 cp to about 8000 cp at about 20°C, and a shear rate of 1s. -1 The shear rate.

[0338] In some embodiments, the aqueous ophthalmic formulation contains a viscosity enhancer sufficient to provide a viscosity of about 500 to 50,000 centipoise, about 750 to 50,000 centipoise, about 1,000 to 50,000 centipoise, about 1,000 to 40,000 centipoise, about 2,000 to 30,000 centipoise, about 3,000 to 20,000 centipoise, about 4,000 to 10,000 centipoise, or about 5,000 to 8,000 centipoise.

[0339] In some embodiments, the compositions described herein are low-viscosity compositions at body temperature. In some embodiments, the low-viscosity compositions contain about 1% to about 10% of a viscosity enhancer (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low-viscosity compositions contain about 2% to about 10% of a viscosity enhancer (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low-viscosity compositions contain about 5% to about 10% of a viscosity enhancer (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low-viscosity ophthalmic compositions described herein are substantially free of viscosity enhancers (e.g., gelling components, such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the low-viscosity ophthalmic compositions described herein provide an apparent viscosity of about 100 cP to about 10,000 cP. In some embodiments, the low-viscosity ophthalmic compositions described herein provide an apparent viscosity of about 500 cP to about 10,000 cP. In some embodiments, the low-viscosity ophthalmic compositions described herein provide an apparent viscosity of about 1,000 cP to about 10,000 cP.

[0340] Volume molar osmotic concentration

[0341] In some embodiments, the compositions disclosed herein are formulated to not disrupt the ion balance of the eye. In some embodiments, the compositions disclosed herein have the same or substantially the same ion balance as the eye. In some embodiments, the compositions disclosed herein do not disrupt the ion balance of the eye.

[0342] As used herein, “osmolarity / osmolality” or “deliverable osmolarity / osmolality” means the osmolarity / osmolality of a composition, as determined by measuring the osmolarity / osmolality of the ophthalmic agent and all excipients except gelling agents and / or thickeners (e.g., polyoxyethylene-polyoxypropylene copolymer, carboxymethyl cellulose, etc.). The osmolarity / osmolality of the compositions disclosed herein is measured by suitable methods, such as the freezing point depression method described in Viegas et al., Int. J. Pharm., 1998, 160, 157-162. In some cases, the osmolarity / osmolality of the compositions disclosed herein is measured by vapor pressure osmolarity determination (e.g., vapor pressure reduction method), which allows for the determination of the osmolarity / osmolality of the composition at higher temperatures. In some cases, the vapor pressure reduction method allows for the determination of the volumetric molar osmotic pressure concentration of a composition containing a gelling agent (e.g., a thermally reversible polymer) at a higher temperature, where the gelling agent is in gel form.

[0343] In some embodiments, the volumetric molality at the target site of action (e.g., the eye) is substantially the same as the delivery volumetric molality of the composition described herein. In some embodiments, the composition described herein has a deliveryable volumetric molality of about 150 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 350 mOsm / L, about 280 mOsm / L to about 370 mOsm / L, or about 250 mOsm / L to about 320 mOsm / L.

[0344] The actual weight molar osmotic pressure concentrations of the ophthalmic compositions disclosed herein are about 100 mOsm / kg to about 1000 mOsm / kg, about 200 mOsm / kg to about 800 mOsm / kg, about 250 mOsm / kg to about 500 mOsm / kg, or about 250 mOsm / kg to about 320 mOsm / kg, or about 250 mOsm / kg to about 350 mOsm / kg, or about 280 mOsm / kg to about 320 mOsm / kg. In some embodiments, the compositions described herein have a practical capacity molar osmotic pressure concentration of about 100 mOsm / L to about 1000 mOsm / L, about 200 mOsm / L to about 800 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 350 mOsm / L, about 250 mOsm / L to about 320 mOsm / L, or about 280 mOsm / L to about 320 mOsm / L.

[0345] In some embodiments, suitable tonic modifiers include, but are not limited to, any pharmaceutically acceptable sugar, salt, or any combination or mixture thereof, such as, but not limited to, dextrose, glycerol, mannitol, sorbitol, sodium chloride, and other electrolytes. In some cases, the tonic modifier is selected from sodium chloride, sodium nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dextrose, mannitol, sorbitol, glucose, sucrose, urea, propylene glycol, glycerol, or combinations thereof.

[0346] In some embodiments, the ophthalmic compositions described herein contain one or more salts in an amount required to achieve an acceptable weight-molar osmolar concentration. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0347] sterility

[0348] In some embodiments, the composition is sterile. Means and processes for sterilizing the pharmaceutical compositions disclosed herein for human use are included within the embodiments disclosed herein. The objective is to provide safe pharmaceutical products that are relatively free of microorganisms that can cause infection. The U.S. Food and Drug Administration has provided regulatory guidance in the publication “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing” (incorporated herein by reference in its entirety), available at http: / / www.fda.gov / cder / guidance / 5882fnl.htm.

[0349] As used herein, sterilization means a process used to destroy or remove microorganisms present in a product or packaging. Any suitable method that can be used to sterilize objects and compositions may be used. Methods for inactivating microorganisms include, but are not limited to, the application of extreme heat, lethal chemicals, or gamma radiation. In some embodiments, the process for preparing ophthalmic formulations includes subjecting the formulation to a sterilization method selected from thermal sterilization, chemical sterilization, radiation sterilization, or filtration sterilization. The method used depends largely on the nature of the device or composition to be sterilized. Detailed descriptions of many sterilization methods are given in Chapter 40 of Remington: The Science and Practice of Pharmacy, published by Lippincott, Williams, and Wilkins, and that document is incorporated herein by reference to content relevant to the subject matter of this invention.

[0350] filter

[0351] Sterilization by filtration is a method for removing microorganisms from a solution without destroying them. Membrane filters are used to filter heat-sensitive solutions. Such filters are thin, strongly homogeneous polymers of mixed cellulose esters (MCE), polyvinylidene fluoride (PVF; also known as PVDF), or polytetrafluoroethylene (PTFE) with pore sizes ranging from 0.1 to 0.22 μm. Optionally, different membranes are used to filter solutions with different characteristics. For example, PVF and PTFE membranes are well-suited for filtering organic solvents, while aqueous solutions are filtered through PVF or MCE membranes. Filter devices are available for use at many scales, ranging from single-point-of-use disposable filters attached to syringes to commercial-scale filters used in manufacturing plants. Membrane filters are sterilized by autoclaving or chemical sterilization. Validation of membrane filtration systems follows a standardized protocol (Microbiological Evaluation of Filters for Sterilizing Liquids, Vol. 4, No. 3, Washington, DC: Health Industry Manufacturers Association, 1981) and involves using known quantities (approximately 10...) 7 / cm 2 Abnormally small microorganisms, such as Brevundimonas diminuta (ATCC 19146), can attack membrane filters.

[0352] Pharmaceutical compositions may optionally be sterilized by passing through a membrane filter. Formulations containing nanoparticles (US Patent 6,139,870) or multilayer vesicles (Richard et al., International Journal of Pharmaceutics (2006), 312(1-2):144-50) are suitable for sterilization by filtration through a 0.22 μm filter without damaging their tissue structure.

[0353] In some embodiments, the methods disclosed herein include sterilizing the formulation (or its components) by means of filtration sterilization. In ophthalmic gel compositions comprising thermosetting polymers, filtration is performed at a temperature lower than the gel temperature (Tgel) of the formulation described herein (e.g., about 5°C) and with a viscosity (e.g., a theoretical value below 100 cP) that allows for filtration by a peristaltic pump within a reasonable time.

[0354] Radiation sterilization

[0355] One advantage of radiation sterilization is its ability to sterilize a wide variety of products without thermal degradation or other damage. Commonly used radiation is beta radiation or alternatives derived from... 60Gamma radiation from a Co source. The penetrating power of gamma radiation allows it to be used for sterilization of many product types, including solutions, compositions, and non-homogeneous mixtures. The bactericidal effect of radiation is caused by the interaction of gamma radiation with biomolecules. This interaction generates charged substances and free radicals. Subsequent chemical reactions, such as rearrangement and cross-linking processes, lead to the loss of normal function of these biomolecules. The formulations described herein may also optionally be sterilized using beta radiation.

[0356] Heat sterilization

[0357] Many methods are available for sterilization by applying high heat. One method is to use a saturated steam autoclave. In this method, saturated steam at a temperature of at least 121°C is brought into contact with the object to be sterilized. In the case of the object to be sterilized, heat is transferred directly to the microorganisms, or indirectly by heating the aqueous solution to be sterilized. This method is widely used because it makes the sterilization process flexible, safe, and economical.

[0358] microorganism

[0359] In some embodiments, the composition is substantially free of microorganisms. Acceptable bioburden or sterility levels are based on applicable criteria defining a therapeutically acceptable composition, including but not limited to the United States Pharmacopeia (UPP) guidelines. <1111> Chapters and below, etc. For example, acceptable sterility (e.g., bioburden) levels include about 10 colony-forming units (cfu) / g of formulation, about 50 cfu / g of formulation, about 100 cfu / g of formulation, about 500 cfu / g of formulation, or about 1000 cfu / g of formulation. In some embodiments, acceptable bioburden levels or sterility for a formulation include less than 10 cfu / mL of microbial agent, less than 50 cfu / mL of microbial agent, less than 500 cfu / mL of microbial agent, or less than 1000 cfu / mL of microbial agent. Additionally, acceptable bioburden levels or sterility include excluding specified harmful microbial agents. For example, specified harmful microorganisms include, but are not limited to, Escherichia coli, Salmonella sp., Pseudomonas aeruginosa, and / or other specific microorganisms.

[0360] A crucial part of the sterility assurance quality control, quality assurance, and validation process is the method of sterility testing. For example, sterility testing is performed using two methods. The first is direct inoculation, where a sample of the test composition is added to a growth medium and incubated for a period of up to 21 days. Turbidity of the growth medium indicates contamination. Disadvantages of this method include the small sample size of the bulk material, thus reducing sensitivity, and the reliance on visual observation to detect microbial growth. An alternative method is membrane filtration sterility testing. In this method, a volume of product is passed through a small membrane filter paper. The filter paper is then placed in a culture medium to promote microbial growth. This method offers the advantage of higher sensitivity because the entire bulk product is sampled. Alternatively, membrane filtration sterility testing can be performed using a commercially available Millipore Steritest sterility testing system. For filtration testing of creams or ointments, the Steritest filtration system No. TLHVSL210 is used. For filtration testing of emulsions or viscous products, the Steritest filtration system No. TLAREM210 or TDARM210 is used. For filtration testing of pre-filled syringes, Steritest filtration system No. TTHASY210 was used. For filtration testing of materials dispensed as aerosols or foams, Steritest filtration system No. TTHVA210 was used. For filtration testing of soluble powders in ampoules or vials, Steritest filtration systems No. TTHADA210 or TTHADV210 were used.

[0361] Tests for *Escherichia coli* and *Salmonella* include incubation in lactose broth at 30-35°C for 24-72 hours, incubation in MacConkey and / or EMB agar for 18-24 hours, and / or Rappaport medium. Tests for *Pseudomonas aeruginosa* detection include the use of NAC agar. (United States Pharmacopeia, p. 10) <62> The chapter further outlines the testing procedures for the specified harmful microorganisms.

[0362] Ophthalmic Gel VAP-1 Composition

[0363] Gels are defined in several ways. For example, the United States Pharmacopeia defines a gel as a semi-solid system consisting either of a suspension of small inorganic particles or of large organic molecules permeated by a liquid. Gels can be single-phase or two-phase systems. Single-phase gels consist of organic macromolecules uniformly distributed throughout the liquid in such a way that there is no clear boundary between the dispersed macromolecules and the liquid. Some single-phase gels are prepared from synthetic macromolecules (e.g., carbomer) or from natural gums (e.g., tragacanth gum). In some embodiments, single-phase gels are typically aqueous, but can also be prepared using alcohols and oils. Two-phase gels consist of a network of discrete small particles.

[0364] In some embodiments, the gels are also classified as hydrophobic or hydrophilic. In some embodiments, a non-limiting example of a hydrophobic gel has a matrix comprising liquid paraffin having a polyethylene or fatty oil gelled with silica gel or aluminum or zinc soap. In contrast, a non-limiting example of a hydrophilic gel has a matrix comprising water, glycerol, or propylene glycol gelled with a suitable gelling agent (e.g., astragalus gum, starch, cellulose derivatives, carboxyvinyl polymers, and magnesium-aluminum silicates). In some embodiments, the rheology of the compositions disclosed herein is pseudoplastic, plastic, thixotropic, or expansive.

[0365] In some embodiments, the ophthalmic composition is an ophthalmic gel, and the ophthalmologically acceptable carrier comprises water and at least one viscosity enhancer. In some embodiments, the viscosity enhancer is selected from cellulose-based polymers, polyoxyethylene-polyoxypropylene triblock copolymers, dextran-based polymers, polyvinyl alcohol, dextrin, polyvinylpyrrolidone, polyalkylene glycol, chitosan, collagen, gelatin, hyaluronic acid, or combinations thereof.

[0366] In some embodiments, the ophthalmic gel compositions described herein are in a semi-solid or gel-like state prior to topical application (e.g., at room temperature). Suitable viscosity enhancers for such gels, by way of example only, include gelling agents and suspending agents. In one embodiment, the viscosity-enhancing formulation does not contain a buffer solution. In other embodiments, the viscosity-enhancing formulation contains a pharmaceutically acceptable buffer solution. If necessary, sodium chloride or other tensioning agents may be optionally used to adjust the tension.

[0367] For example, ophthalmologically acceptable viscosity enhancers include hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, and sodium hyaluronate. Other viscosity enhancers compatible with the target ocular site include, but are not limited to, gum arabic, agar, magnesium aluminum silicate, sodium alginate, sodium stearate, fucus vesiculosus, bentonite, carbomer, carrageenan, carbopol, xanthan gum, cellulose, microcrystalline cellulose (MCC), carotenoid gum, chitin, carboxymethyl chitosan, chondrus, dextrose, red algae gum, gelatin, and Ghatti. Guar gum, lithium montmorillonite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, tung oil gum, yellow polysaccharide gum, astragalus gum, ethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), oxidized polygelatin, pectin, polygelatin peptides, povidone, propylene carbonate, methyl vinyl ether / maleic anhydride copolymer (PVM / MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (CMC), silica, polyvinylpyrrolidone (PVP: povidone) (dextrose, maltodextrin, and sucralose) or combinations thereof. In a particular embodiment, the viscosity-enhancing excipient is a combination of MCC and CMC. In another embodiment, the viscosity enhancer is carboxymethyl chitosan or a combination of chitin and alginate. The combination of chitin and alginate with the ophthalmic preparations disclosed herein acts as a controlled-release formulation, limiting the diffusion of the ophthalmic preparation from the formulation. Furthermore, the combination of carboxymethyl chitosan and alginate is optionally used to help increase the molar osmotic concentration of the ophthalmic preparation in the eye.

[0368] In some embodiments, the viscosity-enhancing formulation comprises about 0.1 mM to about 100 mM of an ophthalmic agent, a pharmaceutically acceptable viscosity agent, and water for injection, wherein the concentration of the viscosity agent in the water is sufficient to provide a viscosity-enhancing formulation having a final viscosity of about 100 cP to about 100,000 cP. In some embodiments, the viscosity of the gel is in the range of about 100 cP to about 50,000 cP, about 100 cP to about 1,000 cP, about 500 cP to about 1,500 cP, about 1,000 cP to about 3,000 cP, about 2,000 cP to about 8,000 cP, about 4,000 cP to about 50,000 cP, about 10,000 cP to about 500,000 cP, and about 15,000 cP to about 1,000,000 cP. In other embodiments, when an even more viscous medium is required, the biocompatible gel comprises at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 70%, at least about 75%, or even at least about 80% (by weight) of an ophthalmic agent. In highly concentrated samples, the biocompatible viscosity-enhancing formulation comprises at least about 25%, at least about 35%, at least about 45%, at least about 55%, at least about 65%, at least about 75%, at least about 85%, at least about 90%, or at least about 95% (by weight) or more of an ophthalmic agent.

[0369] In one embodiment, the pharmaceutically acceptable, ophthalmologically acceptable, viscosity-enhancing formulation comprises at least one ophthalmic agent and at least one gelling agent. Suitable gelling agents for preparing gel formulations include, but are not limited to, cellulose, cellulose derivatives, cellulose ethers (e.g., carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, or methyl cellulose), guar gum, xanthan gum, locust bean gum, alginate (e.g., alginic acid), silicates, starch, tragacanth gum, carboxyvinyl polymers, carrageenan, paraffin, petrolatum, and any combination or mixture thereof. In some other embodiments, hydroxypropyl methyl cellulose is used. As a gelling agent. In some embodiments, the viscosity enhancer described herein is also used as a gelling agent for the gel formulations presented herein.

[0370] In some embodiments, the ophthalmic gel compositions described herein are in-situ gel formulations. In some cases, in-situ gel formation is based on the increased pre-corneal residence time of the ophthalmic composition, which improves ocular bioavailability, corneal mucosal adhesion, lysosomal interactions and ionic gelation, improved corneal absorption, thermal gelation, or a combination thereof. In some cases, the in-situ gel formulation is activated by pH, temperature, ions, UV, or solvent exchange.

[0371] In some cases, the ophthalmic gel composition comprises a VAP-1 inhibitor and one or more gelling agents. In some cases, the gelling agent includes, but is not limited to, poloxamer (e.g., poloxamer 407), tetronics, ethyl (hydroxyethyl) cellulose, cellulose acetate phthalate (CAP), carboplatin (e.g., carboplatin 1342P NF, carboplatin 980NF), and alginate (e.g., low-acetyl gellan gum). Gellan gum, hyaluronic acid, pluronic (e.g., Pluronic F-127), chitosan, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), dextran, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), methylcellulose (MC), thiolated xyloglucan, polymethacrylic acid (PMMA), polyethylene glycol (PEG), pseudolatex, xyloglucan, or combinations thereof.

[0372] In some cases, in-situ gel formation further includes a permeation enhancer. In some cases, this permeation enhancer includes surfactants (e.g., nonionic surfactants), benzalkonium chloride, EDTA, surfactant heteroglycosides, calcium chelating agents, hydroxypropyl beta-cyclodextrin (HPβCD), bile salts, etc.

[0373] In some embodiments, other gel formulations are useful, and are therefore considered to fall within the scope of this invention, depending on the specific ophthalmic preparation, other pharmaceutical agents, or excipients / additives used. For example, other commercially available glycerol-based gels, glycerol-derived compounds, conjugated or cross-linked gels, matrices, hydrogels and polymers, as well as gelatin and its derivatives, alginate and alginate-based gels, and even various natural and synthetic hydrogels and hydrogel-derived compounds are contemplated for use in the ophthalmic preparations described herein. In some embodiments, ophthalmologically acceptable gels include, but are not limited to, alginate hydrogels. (ConvaTec, Princeton, NJ) Hydroactive Gel (ConvaTec) (Johnson & Johnson Medical, Arlington, Tex.); (V) Acemannan Hydrogel (Carrington Laboratories, Inc., Irving, Tex.); Glycerin Gel Hydrogel (Swiss-American Products, Inc., Dallas, Tex.) and Sterile (Johnson & Johnson). In other embodiments, the biodegradable biocompatible gel also represents compounds present in ophthalmologically acceptable formulations described and disclosed herein.

[0374] In some embodiments, the viscosity enhancer is a cellulose-based polymer selected from cellulose gum, alkyl cellulose, hydroxy-alkyl cellulose, hydroxy-alkylalkyl cellulose, carboxy-alkyl cellulose, or combinations thereof. In some embodiments, the viscosity enhancer is hydroxy-alkylalkyl cellulose. In some embodiments, the suspending agent is hydroxypropyl methylcellulose.

[0375] In some embodiments, the viscosity-enhancing formulation is characterized by a phase transition between room temperature and body temperature (including that of individuals with severe fever, e.g., up to about 42°C). In some embodiments, the phase transition occurs at temperatures 1°C, 2°C, 3°C, 4°C, 6°C, 8°C, or 10°C below body temperature. In some embodiments, the phase transition occurs at temperatures about 15°C, 20°C, or 25°C below body temperature. In specific embodiments, the gelation temperature (Tgelation) of the formulation described herein is about 20°C, about 25°C, or about 30°C. In some embodiments, the gelation temperature (Tgelation) of the formulation described herein is about 35°C or about 40°C. Body temperature is defined as including the body temperature of a healthy or unhealthy individual, including the body temperature of an individual with a fever (up to about 42°C). In some embodiments, the pharmaceutical composition described herein is a liquid at approximately room temperature and is administered at or near room temperature.

[0376] Polyoxypropylene and polyoxyethylene copolymers (e.g., polyoxyethylene-polyoxypropylene triblock copolymers) form thermosetting gels when incorporated into aqueous solutions. These polymers have the ability to transition from a liquid to a gel state at temperatures close to body temperature, thus allowing for the application of useful formulations to the target ocular site. The liquid-to-gel phase transition depends on the polymer concentration and composition in the solution.

[0377] In some embodiments, the amount of the thermosetting polymer in any formulation described herein is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40% of the total weight of the formulation. In some embodiments, the amount of the thermosetting polymer in any formulation described herein is about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% of the total weight of the formulation. In some embodiments, the amount of the thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 7.5% of the total weight of the formulation. In some embodiments, the amount of the thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 10% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 11% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 12% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 13% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 14% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 15% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 16% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 17% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 18% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 19% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 20% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 21% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 23% of the total weight of the formulation. In some embodiments, the amount of a thermosetting polymer (e.g., poloxamer 407) in any formulation described herein is about 25% of the total weight of the formulation.In some embodiments, the amount of thickener (e.g., gelling agent) in any formulation described herein is about 1%, about 5%, about 10%, or about 15% of the total weight of the formulation. In some embodiments, the amount of thickener (e.g., gelling agent) in any formulation described herein is about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% of the total weight of the formulation.

[0378] In an alternative embodiment, the thermogel is a PEG-PLGA-PEG triblock copolymer (Jeong et al., Nature (1997), 388:860-2; Jeong et al., J. Control. Release (2000), 63:155-63; Jeong et al., Adv. Drug Delivery Rev. (2002), 54:37-51). This polymer exhibits sol-gel properties at concentrations of about 5% w / w to about 40% w / w. Depending on the desired properties, the lactide / glycolic acid molar ratio in the PLGA copolymer ranges from about 1:1 to about 20:1. The resulting copolymer is soluble in water at room temperature and forms a free-flowing liquid, but forms a hydrogel at body temperature. One commercially available PEG-PLGA-PEG triblock copolymer is RESEROMER RGP t50106, manufactured by Boehringer Ingelheim. The material consists of a 50:50 poly(DL-lactide-co-glycolic acid) PLGA copolymer and 10% w / w PEG, and has a molecular weight of approximately 6000.

[0379] Other biodegradable thermoplastic polyesters include (Provided by Atrix Laboratories, Inc.) and / or those disclosed, for example, in U.S. Patent Nos. 5,324,519, 4,938,763, 5,702,716, 5,744,153, and 5,990,194; wherein suitable biodegradable thermoplastic polyesters are disclosed as thermoplastic polymers. Examples of suitable biodegradable thermoplastic polyesters include polylactide, polyglycolic acid, polycaprolactone, copolymers thereof, terpolymers thereof, and any combination thereof. In some such embodiments, suitable biodegradable thermoplastic polyesters are polylactide, polyglycolic acid, copolymers thereof, terpolymers thereof, or combinations thereof. In one embodiment, the biodegradable thermoplastic polyester is a 50 / 50 poly(DL-lactide-co-glycolic acid) having carboxyl end groups; present in about 30 wt.% to about 40 wt.% of the composition; and having an average molecular weight of about 23,000 to about 45,000. Alternatively, in another embodiment, the biodegradable thermoplastic polyester is a 75 / 25 poly(DL-lactide-co-glycolic acid) without carboxyl end groups; present in about 40 wt.% to about 50 wt.% of the composition; and having an average molecular weight of about 15,000 to about 24,000. In other or alternative embodiments, the end groups of the poly(DL-lactide-co-glycolic acid) are hydroxyl, carboxyl, or ester, depending on the polymerization method. Condensation polymerization of lactic acid or glycolic acid provides polymers having terminal hydroxyl and carboxyl groups. Ring-opening polymerization of cyclic lactide or glycolide monomers with water, lactic acid, or glycolic acid provides polymers with the same end groups. However, ring-opening polymerization of cyclic monomers with monofunctional alcohols such as methanol, ethanol, or 1-dodecanoic acid provides polymers having one hydroxyl group and one ester end group. Ring-opening polymerization of cyclic monomers with diols such as 1,6-hexanediol or polyethylene glycol provides polymers having only hydroxyl end groups.

[0380] Because thermosetting gel polymer systems dissolve more completely at lower temperatures, solubilization methods involve adding the required amount of polymer to a given volume of water to be used at a lower temperature. Typically, after wetting the polymer by shaking, the mixture is capped and placed in a cooling chamber or thermostatic container at approximately 0–10°C to dissolve the polymer. The mixture is stirred or shaken to further dissolve the thermosetting gel polymer. Ophthalmic preparations and various additives, such as buffers, salts, and preservatives, are then added and dissolved. In some cases, if the medication is insoluble in water, it is suspended. The pD (potential density) is adjusted by adding a suitable buffer.

[0381] Ophthalmic ointment VAP-1 inhibitor composition

[0382] Ointments are homogeneous, viscous, semi-solid preparations intended for external application to the skin or mucous membranes, most commonly high-viscosity, oily viscous oils (e.g., 80% oil - 20% water). Ointments have a water number that defines the maximum amount of water they contain. They are used as emollients or for applying active ingredients to the skin for protective, therapeutic, or preventative purposes, and the degree of occlusion is desired. Ointments are used topically on many body surfaces, including the mucous membranes of the eyes (ophthalmic ointments).

[0383] The medium of an ointment is called the ointment base. The choice of base depends on the clinical indication of the ointment. Different types of ointment bases include: hydrocarbon bases, such as hard paraffin, soft paraffin, microcrystalline wax, and ceresin; absorbent bases, such as lanolin and beeswax; water-soluble bases, such as polyethylene glycol 200, 300, and 400; emulsifying bases, such as emulsifying waxes and cetrimonium bromide; and vegetable oils, such as olive oil, coconut oil, sesame oil, almond oil, and peanut oil.

[0384] Ointments are formulated using hydrophobic, hydrophilic, or water-emulsifiable bases to provide a formulation that is immiscible, miscible, or emulsifiable with skin secretions. In some embodiments, the ointment is also derived from a hydrocarbon (fatty), absorbable, water-removable, or water-soluble base. The active agent is dispersed in the base and subsequently separated after the drug penetrates to the target site (e.g., a membrane).

[0385] The present invention recognizes that it is sometimes difficult to incorporate low concentrations of a drug into an ointment with sufficient dose-mixing uniformity for effective treatment of a symptom or disease. In some embodiments, poly(ethylene glycol), polyethoxylated castor oil ( EL), an alcohol having 12-20 carbon atoms, or a mixture of two or more of the components are effective excipients for dispersing and / or dissolving effective amounts of ophthalmic drugs (specifically ascomycin and staurosporine derivatives) in an ointment matrix (specifically in an ointment matrix that substantially contains oily and hydrocarbon components), and the resulting ointment is well tolerated by the skin and ocular tissues.

[0386] This disclosure further recognizes that when the composition is applied topically to the ocular surface (specifically, the sclera of the patient), the ophthalmic drug, such as a VAP-1 inhibitor, incorporated into the ointment composition described herein targets the patient's choroid and / or retina. In some embodiments, the ophthalmic ointment composition comprises an ophthalmic drug, an ointment base, and a reagent for dispersing and / or dissolving the drug in the ointment base, the reagent being selected from poly(ethylene glycol), polyethoxylated castor oil, alcohols having 12-20 carbon atoms, and mixtures of two or more of the components.

[0387] In some embodiments, the ointment base includes ophthalmologically acceptable oil and fat bases, such as natural waxes, such as white and yellow beeswax, carnauba wax, lanolin, purified lanolin, anhydrous lanolin; petroleum waxes, such as hard paraffin, microcrystalline wax; hydrocarbons, such as liquid paraffin, white and yellow soft paraffin, white petrolatum, yellow petrolatum; or combinations thereof.

[0388] The oil and fat matrices mentioned above are described in more detail in, for example, the British Pharmacopoeia 2001 edition or the European Pharmacopoeia 3rd edition.

[0389] In some embodiments, the ointment matrix is ​​present in an amount of about 50% to about 95%, preferably 70% to 90% (by weight), based on the total weight of the composition.

[0390] The preferred ointment base comprises one or more natural waxes (as shown above), preferably lanolin wax and one or more hydrocarbons (as shown above), preferably soft paraffin or petrolatum, more preferably one or more combinations of liquid paraffin.

[0391] The specific implementation of the ointment base described above includes, for example, 5-17 parts by weight of lanolin, 50-65 parts by weight of white petrolatum, and 20-30 parts by weight of liquid paraffin.

[0392] In some embodiments, the agent used to disperse and / or dissolve the ophthalmic drug in the ointment base is selected from polyethylene glycol, polyethoxylated castor oil, alcohols having 12-20 carbon atoms, and mixtures of two or more of the components. The agent is preferably used in an amount of 1-20 percent, more preferably 1-10 percent, based on the weight of the entire semi-solid ophthalmic composition.

[0393] Alcohols with 12-20 carbon atoms specifically include octadecyl alcohol (C64- ... 18 H 37 OH), hexadecyl alcohol (C 16 H 33 OH) and mixtures thereof. Preferred are so-called hexadecanoic acid alcohol, which is essentially composed of octadecanoic acid and hexadecanoic acid and preferably contains not less than 40% by weight of octadecanoic acid and the total amount of octadecanoic acid and hexadecanoic acid reaches at least 90% by weight of solid alcohol, and compositions containing not less than 80% by weight of hexadecanoic acid alcohol and emulsifiers (especially sodium hexadecanoic acid sulfate and / or sodium lauryl sulfate, preferably not less than 7% by weight of emulsifiers).

[0394] Polyethoxylated castor oil is the product of the reaction of natural or hydrogenated castor oil with ethylene glycol. In some cases, such products are obtained in a known manner, for example by reacting natural or hydrogenated castor oil or a portion thereof with ethylene oxide at a molar ratio of, for example, about 1:30 to about 1:60, and optionally removing the free polyethylene glycol component from the product according to the methods disclosed, for example, in German Auslegeschriften 1,182,388 and 1,518,819. Particularly suitable and preferred are products marketed under the trade name. EL's commercially available products have a molecular weight (measured by vapor osmotic pressure) of approximately 1630, a saponification number of approximately 65-70, an acid number of approximately 2, an iodine number of approximately 28-32, and an nD 25 of approximately 1.471. Other products suitable for this category include, for example, HCO-60, a product of the reaction of hydrogenated castor oil and ethylene oxide, exhibits the following characteristics: acid number = approximately 0.3; saponification number = approximately 47.4; hydroxyl value = approximately 42.5; pH (5%) = approximately 4.6; color APHA = approximately 40; mp = approximately 36.0℃; freezing point = approximately 32.4℃; H2O content (%, KF) = approximately 0.03.

[0395] According to the present invention, polyethylene glycol is used in some embodiments as a reagent for dispersing and / or dissolving ophthalmic drugs in an ointment base. Suitable polyethylene glycols generally have the general formula H—(OCH2—CH2). n A mixture of polymeric compounds of OH, wherein the subscript n is typically in the range of 4-230, and the average molecular weight is from about 200 to about 10,000. Preferably, n is a number from about 6 to about 22 and the average molecular weight is between about 300 and about 1,000; more preferably, n is in the range of about 6 to about 13 and the average molecular weight is from about 300 to about 600; most preferably, n has a value of about 8.5 to about 9 and the relative molecular weight is about 400. Suitable poly(ethylene glycol) is commercially available, for example, poly(ethylene glycol) with average molecular weights of about 200, 300, 400, 600, 1000, 1500, 2000, 3000, 4000, 6000, 8000, and 10000.

[0396] Poly(ethylene glycol), particularly the preferred type described in the above paragraph, is preferably used in an amount of 1-10% by weight of the entire semi-solid ophthalmic composition, more preferably 1-5% by weight.

[0397] A particularly preferred embodiment of the composition according to this disclosure comprises an agent for dispersing and / or dissolving the drug in an ointment base, the agent being selected from polyethylene glycol, polyethoxylated castor oil, and preferably a mixture of said components.

[0398] Gel / Ointment Viscosity

[0399] In some embodiments, the composition has a Brookfield RVDV viscosity of about 10,000 cp to about 300,000 cp at about 20°C and a 1s... -1 The shear rate. In some embodiments, the composition has a Brookfield RVDV viscosity of about 15,000 cp to about 200,000 cp at about 20°C, and a shear rate of 1s. -1 The shear rate. In some embodiments, the composition has a Brookfield RVDV viscosity of about 50,000 cp to about 150,000 cp at about 20°C, and a shear rate of 1s. -1 The shear rate. In some embodiments, the composition has a Brookfield RVDV viscosity of about 70,000 cp to about 130,000 cp at about 20°C, and a shear rate of 1s. -1 The shear rate. In some embodiments, the composition has a Brookfield RVDV viscosity of about 90,000 cp to about 110,000 cp at about 20°C, and a shear rate of 1s. -1 The shear rate.

[0400] In some embodiments, the ophthalmic gel formulation contains a viscosity enhancer sufficient to provide viscosities of about 500 to 1,000,000 centipoise, about 750 to 1,000,000 centipoise, about 1,000 to 1,000,000 centipoise, about 1,000 to 400,000 centipoise, about 2,000 to 100,000 centipoise, about 3,000 to 50,000 centipoise, about 4,000 to 25,000 centipoise, about 5,000 to 20,000 centipoise, or about 6,000 to 15,000 centipoise. In some embodiments, the ophthalmic gel formulation contains a viscosity enhancer sufficient to provide viscosities of about 500,000 to 1,000,000 centipoise.

[0401] In some embodiments, the compositions described herein are low-viscosity compositions at body temperature. In some embodiments, the low-viscosity compositions contain about 1% to about 10% of a viscosity enhancer (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low-viscosity compositions contain about 2% to about 10% of a viscosity enhancer (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low-viscosity compositions contain about 5% to about 10% of a viscosity enhancer (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the low-viscosity ophthalmic compositions described herein are substantially free of viscosity enhancers (e.g., gelling components, such as polyoxyethylene-polyoxypropylene copolymers). In some embodiments, the low-viscosity ophthalmic compositions described herein provide an apparent viscosity of about 100 cP to about 10,000 cP. In some embodiments, the low-viscosity ophthalmic compositions described herein provide an apparent viscosity of about 500 cP to about 10,000 cP. In some embodiments, the low-viscosity ophthalmic compositions described herein provide an apparent viscosity of about 1,000 cP to about 10,000 cP.

[0402] In some embodiments, the compositions described herein are viscous compositions at body temperature. In some embodiments, the viscous composition contains about 10% to about 25% of a viscosity enhancer (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the viscous composition contains about 14% to about 22% of a viscosity enhancer (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the viscous composition contains about 15% to about 21% of a viscosity enhancer (e.g., a gelling component, such as a polyoxyethylene-polyoxypropylene copolymer). In some embodiments, the viscous ophthalmic composition described herein provides an apparent viscosity of about 100,000 cP to about 1,000,000 cP. In some embodiments, the viscous ophthalmic composition described herein provides an apparent viscosity of about 150,000 cP to about 500,000 cP. In some embodiments, the viscous ophthalmic composition described herein provides an apparent viscosity of about 250,000 cP to about 500,000 cP. In some such embodiments, the adhesive ophthalmic composition is liquid at room temperature and gels at a temperature approximately between room temperature and body temperature (including severe fever, such as an individual with a maximum of about 42°C). In some embodiments, the adhesive ophthalmic composition is administered as a single therapy to treat the ophthalmic diseases or conditions described herein.

[0403] In some embodiments, the viscosity of the gel formulations described herein is measured by any of the methods described. For example, in some embodiments, the viscosity of the gel formulations described herein is calculated using an LVDV-II+CP Cone Plate Viscometer and a Cone Spindle CPE-40. In other embodiments, the viscosity of the gel formulations described herein is calculated using a Brookfield (shaft and cup) viscometer. In some embodiments, the viscosity range mentioned herein is measured at room temperature. In other embodiments, the viscosity range mentioned herein is measured at body temperature (e.g., at the average body temperature of a healthy person).

[0404] Uniformity of gel / ointment dosage

[0405] Typical ophthalmic gels are packaged in eye drop bottles and applied as drops. For example, a single application (i.e., a single dose) of an ophthalmic gel includes applying one, two, three, or more drops into a patient's eye. Similarly, typical ophthalmic ointments are packaged in tubes or other squeezeable containers having a dispensing nozzle (through which an ointment strip is delivered). For example, a single application (i.e., a single dose) of an ophthalmic ointment includes applying one or more strips into a patient's eye. In some embodiments, a dose of the ophthalmic gel described herein is one drop of gel composition from an eye drop bottle. In some embodiments, a dose of the ophthalmic ointment is one strip of ointment composition dispensed through a nozzle of a dispensing tube.

[0406] In some cases, the description herein includes ophthalmic gel compositions that provide a uniform concentration between doses. In some cases, the uniform concentration between doses does not present a significant variation in drug content between doses. In some cases, the uniform concentration between doses provides a consistent drug content between doses.

[0407] In some cases, the description herein includes ophthalmic ointment compositions that provide uniform concentrations between doses. In some cases, uniform concentrations between doses do not present significant variations in drug content between doses. In some cases, uniform concentrations between doses provide consistent drug content between doses.

[0408] In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 50%. In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 40%. In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 30%. In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 20%. In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 10%. In some embodiments, the composition has an inter-dose ophthalmic concentration variation of less than 5%.

[0409] In some embodiments, the dose-interval ophthalmic concentration variation is based on 10 consecutive doses. In some embodiments, the dose-interval ophthalmic concentration variation is based on 8 consecutive doses. In some embodiments, the dose-interval ophthalmic concentration variation is based on 5 consecutive doses. In some embodiments, the dose-interval ophthalmic concentration variation is based on 3 consecutive doses. In some embodiments, the dose-interval ophthalmic concentration variation is based on 2 consecutive doses.

[0410] In some embodiments, the ophthalmic gel compositions and ophthalmic ointment compositions described herein are “shake-free” formulations.

[0411] In some embodiments, the composition is stored in a plastic container. In some embodiments, the plastic container is made of low-density polyethylene (LDPE).

[0412] The compounds considered in this disclosure (e.g., VAP-1 inhibitors) may be in the form of any other suitable pharmaceutical composition currently known or to be developed in the future.

[0413] IV. Instructions for Use

[0414] Inhibition of vascular adhesion protein-1

[0415] VAP-1 is a therapeutic target for treating vascular and inflammation-related diseases. Methods for inhibiting VAP-1 include, but are not limited to, small interfering RNA, functional blocking antibodies, and small molecule inhibitors. Clinical trials using oral VAP-1 inhibitors have been conducted and have demonstrated safety. Examples of VAP-1 inhibitors include, but are not limited to, ASP8232, BTT-1029, PXS-4728A, BTT-1023, LJP-1207, LJP-1586, SZE5302, Antibody 7-88, BTT-2052, PXS-4681A, PXS-4159A, BTT-2027, mofeglan hydrochloride, aminohexose, hydrazine derivatives, propenyl and propargylamines, 4-substituted 2-butynylamines, haloallylamines, pyrroline derivatives, propargyl diamine, allylamine, diamines, 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine derivatives, thiocarbamoyl derivatives, carboxamides, sulfonamides, thiazoles and / or guanidine derivatives, oxime derivatives, dihydrazines, arylalkylamines, oxazolidinones, haloalkylamines, phenylphosphine, and imidazopyridine derivatives.

[0416] Uveitis is a general term to describe a group of inflammatory diseases that cause swelling and damage to the tissues of the eye. The term "uveitis" is used because the disease typically affects a part of the eye called the uvea. However, uveitis is not limited to the uvea. These diseases can also affect the lens, retina, optic nerve, and vitreous humor, leading to decreased vision or blindness. Common symptoms of uveitis include decreased vision, pain, light sensitivity, and increased floaters.

[0417] The uvea is the middle layer of the eye and contains most of its blood vessels. This is one way inflammatory cells enter the eye. The uvea lies between the sclera—the white outer layer of the eye—and the inner layer called the retina, which is composed of the iris, ciliary body, and choroid. Uveitis primarily damages vision by causing problems with the lens, retina, optic nerve, and vitreous body. Specific types of uveitis are classified according to their location in the eye, including anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis.

[0418] Uveitis is primarily caused by an inflammatory response within the eye. Typical inflammatory responses leading to uveitis include attacks from the body's own immune system, infections or tumors occurring in the eye or other parts of the body, eye injuries, and toxins that may enter the eye.

[0419] Diagnosis of uveitis may involve a thorough examination and recording a complete patient history. Laboratory tests may be performed to rule out infection or autoimmune diseases. A central nervous system evaluation is typically performed on individuals with a subgroup of intermediate uveitis (called pars plana cyclitis) to determine if they have multiple sclerosis (often associated with pars plana cyclitis). Exemplary ophthalmological examinations used include: a visual acuity chart or diopter test to measure whether a patient's vision is impaired; funduscopy, in which the pupil is dilated with eye drops and then light is visualized using an instrument called an ophthalmoscope for non-invasive examination of the posterior and internal parts of the eye; measurement of intraocular pressure; and slit-lamp examination, which non-invasively examines most of the eye.

[0420] Treatment for uveitis primarily aims to eliminate inflammation, relieve pain, prevent further tissue damage, and restore vision. The specific treatment depends on the type of uveitis the patient has.

[0421] Treatment can also depend on the specific type of uveitis the patient has. Treatment for anterior uveitis includes, for example, dilating the pupil with eye drops to prevent spasm of the iris and ciliary body, or reducing inflammation with eye drops. Intermediate, posterior, and panuveitis are usually treated with periocular injections, oral medications, or, in some cases, surgically implanted delayed-release capsules into the eye.

[0422] One aspect provides a method for inhibiting vascular adhesion protein-1 (VAP-1), the method comprising contacting VAP-1 with a compound comprising the structural formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Another aspect provides a method for inhibiting vascular adhesion protein-1 (VAP-1), comprising contacting VAP-1 with a pharmaceutical composition comprising a compound comprising the structural formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A) and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient.

[0423] One aspect provides a method for treating or preventing a VAP-1-mediated disease or condition, comprising administering to a subject in need a therapeutically effective amount of a compound comprising the structural formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A), and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. Another aspect provides a method for treating or preventing a VAP-1-mediated disease or condition, comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising a compound comprising the structural formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A), and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and at least one pharmaceutically acceptable excipient.

[0424] In another aspect, a method for treating or preventing an ophthalmic disease or condition in a subject of need is provided, comprising administering to the subject a therapeutically effective amount of a compound of structural formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A), and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In yet another aspect, a method for treating or preventing an ophthalmic disease or condition in a subject of need is provided, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of structural formula (IV), (IV-A), (IV-B), (VA), (VB), (VI-A), (VI-B), (VII-A), and / or (VII-B), or an olefinic isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and at least one pharmaceutically acceptable excipient.

[0425] In some embodiments, the VAP-1-mediated disease or condition is uveitis. In some embodiments, the ophthalmic disease or condition is uveitis. In some embodiments, the compounds or compositions disclosed herein are applied topically.

[0426] The amount of the disclosed compound administered to a subject may depend on, for example, the purpose of administration (e.g., the desired degree of relief); the age, weight, sex, health, and physical condition of the subject administering the formulation; the route of administration; and the nature of the disease, condition, illness, or its symptoms. The dosing regimen may also take into account the presence, nature, and extent of any adverse reactions associated with the administered agent. Effective doses and dosing regimens can be readily determined by, for example, safety and dose escalation studies, in vivo studies (e.g., animal models), and other methods known to the craft.

[0427] Typically, dosing parameters indicate a dose less than the amount that could cause irreversible toxicity to the subject (maximum tolerated dose (MTD)) and not less than the amount required to produce a measurable effect in the subject. Such a dose depends, for example, on pharmacokinetic and pharmacodynamic parameters related to ADME, and takes into account the route of administration and other factors.

[0428] The effective dose (ED) is the amount or quantity of a drug that produces a therapeutic response or desired effect in a subset of subjects who receive the drug. The "median effective dose" or ED of a drug is... 50 This refers to the dosage or amount of the drug that produces a therapeutic response or desired effect in 50% of the population receiving the drug. Although ED 50It is often used as a measure of the reasonable expectation of a drug's effect, but considering all relevant factors, it may not necessarily be the dose that a clinician would deem appropriate. Therefore, in some cases, the effective dose is greater than the calculated ED. 50 In other cases, the effective quantity is less than the calculated ED. 50 In other cases, the effective quantity equals the calculated ED. 50 .

[0429] Furthermore, the effective dose of the compounds disclosed herein can be the amount that produces the desired result relative to a healthy subject when administered to a subject at one or more doses. For example, for a subject suffering from a specific condition, the effective dose can be a dose that improves the diagnostic parameters, measures, biomarkers, etc., of the condition by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, wherein 100% is defined as the diagnostic parameters, measures, biomarkers, etc., exhibited by a normal subject.

[0430] In some embodiments, the compounds contemplated in this disclosure may be administered (e.g., orally) at dose levels of about 0.01 mg / kg to about 1000 mg / kg or about 1 mg / kg to about 100 mg / kg of the subject's body weight once, twice, three times, four times or more daily to achieve the desired therapeutic effect. For oral administration, the composition may be provided in tablet, capsule, or other forms, containing 0.05 to 1000 mg of the active ingredient, particularly in doses of 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 125.0, 150.0, 175.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient. Pharmaceutically acceptable carriers, diluents, and / or excipients may be present in amounts from about 0.1 g to about 10 g.

[0431] In some implementations, a "unit dosage form" contains a dose of the desired compound. The term "unit dosage form" refers to a physically discrete unit, each containing a predetermined amount of the compound sufficient to produce the desired effect (e.g., a VAP-1 inhibitor). It should be understood that the parameters of the unit dosage form will depend on the specific drug and the desired effect.

[0432] In some embodiments, the ophthalmic composition is formulated as an ophthalmic solution for the treatment of uveitis.

[0433] In some embodiments, this document discloses a method for preventing the development of uveitis, the method comprising administering an effective amount of the ophthalmic composition described herein to the eye of an individual in need. In some embodiments, this document describes a method for preventing or inhibiting the development of uveitis, the method comprising administering an effective amount of an ophthalmic composition to the eye of an individual in need, the ophthalmic composition comprising about 0.001 wt% to about 50 wt% of a VAP-1 compound. In some embodiments, the ophthalmic composition is administered at predetermined time intervals over an extended period of time. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the ophthalmic composition is administered every other day. In some embodiments, the ophthalmic composition is administered over a period of 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, or 12-15 years.

[0434] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or variations thereof are suggestive to those skilled in the art and are included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

[0435] V. Example

[0436] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or variations thereof are suggestive to those skilled in the art and are included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

[0437] Identification of VAP-1 inhibitors

[0438] In some embodiments, the compounds described herein have at least one property or characteristic of therapeutic significance. Candidate inhibitors can be identified using, for example, assays or models recognized in the art. The Examples section describes assays for determining the VAP-1 inhibitory activity of the compounds described herein, as well as assays that can be used to evaluate one or more characteristics of the compounds; other procedures, assays, etc., that can be used to generate data and information that can be used to evaluate the VAP-1 inhibitors described herein will be known to those skilled in the art.

[0439] Following identification, candidate inhibitors can be further evaluated using techniques that provide data on inhibitor properties (e.g., pharmacokinetic parameters). Comparison of candidate inhibitors with reference standards (which may be the "best-in-class" of current inhibitors) demonstrates the potential feasibility of such drug candidates. VAP-1 inhibitors that can be used as reference or benchmark compounds include those that have demonstrated proven activity and properties. Other methods for analyzing candidate inhibitors will be apparent to those skilled in the art.

[0440] Synthesis details

[0441] The following general schemes represent synthetic methods that can be used to prepare the compounds of this disclosure, as well as common chemical intermediates produced in their preparation. Those skilled in the art will recognize that these schemes are merely representative, and in many cases, alternative synthetic methods can be employed.

[0442] The following embodiments are provided to provide those skilled in the art with a complete disclosure and description of how to implement and use this disclosure, and are not intended to limit the scope of what the inventors consider to be part of its disclosure, nor to represent that the following experiments were performed, or that they are all possible experiments. It should be understood that the exemplary description need not be written in the present tense, but rather that descriptions can be made to generate data, etc., of the properties described herein. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be taken into account.

[0443] Unless otherwise specified, parts are by weight, molecular weight is by weight-average molecular weight, temperature is in degrees Celsius (°C), and pressure is atm or near atm. Standard abbreviations are used, including the following: wt = wild type; bp = base pair; kb = kilobase; nt = nucleotide; aa = amino acid; s or sec = second; min = minute; h or hr = hour; ng = nanogram; μg = microgram; mg = milligram; g = gram; kg = kilogram; dl or dL = deciliter; μl or μL = microliter; ml or mL = milliliter; l or L = liter; mM = micromolar; mM = millimole; M = mole; kDa = kilodalton; im = intramuscular; ip = intraperitoneal; SC or SQ = subcutaneous; QD = once daily; BID = twice daily; QW = once weekly; QM = once monthly; psi = pound per square inch; HPLC = high performance HPLC. Liquid chromatography; BW = body weight; U = unit; ns = no statistical significance; HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); TFA = trifluoroacetic acid; MBTE = methyl tert-butyl ether; DCM = dichloromethane; PBS = phosphate buffered saline; IHC = immunohistochemistry; DMSO = dimethyl sulfoxide; EtOAc = ethyl acetate; EtOH = ethanol; DMEM = Dulbeco modified Eagle medium; EDTA = ethylenediaminetetraacetic acid; Me = methyl; Et = ethyl; S - singlet; D - doublet; dd - doublet; m - multiplet.

[0444] General preparation of hydrazine starting materials:

[0445] General Experimental Procedure A: BBr3-mediated demethylation

[0446] Add BBr3 (3 eq) to a stirred solution of (hetero)arylmethoxy (1 eq) in DCM. Stir the reaction at 18°C ​​for 1 hour. Add MeOH and remove volatiles under reduced pressure. Partition the obtained residue between a saturated aqueous solution of NaHCO3 and EtOAc. Separate the layers, wash the aqueous phase with EtOAc, and dry the combined organic matter with Na2SO4. Filter and concentrate under reduced pressure to obtain the desired product.

[0447] General Experimental Procedure B Alkylation with fluoroallylamine

[0448] K₂CO₃ (1.2 eq) was added to a stirred solution of (hetero)aryl alcohol (1.1 eq) in DMF, followed by the addition of tert-butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (1 eq). The reaction was stirred at 70 °C for 15 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting crude residue was purified by automated rapid column chromatography to obtain the desired product.

[0449] General Experimental Procedure C HCl-mediated Boc deprotection / TsOH salt formation

[0450] 4M HCl in dioxane was added to N-Boc amine. The reaction was stirred at 18°C ​​for 15 hours. Volatile substances were removed under reduced pressure, and the residue was free-based using an SCX-2 precipitator and purified by automated rapid column chromatography. 1 eq or 2 eq of p-toluenesulfonic acid (toluenesulfonic acid or TsOH) in methanol (2 mL) was added to the obtained residue, and the solvent was removed under reduced pressure to obtain the desired product.

[0451] General Experimental Procedure D 6,5-Heteroaromatic ring formation using α-bromo-one

[0452] α-bromo-one (1.2 eq) was added to a stirred solution of heteroarylamine (1 eq) in EtOH. The solution was heated to 80 °C and held for 1.5 hr. The reaction was then post-treated. The solvent was removed under reduced pressure, and the residue was dissolved in DCM, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude residue was purified to the desired product by automated rapid column chromatography.

[0453] General Experimental Procedures Part E 1 N-Amination using O-(trimethylbenzenesulfonyl)hydroxylamine

[0454] O-(tris(methyltrimethylol)sulfonyl)hydroxylamine (2 eq) was added in portions to a suspension of heteroarylamines (1 eq) in DCM while maintaining the temperature below 22°C. The suspension was stirred at 18°C ​​for 15 hours. The solid was filtered off and washed with DCM. The residue was dried under reduced pressure at 18°C ​​to obtain the desired product.

[0455] General Experimental Procedures Part E 2 6,5-Heteroaromatic ring formation using valeryl chloride

[0456] A mixture of N-aminoheteroarylamine (1 eq) and pyridine was added with valeryl chloride (2 eq). The mixture was stirred overnight at 100 °C under nitrogen. The mixture was concentrated under vacuum, and the residue was stirred in a mixture of saturated aqueous Na₂CO₃ and DCM. After 1 hour, the aqueous layer was extracted with DCM. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The obtained residue was purified to the desired product by automated rapid column chromatography.

[0457] LCMS

[0458] The instruments used were an Agilent 1290 series equipped with a UV detector and an HP 6130MSD mass detector equipped with a Waters XBridgeBEH C18 XP (2.1 x 50 mm, 2.5 μm) column. The mass detector ionized both positive and negative conjugates at atmospheric pressure via electrospray ionization.

[0459] LCMS method "28817C TFA LCMS-5C-3.M"

[0460] The method used is as follows:

[0461] Mobile phase A: Trifluoroacetic acid (aqueous solution; 0.05%)

[0462] Mobile phase B: Acetonitrile

[0463] Pump flow rate: 0.6 ml / min

[0464] • UV detection: 215, 268nm

[0465] Injection volume: 0.2 μl

[0466] Runtime: 3.5 min

[0467] Column temperature: 35℃

[0468] Pump program: gradient

[0469] Time (min) ％A ％B 0.0 95 5 0.5 95 5 2.5 10 90

[0470] LCMS Method "General 3"

[0471] • Mobile phase A: 10 mM NH4Ac in a 20:1 water:MeCN solution

[0472] Mobile phase B: MeCN

[0473] Pump flow rate: 0.6 ml / min

[0474] • UV detection: 215, 268nm

[0475] Injection volume: 0.2 μl

[0476] Runtime: 3.0 min

[0477] Column temperature: 30℃

[0478] Pump program: gradient

[0479] Time (min) ％A ％B 0.0 80 20 1.5 5 95 2.5 5 95 2.6 80 20

[0480] LCMS Method "General 4"

[0481] • Mobile phase A: 10 mM NH4Ac in a 20:1 water:MeCN solution

[0482] Mobile phase B: MeCN

[0483] Pump flow rate: 0.6 ml / min

[0484] • UV detection: 215, 268nm

[0485] Injection volume: 0.2 μl

[0486] Runtime: 3.0 min

[0487] Column temperature: 30℃

[0488] Pump program: gradient

[0489] Time (min) ％A ％B 0.0 95 5 1.5 5 95 2.5 5 95 2.6 95 5

[0490] LCMS Method "General +-"

[0491] The method used is as follows:

[0492] Mobile phase A: Trifluoroacetic acid (aqueous solution; 0.05%)

[0493] Mobile phase B: Acetonitrile

[0494] Pump flow rate: 1 ml / min

[0495] • UV detection: 220, 254nm

[0496] Injection volume: 5 μl

[0497] Runtime: 24 minutes

[0498] Column temperature: 35℃

[0499] Pump program: gradient

[0500] Time (min) ％A ％B 0.0 90 10 15.0 30 70 17.0 5 95 20.0 5 95 20.01 90 10 24.0 90 10

[0501] Exemplary compounds

[0502] Example 1

[0503] (E)-2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-ene-1-amine bis(4-methylbenzenesulfonate)

[0504]

[0505] Step 1. 2-Butyl-6-methoxyimidazo[1,2-a]pyridine was prepared according to general experimental procedure D. 5-Methoxypyridine-2-amine (500 mg, 4.03 mmol) yielded 2-butyl-6-methoxyimidazo[1,2-a]pyridine (760 mg, 40%) as a yellow oil. LCMS (General 3) RT: 0.89 min; Yield: 75%; m / z 205.1 (M+H) + ).

[0506] Step 2.2 2-Butylimidazo[1,2-a]pyridine-6-ol was prepared according to General Procedure A. 2-Butyl-6-methoxyimidazo[1,2-a]pyridine (1.25 g, 6.12 mmol) yielded 2-butylimidazo[1,2-a]pyridine-6-ol (870 mg, 70%) as a grayish-white solid. LCMS (General 3) RT: 0.60 min; Yield: 88%; m / z 191.4 (M+H) + ).

[0507] Step 3. (E)-(2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate was prepared according to General Procedure B. 2-Butylimidazo[1,2-a]pyridin-6-ol (181 mg, 0.95 mmol) yielded (E)-(2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (192 mg, 53%), as a pale yellow oil. LCMS (General 3) RT: 1.18 min; Yield: 66%; m / z 378.1 (M+H) + ).

[0508] Step 4. (E)-2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine bis(4-methylbenzenesulfonate) was prepared according to general experimental procedure C. Tert-butyl carbamate (192 mg, 0.51 mmol) yielded (E)-2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine bis(4-methylbenzenesulfonate) (73 mg, 23%), as a beige solid. LCMS: (28817C TFALCMS-5C-3.M) RT: 1.230 min; Yield: 94.2%; m / z 278.2 (M+H) + ). 1H NMR (300MHz, DMSO-d6) δ8.35(d,J=2.3Hz,1H),8.10(s,3H),7.70(s,1H),7.55–7.43(m,4H),7.29–7.00(m,3H),4.58(d,J=3.5Hz,2 H), 3.62 (d, J = 2.2Hz, 2H), 2.67 (t, J = 7.6Hz, 2H), 2.26 (s, 3H), 1.63 (p, J = 7.5Hz, 2H), 1.32 (q, J = 7.4Hz, 2H), 0.89 (t, J = 7.3Hz, 3H).

[0509] Example 2

[0510] (E)-2-(((2-Butylimidazo[1,2-a]pyridin-7-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine-4-methylbenzenesulfonate

[0511]

[0512] Step 1. 2-Butyl-7-methoxyimidazo[1,2-a]pyridine was prepared according to general experimental procedure D. 4-Methoxypyridine-2-amine (500 mg, 4.03 mmol) yielded 2-butyl-7-methoxyimidazo[1,2-a]pyridine (760 mg, 40%) as a yellow oil. LCMS (General 3) RT: 0.82 min; Yield: 75%; m / z 205.2 (M+H) + ).

[0513] Step 2.2 2-Butylimidazo[1,2-a]pyridine-7-ol was prepared according to General Procedure A. 2-Butyl-7-methoxyimidazo[1,2-a]pyridine (760 mg, 3.72 mmol) yielded 2-butylimidazo[1,2-a]pyridine-7-ol (167 mg, 24%) as a grayish-white solid. LCMS (General 3) RT: 0.49 min; Yield: 64%; m / z 191.4 (M+H) + ).

[0514] Step 3. (E)-(2-(((2-Butylimidazo[1,2-a]pyridin-7-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate was prepared according to General Procedure B. 2-Butylimidazo[1,2-a]pyridin-7-ol (167 mg, 0.87 mmol) yielded (E)-(2-(((2-Butylimidazo[1,2-a]pyridin-7-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (140 mg, 43%), as a pale yellow oil. LCMS (General 3) RT: 1.17 min; Yield: 79%; m / z 378.2 (M+H) + Step 4. (E)-2-(((2-Butylimidazo[1,2-a]pyridin-7-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate was prepared according to general experimental procedure C. (E)-(2-(((2-Butylimidazo[1,2-a]pyridin-7-yl)oxy)methyl)-3-fluoroallyl)carbamate tert-butyl ester (140 mg, 0.37 mmol) yielded (E)-2-(((2-Butylimidazo[1,2-a]pyridin-7-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate (64 mg, 38%), as a beige solid. LCMS: (28817CTFA LCMS-5C-3.M) RT: 1.323 min; Yield: 93.3%; m / z 278.2 (M+H) + ). 1 H NMR (300MHz, DMSO-d6) δ8.35(d,J=7.5Hz,1H),8.05(s,3H),7.63–7.38(m,3H),7.33–6.86(m,4H),6.65(dd,J=7.5,2.5Hz,1H),4.65( d,J=3.5Hz,2H),3.61(s,2H),2.61(t,J=7.5Hz,2H),2.26(s,3H),1.61(p,J=7.5Hz,2H),1.32(q,J=7.4Hz,2H),0.88(t,J=7.3Hz,3H).

[0515] Example 3

[0516] (E)-2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine-4-methylbenzenesulfonate

[0517]

[0518] Step 1. 2-Imino-4-methoxypyridine-1(2H)-amine 2,4,6-trimethylbenzenesulfonate was prepared according to General Experimental Procedure, Part E, Section 1. O-(trimethylbenzenesulfonyl)hydroxylamine (2.8 g, 2 eq, 12.1 mmol) was added fractionally to a suspension of 2-amino-4-methoxypyridine (0.75 g, 6.06 mmol) in DCM (35 mL) while maintaining the temperature below 22 °C. The suspension was stirred at 18 °C for 15 hr. The solid was filtered off and washed with DCM (40 mL). The residue was dried under reduced pressure at 18 °C to give 2-imino-4-methoxypyridine-1(2H)-amine 2,4,6-trimethylbenzenesulfonate (1.84 g, 43%) as a white solid. LCMS (General 3) RT: 0.41 min; Yield: 80%; m / z 140.4 (M+H) + ).

[0519] Step 2.2 Butyl-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine was prepared according to Part E, Section 2 of the general experimental procedure. Vanoyl chloride (1.24 mL, 2 eq, 10.4 mmol) was added to a mixture of 2-imino-4-methoxypyridine-1(2H)-amine 2,4,6-trimethylbenzenesulfonate (1.84 g, 5.18 mmol) and pyridine (21 mL). The mixture was stirred at 100 °C for 15 hr under nitrogen. The mixture was concentrated under reduced pressure, and the residue was stirred in a mixture of saturated aqueous Na₂CO₃ solution (20 mL) and DCM (20 mL). After 1 hr, the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give 0.70 g of a deep red solid. The residue was purified by automated rapid column chromatography to give 2-butyl-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine (325 mg, 31%) as a white solid. LCMS (General 3) RT: 0.80 min; Yield: 95%; m / z 206.4 (M+H) + ).

[0520] Step 3.2 2-Butyl-[1,2,4]triazolo[1,5-a]pyridine-7-ol was prepared according to General Procedure A. 2-Butyl-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine (470 mg, 2.3 mmol) yielded 2-Butyl-[1,2,4]triazolo[1,5-a]pyridine-7-ol (291 mg, 66%) as a grayish-white solid. LCMS (General 3) RT: 0.57 min; Yield: 99%; m / z 192.4 (M+H) + ).

[0521] Step 4. (E)-(2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate was prepared according to General Procedure B. 2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-7-ol (291 mg, 1.52 mmol) yielded (E)-(2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (405 mg, 70%), a white solid. LCMS (General 3) RT: 1.14 min; Yield: 86%; m / z 379.3 (M+H) + ).

[0522] Step 5. (E)-2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate was prepared according to general experimental procedure C. (E)-(2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (405 mg, 1.07 mmol) yielded (E)-2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate (158 mg, 32%), a grayish-white solid. LCMS (28817C TFALCMS-5C-3M) RT: 1.37 min; Yield: 98%; m / z 279.2 (M+H) + ). 1 H NMR (299MHz, methanol-d4) δ8.56 (d, J=7.5Hz, 1H), 7.77–7.62 (m, 2H), 7.29 (d, J= 80.7Hz,1H),7.26–7.18(m,2H),7.12(d,J=2.6Hz,1H),6.92(dd,J=7.5,2. 6Hz,1H),4.79–4.73(m,2H),3.88–3.82(m,2H),2.86(t,J=7.6Hz,2H),2.3 6(s,3H),1.80(q,J=7.6Hz,2H),1.51–1.35(m,2H),0.97(t,J=7.4Hz,3H).

[0523] Example 4

[0524] (E)-2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine-4-methylbenzenesulfonate

[0525]

[0526] Step 1. 2-Imine-5-methoxypyridine-1(2H)-amine 2,4,6-trimethylbenzenesulfonate was prepared according to General Procedure E, Part 1. 2-Amino-5-methoxypyridine (0.75 g, 6.06 mmol) yielded 2-imino-5-methoxypyridine-1(2H)-amine 2,4,6-trimethylbenzenesulfonate (383 mg, 13%) as a grayish-white solid. LCMS (General 3) RT: 0.32 min; Yield: 76%; m / z 140.4 (M+H) + ).

[0527] Step 2.2 2-Butyl-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine was prepared according to General Experimental Procedure, Part E, Section 2. 2-Imino-5-methoxypyridine-1(2H)-amine 2,4,6-trimethylbenzenesulfonate (265 mg, 0.781 mmol) yielded 2-butyl-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine (39 mg, 24%) as a white solid. LCMS (General 3) RT: 0.82 min; Yield: 88%; m / z 206.2 (M+H) + ).

[0528] Step 3.2 2-Butyl-[1,2,4]triazolo[1,5-a]pyridine-6-ol was prepared according to General Procedure A. 2-Butyl-6-methoxy-[1,2,4]triazolo[1,5-a]pyridine (1.25 g, 6.09 mmol) yielded 2-Butyl-[1,2,4]triazolo[1,5-a]pyridine-6-ol (0.69 g, 59%), a white solid. LCMS (General 3) RT: 0.59 min; Yield: 99%; m / z 192.3 (M+H) + ).

[0529] Step 4. (E)-(2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate was prepared according to General Procedure B. 2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-6-ol (250 mg, 1.31 mmol) yielded (E)-(2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (454 mg, 92%), as a yellow oil. LCMS (General 3) RT: 1.15 min; Yield: 97%; m / z 379.3 (M+H) + ).

[0530] Step 5. (E)-2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate was prepared according to general experimental procedure C. (E)-(2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (454 mg, 1.20 mmol) yielded (E)-2-(((2-Butyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate (156 mg, 29%), a grayish-white solid. LCMS (28817C TFALCMS-5C-3.M) RT: 1.39 min; Yield: 96%; m / z 279.2 (M+H) + ). 1 H NMR (299MHz, chloroform-d) δ8.01(s,1H),7.54(dd,J=9.6,0.8Hz,1H),6.77(d,1H),4.72(s,1H),4.44(dd,J=3.7,1.1 Hz,2H),4.09–3.95(m,2H),2.93–2.83(m,2H),1.93–1.75(m,2H),1.54–1.35(m,11H),0.96(t,J=7.3Hz,3H).

[0531] Example 5

[0532] (Z)-2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine-4-methylbenzenesulfonate

[0533]

[0534] Step 1. 2-Butyl-6-methoxyimidazo[1,2-a]pyridine was prepared according to general experimental procedure D. 5-Methoxypyridine-2-amine (1.0 g, 8.05 mmol) yielded 2-butyl-6-methoxyimidazo[1,2-a]pyridine (1.42 g, 72%) as an orange oil. LCMS (General 3) RT: 0.89 min; Yield: 75%; m / z 205.1 (M+H) + ).

[0535] Step 2.2 2-Butylimidazo[1,2-a]pyridine-6-ol was prepared according to General Procedure A. 2-Butyl-6-methoxyimidazo[1,2-a]pyridine (1.75 g, 6.12 mmol) yielded 2-butylimidazo[1,2-a]pyridine-6-ol (870 mg, 70%) as a grayish-white solid. LCMS (General 3) RT: 0.60 min; Yield: 88%; m / z 191.4 (M+H) + ).

[0536] Step 3. (Z)-(2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate was prepared according to General Procedure B. 2-Butylimidazo[1,2-a]pyridin-6-ol (178 mg, 0.94 mmol) yielded (Z)-(2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (65 mg, 18%) as a brown oil. LCMS (General 3) RT: 1.19 min; Yield: 82%; m / z 378.4 (M+H) + ).

[0537] Step 4. (Z)-2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate was prepared according to general experimental procedure C. (Z)-(2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)carbamate tert-butyl ester (65 mg, 0.17 mmol) yielded (Z)-2-(((2-Butylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate (17.5 mg, 23%), as a brown oil. LCMS: (28817C TFA LCMS-5C-3.M) RT: 1.35 min; Yield: 88.9%; m / z 278.2 (M+H) + ). 1 H NMR (300MHz, DMSO-d6) δ8.24(d,J=2.3Hz,1H),7.76–7.53(m,3H),7.46(d,J=8.1Hz,2H),7.42–7.27(m,2H),7.15–6.93(m,4H),4.66(d, J=2.7Hz,2H),3.52(d,J=3.0Hz,2H),2.62(t,J=7.6Hz,2H),2.27(s,3H),1.68–1.56(m,2H),1.32(q,J=7.4Hz,2H),0.89(t,J=7.3Hz,3H)

[0538] Example 6

[0539] ((E)-2-(((2-Butyrylpyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-ene-1-amine bis(4-methylbenzenesulfonate)

[0540]

[0541] Step 1. 2-(hexane-1-yn-1-yl)-5-methoxypyridine was prepared according to the following procedure. A stirred solution of 2-bromo-5-methoxypyridine (1.88 g, 1 eq, 10 mmol), [(Ph3P)2PdCl2] (351 mg, 0.05 eq, 50 μmol), and copper iodide (I) (190 mg, 0.1 eq, 1.0 mmol) in MeCN (50 mL) was purged with N2 for 30 min. Hexane-1-yn (1.64 g, 2.30 mL, 2.0 eq, 20 mmol) and NEt3 (4.2 mL, 3.0 eq, 30 mmol) were added, and the reaction was heated at 60 °C for 16 hr. The reactants were concentrated under reduced pressure and purified by automated rapid column chromatography to give 2-(hexane-1-yn-1-yl)-5-methoxypyridine as a brown oil (1.60 g, 85%). LCMS (General 3) RT: 1.21 min; Yield: 98.9%; m / z 190.3 (M+H) + ). 1 ¹H NMR (300MHz, chloroform-d) δ 8.25–8.20 (m, 1H), 7.33–7.23 (m, 1H), 7.10 (dd, J = 8.6, 3.0 Hz, 1H), 3.85 (s, 3H), 2.41 (t, J = 7.0 Hz, 2H), 1.66–1.40 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H).

[0542] Step 2.1 The 2,4,6-trimethylbenzenesulfonate of 1-amino-2-(hexane-1-yn-1-yl)-5-methoxypyridine-1-onium was prepared according to the following procedure. O-(trimethylbenzenesulfonyl)hydroxylamine (2.18 g, 1.2 eq, 10.1 mmol) suspended in DCM (40 mL) was added to a stirred solution of 2-(hexane-1-yn-1-yl)-5-methoxypyridine (1.60 g, 1 eq, 8.5 mmol) dissolved in DCM (17 mL) and cooled to 0 °C. The mixture was stirred at 0 °C for 2.5 hr, and then Et₂O (228 mL, 4 V) was added. The obtained solid was filtered, the feed was washed with Et 2O (57 mL), air-dried, and then vacuum-dried to give 1-amino-2-(hexane-1-yn-1-yl)-5-methoxypyridin-1-onthium 2,4,6-trimethylbenzenesulfonate as a grayish-white solid (2.21 g, 65%). LCMS (General 3) RT: 0.40 min; Yield: 21.5%; m / z 199.4 (MH) - RT = 0.60, yield: 78.5%; m / z 205.4 (M+H) + ). 1 H NMR (299MHz, chloroform-d) δ9.44(d,J=2.4Hz,1H),7.53(d,J=9.1Hz,1H),7.39(dd,J=9.1,2.4Hz,1H),6.83(s,2H),4.11(s ,3H),2.71(s,6H),2.60(t,J=7.1Hz,2H),2.23(s,3H),1.73–1.60(m,2H),1.56–1.39(m,2H),0.97(t,J=7.3Hz,3H).

[0543] Step 3.2 2-Butyl-6-methoxypyrazolo[1,5-a]pyridine was prepared according to the following procedure. A solution of 1-amino-2-(hex-1-yn-1-yl)-5-methoxypyridine-1-onium 2,4,6-trimethylbenzenesulfonate (2.21 g, 1 eq, 5.46 mmol) in acetic acid (15.6 mL, 50 eq, 273 mmol) was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (55 mL), washed with saturated NaHCO3 (2 x 11 mL) and brine (11 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-butyl-6-methoxypyrazolo[1,5-a]pyridine (1.07 g, 95.9%) as a deep red oil. LCMS (General 3) RT: 1.25 min; Yield: 100%; m / z 205.4 (M+H) + ). 1H NMR (299MHz, chloroform-d) δ7.99 (dt, J=2.1, 0.8Hz, 1H), 7.28 (dd, J=9.6, 0.8Hz, 1H), 6.85 (dd, J=9.6, 2.2Hz, 1H), 6.21 (s,1H),3.79(s,3H),2.83–2.73(m,2H),1.72(tt,J=7.6,6.4Hz,2H),1.50–1.34(m,2H),0.95(t,J=7.3Hz,3H).

[0544] Step 4.2 2-Butylpyrazolo[1,5-a]pyridine-6-ol was prepared according to General Procedure A. 2-Butyl-6-methoxypyrazolo[1,5-a]pyridine yielded 2-butylpyrazolo[1,5-a]pyridine-6-ol as a brown solid (993 mg, 97%). LCMS (General 3) RT: 0.97 min; Yield: 94.4%; m / z 191.4, m / z 189.4 (MH) - . 1 H NMR (300MHz, chloroform-d) δ7.87 (dt, J=2.0, 1.0Hz, 1H), 7.16 (dd, J=9.5, 0.8Hz, 1H), 6.77 (dd, J=9.5, 2.0Hz, 1H ), 6.14(d,J=0.8Hz,1H),2.78–2.68(m,2H),1.75–1.60(m,2H),1.45–1.30(m,2H),0.90(t,J=7.3Hz,3H).

[0545] Step 5. (E)-(2-(((2-Butyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate was prepared according to General Procedure B. 2-Butyrazolo[1,5-a]pyridin-6-ol yielded (E)-(2-(((2-Butyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (98 mg, 47%), a pale yellow waxy substance. LCMS (General 3) RT: 1.46 min; Yield: 90.8%; m / z 378.3 (M+H) + ). 1H NMR (299MHz, chloroform-d) δ8.04–7.99(m,1H),7.31(dd,J=9.5,0.8Hz,1H),6.91–6.84(m,1H),6.76(d,J=81.8Hz,1H),6.23(s,1H),4.74(s, 1H),4.40(dd,J=3.7,1.1Hz,2H),4.06–3.96(m,2H),2.84–2.72(m,2H),1.79–1.65(m,2H),1.50–1.34(m,11H),0.95(t,J=7.3Hz,3H). 19 FNMR (282MHz, chloroform-d) δ -127.57 (d, J = 82.3Hz).

[0546] Step 6. ((E)-2-(((2-Butyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine bis(4-methylbenzenesulfonate) was prepared according to general experimental procedure C. Tert-butyl carbamate yielded ((E)-2-(((2-Butyrazolo[1,5-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)carbamate as a white solid (77 mg, 53%). LCMS (28817C TFA LCMS-5C-3.M) RT: 1.76 min; Yield: 98.2%; m / z 278.1 (M+H) + ). 1 HNMR(300MHz,DMSO-d6)δ8.43–8.35(m,1H),7.99(s,3H),7.53–7.16(m,6H),7.13–7.06(m,4H),7.00(dd,J=9.6,2.2Hz,1H),6.32(s,1H), 4.58(d,J=3.8Hz,2H),3.69–3.54(m,2H),2.69(t,J=7.6Hz,2H),2.27(s,6H),1.71–1.55(m,2H),1.41–1.25(m,2H),0.89(t,J=7.3Hz,3H). 19 F NMR (282MHz, DMSO-d6) δ-122.07 (d, J=82.1Hz).

[0547] Example 7

[0548] (E)-2-(((2-Butylimidazo[1,2-b]pyridazin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine-4-methylbenzenesulfonate

[0549]

[0550] Step 1. 2-Butyl-6-methoxyimidazo[1,2-b]pyridazine was prepared according to general experimental procedure D. 1-Bromohexane-2-one (735 mg, 1.2 eq, 4.10 mmol) was added to a stirred solution of 6-methoxypyridazine-3-amine (428 mg, 1 eq, 3.42 mmol) in EtOH (20 mL). The solution was heated to 80 °C and held for 1.5 hr. The reaction was then post-treated. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (20 mL), washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude residue was purified by automated rapid column chromatography to give 2-butyl-6-methoxyimidazo[1,2-b]pyridazine (384 mg, 55%) as a colorless oil. LCMS (General 3) RT: 1.07 min; Yield: 98%; m / z 206.2 (M+H) + ).

[0551] Step 2.2 2-Butylimidazo[1,2-b]pyridazine-6-ol was prepared according to General Procedure A. 2-Butyl-6-methoxyimidazo[1,2-b]pyridazine (171 mg, 0.83 mmol) yielded 2-butylimidazo[1,2-b]pyridazine-6-ol (137 mg, 86%) as a brown oil. LCMS (General 3) RT: 0.64 min; Yield: 74%; m / z 190.4 (M+H) + ).

[0552] Step 3. (E)-(2-(((2-Butylimidazo[1,2-b]pyridazin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate was prepared according to General Experimental Procedure B. 2-Butylimidazo[1,2-b]pyridazin-6-ol (89 mg, 0.47 mmol) yielded (E)-(2-(((2-Butylimidazo[1,2-b]pyridazin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (89 mg, 50%), as a yellow oil. 1H NMR (300MHz, chloroform-d) δ7.69(d,J=9.6Hz,1H),7.49(s,1H),6.80(d,J=82.1Hz,1H),6.60(d,J=9.6Hz,1H),4.85–4.6 6(m,3H),4.08–3.89(m,3H),2.76(t,J=7.7Hz,2H),1.82–1.63(m,3H),1.53–1.32(m,13H),0.95(t,J=7.3Hz,3H).

[0553] Step 4. (E)-2-(((2-Butylimidazo[1,2-b]pyridazin-6-yl)oxy)methyl)-3-fluoroprop-2-ene-1-amine-4-methylbenzenesulfonate was prepared according to general experimental procedure C.

[0554] (E)-(2-(((2-Butylimidazo[1,2-b]pyridazin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (89 mg, 0.24 mmol) yielded (E)-2-(((2-Butylimidazo[1,2-b]pyridazin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine-4-methylbenzenesulfonate (36.8 mg, 35%), as an orange solid. LCMS: (28817C TFA LCMS-5C-3.M) RT: 1.299 min; Yield: 88.45%; m / z 279.20 (M+H) + ). 1 H NMR (300MHz, DMSO-d6) δ8.15(d,J=10.4Hz,2H),8.00(s,3H),7.60–7.25(m,3H),7.16(d,J=9.7Hz,1H),7.09(d,J=7.9Hz,3H),4.88(d,J =3.5Hz,2H),3.67(d,J=6.3Hz,4H),2.74(t,J=7.3Hz,3H),2.27(s,5H),1.66(p,J=7.6Hz,2H),1.41–1.25(m,3H),0.90(t,J=7.3Hz,3H)

[0555] Example 8

[0556] (E)-2-(((2-Butyrylpyrazolo[1,5-a]pyridin-5-yl)oxy)methyl)-3-fluoroprop-2-ene-1-amine bis(4-methylbenzenesulfonate)

[0557]

[0558] Step 1. 1-Amino-4-methoxypyridine-1-onthium 2,4,6-trimethylbenzenesulfonate was prepared according to the following procedure. O-(trimethylbenzenesulfonyl)hydroxylamine (2.58 g, 1.2 eq, 12 mmol) suspended in DCM (24 mL) was slowly added to a stirred solution of 4-methoxypyridine (1.09 g, 1 eq, 10 mmol) cooled to 0 °C in DCM (20 mL). The mixture was stirred at 0 °C for 3 hours, then additional MesSO3NH2 (0.65 g) in DCM (6 mL) was added, and the mixture was stirred for 2.5 days. Et2O (200 mL, 4 V) was added; a white paste was separated. The liquid layer was decanted, the paste was washed with Et2O (50 mL), and dried under vacuum to give crude 1-amino-4-methoxypyridine-1-onthium 2,4,6-trimethylbenzenesulfonate (3.51 g, 45%). Purity determined by ¹H NMR: 42%. 1 H NMR(300MHz,DMSO-d6)δ8.63–

[0559] 8.57(m,2H),7.35–7.29(m,2H),6.71(s,2H),4.04(s,3H),2.53(s,6H),2.14(s,3H).

[0560] Step 2.2 Butyl-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate was prepared according to the following procedure. Ethyl 1-amino-4-methoxypyridine-1-onthium 2,4,6-trimethylbenzenesulfonate (3.51 g, 1 eq, 4.5 mmol) was dissolved in anhydrous DMF (15.5 mL), followed by the sequential addition of ethyl hepta-2-acetylacetate (1.9 g, 2.1 mL, 2.7 eq, 12 mmol) and potassium carbonate (1.7 g, 2.7 eq, 12 mmol). The mixture was stirred overnight at 100 °C. An additional ethyl hepta-2-acetylacetate (2.8 g, 3.1 mL, 4.0 eq, 18 mmol) was added, and the mixture was stirred at 100 °C for another day. No further reaction was observed by HPLC. The mixture was cooled to room temperature and then treated with water (62 mL, 4V) and brine (16 mL), followed by extraction with AcOEt (4 × 62 mL). The organic layer was washed with water / brine 1:1 (2 x 62 mL) and brine (62 mL), dried over Na₂SO₄, filtered, and evaporated to give 5.12 g of a dark oil. 2-Butyl-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate was purified by automated rapid chromatography as an orange solid (410 mg, 33%). LCMS (General 3) RT: 1.39 min; Yield: 97.5%; m / z 277.3 (M+H) + ). 1HNMR (300MHz, chloroform-d) δ8.22(dd,J=7.5,0.7Hz,1H),7.41(d,J=2.8Hz,1H),6.54(dd,J=7.5,2.8Hz,1H),4.37(q,J=7 .1Hz,2H),3.91(s,3H),3.07–2.97(m,2H),1.82–1.67(m,2H),1.42(td,J=7.4,3.8Hz,5H),0.96(t,J=7.3Hz,3H).

[0561] Step 3.2 2-Butyl-5-methoxypyrazolo[1,5-a]pyridine was prepared according to the following procedure. Solid 2-butyl-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (410 mg, 1 eq, 1.48 mmol) was added sequentially to water (3.0 mL), 95% H₂SO₄ (1.7 mL, 20 eq, 29.7 mmol), and 1,4-dioxane (6.0 mL). The warm mixture was further heated at 100 °C for 40 h. After cooling to room temperature, the mixture was diluted with water (33 mL) and carefully alkalized with solid sodium carbonate (3.46 g, 22 eq, 32.6 mmol). The resulting mixture was extracted with AcOEt (3 × 45 mL), dried on Na₂SO₄, and evaporated to dryness. 2-Butyl-5-methoxypyrazolo[1,5-a]pyridine was purified by automated rapid chromatography as an orange oil (161 mg, 53%). LCMS (General 3) RT: 1.18 min; Yield: 99.6%; m / z 205.2 (M+H) + ). 1 ¹H NMR (300MHz, chloroform-d) δ 8.17 (dt, J = 7.5, 0.8Hz, 1H), 6.63 (dd, J = 2.7, 0.7Hz, 1H), 6.34 (dd, J = 7.6, 2.7Hz, 1H), 6.10 (d, J = 0.8Hz, 1H), 3.82 (s, 3H), 2.82–2.70 (m, 2H), 1.79–1.63 (m, 2H), 1.49–1.33 (m, 2H), 0.95 (t, J = 7.3Hz, 3H).

[0562] Step 4.2 2-Butylpyrazolo[1,5-a]pyridine-5-ol was prepared according to General Procedure A. 2-Butyl-5-methoxypyrazolo[1,5-a]pyridine (161 mg, 0.79 mmol) yielded 2-butylpyrazolo[1,5-a]pyridine-5-ol as a brown solid (144 mg, 89%). LCMS (General 3) RT: 0.89 min; Yield: 95.6%; m / z 191.4, m / z 189.3 (MH) - .1 HNMR (300MHz, chloroform-d) δ9.50 (s, 1H), 8.14 (dt, J = 7.5, 0.8Hz, 1H), 6.72 (dd, J = 2.6, 0.7Hz, 1H), 6.36 (dd, J = 7.5, 2. 6Hz, 1H), 6.04 (d, J = 0.8Hz, 1H), 2.81–2.71 (m, 2H), 1.78–1.63 (m, 2H), 1.48–1.31 (m, 2H), 0.91 (t, J = 7.3Hz, 3H).

[0563] Step 5. (E)-(2-(((2-Butyrazolo[1,5-a]pyridin-5-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate was prepared according to General Procedure B. This procedure yielded (E)-(2-(((2-Butyrazolo[1,5-a]pyridin-5-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate as a pale yellow waxy substance (28 mg, 24%). LCMS (General 3) RT: 1.36 min; Yield: 96.7%; m / z 378.4, m / z 376.5 (MH) - . 1 H NMR (300MHz, chloroform-d) δ8.18 (dt, J=7.6, 0.8Hz, 1H), 6.76 (dt, J=81.9, 1.1Hz, 1H ),6.65(d,J=2.7Hz,1H),6.34(dd,J=7.5,2.7Hz,1H),6.10(d,J=0.8Hz,1H), 4.76(s,1H),4.47–4.40(m,2H),4.00(dd,J=6.6,2.3Hz,2H),2.82–2.70(m,2 H),1.79–1.64(m,2H),1.49–1.36(m,2H),1.41(s,9H),0.94(t,J=7.3Hz,3H). 19 F NMR (282MHz, chloroform-d) δ -128.06 (d, J = 81.9Hz).

[0564] Step 6. (E)-2-(((2-Butylapazolo[1,5-a]pyridin-5-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine bis(4-methylbenzenesulfonate) was prepared according to general experimental procedure C. (E)-(2-(((2-Butylapazolo[1,5-a]pyridin-5-yl)oxy)methyl)-3-fluoroallyl)carbamate tert-butyl ester (28 mg, 0.074 mmol) yielded (E)-2-(((2-Butylapazolo[1,5-a]pyridin-5-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine bis(4-methylbenzenesulfonate), a white solid (29 mg, 63%). LCMS (28817C TFA LCMS-5C-3.M) RT: 1.67 min; Yield: 94.9%; m / z 278.2 (M+H) + ). 1 H NMR(300MHz,DMSO-d6)δ8.45(d,J=7.5Hz,1H),8.00(s,3H),7.51–7.46(m,4H),7.38 (d,J=81.8Hz,1H),7.13(d,J=7.9Hz,4H),6.99(d,J=2.7Hz,1H),6.52(dd,J=7.5,2. 7Hz,1H),6.22(s,1H),4.63(d,J=3.6Hz,2H),3.73–3.61(m,2H),2.69(t,J=7.6Hz,2 H), 2.30 (s, 6H), 1.66 (p, J = 7.7Hz, 2H), 1.36 (h, J = 7.3Hz, 2H), 0.92 (t, J = 7.3Hz, 3H). 19 F NMR (282MHz, DMSO-d6) δ-121.98 (d, J = 81.4Hz).

[0565] Example 9

[0566] (Z)-2-(((2-Cyclopentylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine-4-methylbenzenesulfonate

[0567]

[0568] Step 1. 2-Cyclopentyl-6-methoxyimidazo[1,2-a]pyridine was prepared according to general experimental procedure D. 2-Bromo-1-cyclopentylethyl-1-one was used. LCMS (general 3) RT: 0.90 min; Yield: 85%; m / z 217.4 (M+H) + ).

[0569] Step 2.2 2-Cyclopentylimidazo[1,2-a]pyridine-6-ol was prepared according to General Procedure A. 2-Cyclopentyl-6-methoxyimidazo[1,2-a]pyridine (725 mg, 3.35 mmol) yielded 2-cyclopentylimidazo[1,2-a]pyridine-6-ol (315 mg, 47%) as a brown solid. LCMS (General 3) RT: 0.60 min; Yield: 77%; m / z 203.4 (M+H) + ).

[0570] Step 3. (Z)-(2-(((2-cyclopentylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate was prepared according to General Procedure B. 2-Cyclopentylimidazo[1,2-a]pyridin-6-ol (190 mg, 0.94 mmol) yielded (Z)-(2-(((2-cyclopentylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (94 mg, 26%) as a brown oil. LCMS (General 3) RT: 1.16 min; Yield: 83%; m / z 390.3 (M+H) + ).

[0571] Step 4. (Z)-2-(((2-Cyclopentylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate was prepared according to general experimental procedure C. (Z)-(2-(((2-Cyclopentylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (94 mg, 0.24 mmol) yielded (Z)-2-(((2-Cyclopentylimidazo[1,2-a]pyridin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate (38 mg, 34%), a beige solid. LCMS: (28817C TFA LCMS-5C-3.M) RT: 1.357 min; Yield: 93%; m / z 290.1 ​​(M+H) + NMR: 1 H NMR (300MHz, DMSO-d6) δ8.40(d,J=2.3Hz,1H),8.05(s,3H),7.79(s,1H),7.58(d,J=9.7Hz,1H),7.46(d,J=8.1Hz,2H),7.42–7.25(m,1H), 7.09(d,J=8.0Hz,3H),4.72(d,J=2.7Hz,2H),3.57(d,J=3.0Hz,2H),3.24–3.08(m,1H),2.27(s,3H),2.12–1.89(m,2H),1.85–1.52(m,6H).

[0572] Example 10

[0573] (E)-(2-(((2-Butylimidazo[1,2-a]pyrimidin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate

[0574]

[0575] Step 1. 2-Butyl-6-methoxyimidazo[1,2-a]pyrimidine was prepared according to General Experimental Procedure 16. 5-Methoxypyrimidine-2-amine (594 mg, 4.75 mmol) yielded 2-butyl-6-methoxyimidazo[1,2-a]pyrimidine (178 mg, 16%) as a yellow solid. LCMS (General 3): RT: 0.71 min, yield: 90%, m / z 206.4 (M+H) + ).

[0576] Step 2.2 2-Butylimidazo[1,2-a]pyrimidin-6-ol was prepared according to General Experimental Procedure 2. 2-Butyl-6-methoxyimidazo[1,2-a]pyrimidine (178 mg, 0.867 mmol) yielded (E)-(2-(((2-butylimidazo[1,2-a]pyrimidin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (105 mg, 61%), as a pale brown solid. LCMS (General 3): RT: 0.52 min, yield: 97%, m / z 192.4 (M+H) + ).

[0577] Step 3. (E)-(2-(((2-Butylimidazo[1,2-a]pyrimidin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate was prepared according to General Experimental Procedure 3. (E)-(2-(((2-Butylimidazo[1,2-a]pyrimidin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (105 mg, 0.55 mmol) yielded (E)-(2-(((2-Butylimidazo[1,2-a]pyrimidin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (30 mg, 15%), as a brown solid. LCMS (General 3): RT: 1.03 min, Yield: 99%, m / z 379.3 (M+H) + ).

[0578] Step 3. (E)-2-(((2-Butylimidazo[1,2-a]pyrimidin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate was prepared according to General Experimental Procedure 5. (E)-(2-(((2-Butylimidazo[1,2-a]pyrimidin-6-yl)oxy)methyl)-3-fluoroallyl)tert-butyl carbamate (30 mg, 0.79 mmol) yielded (E)-2-(((2-Butylimidazo[1,2-a]pyrimidin-6-yl)oxy)methyl)-3-fluoroprop-2-en-1-amine 4-methylbenzenesulfonate (28 mg, 79%), a brown solid. LCMS (28817CTFA LCMS-5C-3.M) RT: 1.224 min; Yield: 98.52%; m / z 279.20 (M+H) + ). 1 HNMR (299MHz, methanol-d4) δ8.61(d,J=2.9Hz,1H),8.47(d,J=2.9Hz,1H),7.72–7.66(m,2H),7.59(s,1H),7.27(d,J=80 .6Hz,1H),7.25–7.19(m,2H),4.68(dd,J=3.5,1.0Hz,2H),3.91–3.83(m,2H),2.79(t,J=7.6Hz,2H),2.35(s,3H).

[0579] Example 11

[0580] Biological samples and assays

[0581] The following general materials and methods are used when indicated, or may be used in the examples. Standard methods in molecular biology are described in the scientific literature (see, for example, Sambrook and Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; and Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc., New York, NY, which describe cloning and DNA mutagenesis in bacterial cells (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugate and protein expression (Vol. 3), and bioinformatics (Vol. 3).

[0582] VAP-1 determination

[0583] The ability of the compounds described herein to inhibit the enzymatic activity of vascular adhesion protein-1 (VAP-1) was determined by fluorescence assay. The assay procedure, provided by R&D Systems, was slightly modified for use as an inhibitor screening assay. This assay involves reacting horseradish peroxidase (HRP) and H2O2... Red was converted to the fluorescent product resorufm, and the H2O2 generated by the oxidative deamination of benzylamine in rhVAP-1 was measured. The reaction buffer was 10 mM NaHCO3, pH 7.4. A standard curve was prepared by serially diluting H2O2 in the reaction buffer. A 10 μM resorufm solution was prepared in the reaction buffer and dispensed into two wells. These wells served as positive controls for maximum fluorescence. The reaction buffer was added to each well to make a final volume of 100 μL in each well. Amplex Red was diluted to 1 mM in the reaction buffer. A 10 U HRP stock solution was prepared in the reaction buffer. The reaction mixture was prepared by mixing equal parts of 1 mM Amplex Red and 10 U HRP with three parts of the reaction buffer. The reaction mixture was added to the appropriate wells to make a final concentration of 0.05 mM Amplex Red and 0.5 U HRP in the wells. A 200 μM benzylamine solution was prepared in the reaction buffer. Benzylamine was added to the appropriate wells to make a final concentration of 50 μM. The inhibitor was diluted 20-fold in DMSO and then dispensed into appropriate wells. LJP-1207 was used as a positive control. rhVAP-1 was purchased from R&D Systems. The concentration used for each batch was determined to ensure that the activity was equal to that of the first batch. Two wells were left empty as controls. The plates were incubated at 37°C for 30 minutes under foil in the dark. The plates were read at 530 / 35 emission and 590 / 35 excitation. Data were processed using Excel and Prism software.

[0584] MAO measurement

[0585] Using a modified Promega MAO-Glo TMThe analytical kit determined the ability of the compounds described herein to inhibit MAO. The substrate ((4S)-4,5-dihydro-2-(6-hydroxybenzothiazolyl)-4-thiazocarboxylic acid) was converted to methyl fluorescein via MAO. The fluorescein was then converted to oxidized fluorescein and light by luciferase. Light was measured using the luminescence setting on a microplate reader. Standard curves were prepared by serially diluting the fluorescein in reaction buffer. The standard kit reaction buffer was 100 mM HEPES (pH 7.5), 5% glycerol. Substrate was dispensed into wells to achieve a final concentration of 10 μM for the MAO-A inhibition assay and 1 μM for the MAO-B inhibition assay. Inhibitors were diluted 4-fold in DMSO and then dispensed into appropriate wells. Clorgyline and Deprenyl were used as positive controls. rhMAO-A and rhMAO-B were purchased from Sigma. MAO-A or MAO-B was added to the appropriate wells. The plate was incubated at room temperature with gentle shaking (90 rpm) for 1 hour. Add an equal volume of the detection reagent (48 μL of detection reagent to 48 μL of reaction). Incubate the plate gently with shaking (90 rpm) at room temperature for 20 minutes. Read the luminescence from the plate. Process the data using Prism software.

[0586] Using a modified Promega MAO-Glo TM The ability of the compounds described herein to inhibit MAO was determined. Following the manufacturer's instructions, the test compound / substrate and enzyme were incubated at room temperature with gentle shaking (90 rpm) for 1 hour, followed by the addition of the assay reagent. An equal volume of assay reagent was added (48 μL assay reagent to 48 μL reaction). The plate was then incubated at room temperature with gentle shaking (90 rpm) for 20 minutes. The plate was read for luminescence. Data processing was performed using Prism software.

[0587] The ability of the compounds described herein to inhibit the enzymatic activity of vascular adhesion protein-1 (VAP-1) was determined by fluorescence assay. The assay procedure, provided by R&D Systems, was slightly modified for use as an inhibitor screening assay. This assay involves reacting horseradish peroxidase (HRP) and H2O2... The red colorant was converted to the fluorescent product resorufm, and the H2O2 generated from the oxidative deamination of benzylamine by rhVAP-1 was measured. Amplex Red, HRP, benzylamine, inhibitor (0.5% v / v using DMSO as a medium), and rhVAP-1 were added to the wells. The determination was performed in 10 mM NaHCO3 at pH 7.4. A standard curve was prepared by serially diluting H2O2 in the reaction buffer. The plate was incubated at 37 °C for 30 min under a foil in the dark. The plate was read at 530 / 35 emission and 590 / 35 excitation. Data processing was performed using Prism software.

[0588] The activities of several compounds of this disclosure were determined using the assays described herein. The potency levels are listed in Table 1.

[0589] Table 1

[0590]

[0591]

[0592]

[0593] Biochemical test IC 50 The data is given within the following range:

[0594] A: ≤0.10μM C: >1.0μM to ≤10μM

[0595] B: >0.10μM to ≤1.0μM D: >10μM to 30μM

[0596] Although this disclosure has been described with reference to the above embodiments, it should be understood that modifications and variations are included within the spirit and scope of this disclosure. Therefore, this disclosure is defined only by the appended claims.

Claims

1. Compounds with structural formula (IV): (IV), Or its pharmaceutically acceptable salt; in: X 1 and X 4 Independently N or CH; where X 1 and X 4 At least one of them is N independently; X 5 For N or CR 5 ; X 6 For N or CR 6 ; Y is –O–; z1 is 1; m5 and m6 are both 2; L 1 For key; R 1 Independently hydrogen, halogen, –CX 1.1 3. -CHX 1.1 2. -CH2X 1.1 –CN, –OCX 1.1 3. –OCHX 1.1 2. Unsubstituted C1-C6 alkyl or unsubstituted C3-C6 cycloalkyl; R 2 It is hydrogen; R 3 and R 4 Independently hydrogen or –F; R 5 It is hydrogen, halogen, or unsubstituted C1-C6 alkyl; R 6 It is hydrogen, halogen, or unsubstituted C1-C6 alkyl; and X 1.1 It can be independently –Cl, –Br, –I, or –F.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 It can be hydrogen or halogen independently.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 It can be hydrogen, –F, –Br or –CH3 independently.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 3 For –F.

5. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen.

6. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 4 For –F.

7. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 4 It is hydrogen.

8. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, comprising a mixture of compounds having the following definition: R 3 For –F and R 4 It is hydrogen; or R 3 It is hydrogen and R 4 For –F.

9. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, comprising a mixture of (E)- and (Z)-olefin isomers.

10. The compound according to claim 9, wherein the ratio of the (E)-isomer or a pharmaceutically acceptable salt thereof to the (Z)-isomer or a pharmaceutically acceptable salt thereof is from 10:1 to 1:

10.

11. The compound according to claim 9, wherein the ratio of the (E)-isomer or a pharmaceutically acceptable salt thereof to the (Z)-isomer or a pharmaceutically acceptable salt thereof is 5:1 to 1:

5.

12. The compound according to claim 9, wherein the ratio of the (E)-isomer or a pharmaceutically acceptable salt thereof to the (Z)-isomer or a pharmaceutically acceptable salt thereof is 1:

1.

13. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 It is an unsubstituted C1-C6 alkyl group.

14. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 It is –(CH2)3CH3.

15. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 It is an unsubstituted C3-C6 cycloalkyl group.

16. A compound, wherein the compound is: Or its pharmaceutically acceptable salt.

17. A pharmaceutical composition comprising the compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

18. The pharmaceutical composition of claim 17, wherein the at least one pharmaceutically acceptable excipient is a pharmaceutically acceptable ophthalmic carrier.

19. Use of any compound of claims 1-16 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating an ophthalmic disease or condition in a subject in need, wherein said ophthalmic disease or condition is uveitis.

20. The use according to claim 19, wherein the drug formulation is for topical application.

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