2-Amino-S6-substituted thiopurine compounds as ENPP1 proteins

Abstract

Provided herein are compounds, pharmaceutical compositions, and methods that can be used to treat cancer, infectious diseases, and other conditions associated with ectonucleotide pyrophosphatase pyrophosphatase-phosphodiesterase (ENPP1) dysfunction.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit and priority of Indian Provisional Application No. 20141037291, filed on September 16, 2019, and Indian Provisional Application 204201017699, filed on April 24, 2020. Each of them is hereby incorporated by reference in its entirety for all purposes.

Background Art

[0002] Background Ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family members include seven isoforms, ENPP1 - 7, which are type II transmembrane glycoproteins or ecto - enzymes. One isoform, ENPP1 (plasma membrane glycoprotein - 1, PC - 1), is involved in many physiological processes such as development, formation, and transport, as well as pathophysiological conditions. Abnormal ENPP1 expression has been detected in breast cancer compared to normal breast epithelium, and there is evidence of its potential in bone metastasis (occurring in about 80% of cases), Hodgkin lymphoma, hepatocellular carcinoma, follicular lymphoma, glioblastoma, and other malignant tumor tissues. Furthermore, mutations in ENPP1 are associated with several disorders including infantile arterial calcification (generalized arterial calcification of infancy or GACI), ossification of the posterior longitudinal ligament of the spine, and insulin signaling and resistance. ENPP1 expression is high in bone and cartilage and is involved in pulmonary and renal fibrosis. A correlation has also been observed between ENPP1 expression and the malignancy classification of astrocytomas. Another study reported that ENPP1 is required to maintain the undifferentiated and proliferative state of glioblastoma stem - like cells. Therefore, ENPP1 appears to be a viable target for the development of novel anti - cancer agents, cardiovascular, diabetes, obesity, and anti - fibrosis therapeutic agents. Furthermore, ENPP1 activity is also involved in diseases caused by bacteria and / or viruses, and thus, modulators of ENPP1 may be useful for the treatment of bacterial and / or viral diseases and conditions.

Summary of the Invention

[0003] Brief Summary This specification describes various embodiments related to compounds, compositions, and methods useful for treating diseases and conditions associated with ENPP1 deficiency. In some embodiments, the compounds disclosed herein are inhibitors of ENPP1.

[0004] In some embodiments, the present disclosure provides a compound of formula (X), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof.

[0005] [Chemical Formula]

[0006] Wherein, L is alkylene, alkenylene, alkylene-S-, alkylene-O-, optionally substituted -alkylene-(NR 5 )-, optionally substituted

[0007] [Chemical Formula]

[0008] optionally substituted

[0009] [Chemical Formula]

[0010] optionally substituted

[0011] [Chemical Formula]

[0012] optionally substituted

[0013] [Chemical Formula]

[0014] Is arbitrarily replaced

[0015] [Chem.]

[0016] Is arbitrarily replaced

[0017] [Chem.] Is arbitrarily replaced

[0018] [Chem.]

[0019] [Chem.]

[0020] Is a linker selected from; U is S or NH; V is OH, NR 2 N 3 Or V and Y 1 And together with the atoms to which they are attached, form an optionally substituted phenyl or pyridinyl ring; W is CH or N; X is O, S, NR 6 ,-CH=CH-, or -CH=N-; Y 1 And Y 2 Are each independently CH or N; R 1 Is H, OH, O-alkyl, alkyl or carbocyclic; R 2 And R 3 Are each independently H, alkyl, alkenyl, or -C(O)alkyl; R 4is carbocyclic, heterocyclic, aryl, or heteroaryl, each of which may be optionally substituted; R 5 is H, alkyl, -C(O)alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 6 is H, alkyl, carbocyclic, alkylene carbocyclic, alkylene aryl, -C(O)alkyl, or -C(O)alkenyl; R 7 is carbocyclic, heterocyclic, or heteroaryl; m is 0, 1, or 2; n is 1, 2, or 3.

[0021] In a further embodiment, the disclosure provides a compound of formula (Y), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof.

[0022]

Chemical formula

[0023] wherein U is C or N; here when U is C, Y is

[0024]

Chemical formula

[0025] ; or when U is N, Y is

[0026]

Chemical formula

[0027] ; V is N or CR 10 ; W is CH or N; X is S, O, N-L-R 11 , or NR 12 ; L is alkylene, alkenylene, optionally substituted -alkylene-(NR 12 )-, optionally substituted

[0028]

Chemical formula

[0029] optionally substituted

[0030]

Chemical formula

[0031] optionally substituted

[0032]

Chemical formula

[0033] optionally substituted

[0034]

Chemical formula

[0035] optionally substituted

[0036]

Chemical formula

[0037]

Chemical formula

[0038] selected from; R 10is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, alkylene carbocyclic, -O-L-R 11 , -S-L-R 11 , -N(R 12 )-L-R 11 , -L-R 11 ; R 11 is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl, each of which may be optionally substituted; R 12 are each independently H, alkyl, alkylene carbocyclic, or carbocyclic, where two R 12 groups, when combined with the carbon atom to which they are attached, can form a heterocyclic ring; R 14 is carbocyclic, heterocyclic, or heteroaryl; R 15 is H, alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; where, when X is N-L-R 11 , V is N or CR 10 , and R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, or alkylene carbocyclic; when X is S, O, NR 12 , V is CR 10 , and R 10 is -O-L-R 11 , -S-L-R 11 , -N(R 12 )-L-R 11 , or -L-R 11 ; when U is N, V is CR 10 , and R 10 is -O-L-R 11 , -S-L-R 11 , -N(R 12 )-L-R 11 , or -L-R 11 ; Z 1 , Z2 , Z 3 , and Z 4 is each independently CR 13 or N; R 13 is H, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oaryl, -C(O)Oalkylenearyl, -C(O)oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN, where two Rs 13 together with the atoms to which they are attached can form a carbocyclic, heterocyclic, or heteroaryl, each optionally substituted; m is 0, 1, or 2; n is 1, 2, or 3.

[0039] In yet another embodiment, the disclosure provides a compound of formula (ZZ), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof.

[0040] [Chemical formula]

[0041] wherein (a) One of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is -L-R 18 -; (b) Two or less of Z 1 , Z 2 , Z 3 or Z 4 are N; and (c) Either Z 6 or Z 7 is N Under the condition that Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and Z 7 are each independently N or CR 22 ; Here, L is a linker selected from -N(R 19 ), -alkylene-(NR 19 ),

[0042]

Chemical formula

[0043] and each is optionally substituted; R 18 is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl, and each of these is optionally substituted; R 19 is H, alkyl, carbocyclic, alkylenecarbocyclic, or alkylenearyl; R 20 is H, alkyl, alkylenecarbocyclic, alkylenearyl; R 21 is carbocyclic, heterocyclic, or heteroaryl; R 22 are each independently halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN; m is 0, 1, or 2; n is 1, 2, or 3.

[0044] Those skilled in the art will understand that the drawings are mainly for illustrative purposes and are not intended to limit the scope of the subject matter of the invention described herein.

Brief Description of the Drawings

[0045]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

DETAILED DESCRIPTION OF THE INVENTION

[0046] All definitions defined and used herein are to be understood to control dictionary definitions, definitions in incorporated documents by reference, and / or the ordinary meaning of defined terms. The use of flow diagrams is not meant to be limiting with respect to the order of operations performed for all embodiments. In the specification and claims, the indefinite articles "a" and "an" as used herein are to be understood to mean "at least one" unless expressly indicated to the contrary.

[0047] Throughout this specification, references to "one embodiment" or "an embodiment" etc. mean that the particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places in this specification are not necessarily all referring to the same embodiment. Further, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms include "a", "an", and "the" unless the context clearly dictates otherwise. Note also that the term "or" is generally used in its sense including "and / or" unless the context clearly dictates otherwise.

[0048] As used in this specification and the claims, the phrase "at least one" referring to a list of one or more elements means at least one element selected from any one or more of the elements in the list of elements, but does not necessarily include at least one of each and every element specifically listed in the list of elements, and is not to be construed as excluding any combinations of elements in the list of elements. This definition also allows for elements to optionally exist, whether or not related, in addition to those specifically identified in the list of elements referred to by the phrase "at least one". Thus, by way of non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently "at least one of A and / or B") may, in one embodiment, include at least one, optionally two or more, of A and no B (and optionally include elements other than B). In another embodiment, it may include at least one, optionally two or more, of B and no A (and optionally include elements other than A). In yet another embodiment, it may include at least one, optionally two or more, of A and at least one, optionally two or more, of B (and optionally include other elements), and so on.

[0049] In the claims, as well as in the above specification, all transitional phrases such as "comprising", "including", "carrying", "having", "containing", "involving", "holding", "consisting of", etc. are to be understood to mean non-limiting, i.e., including but not limited to. As described in Section 2111.03 of the United States Patent and Trademark Office's Manual of Patent Examining Procedure, only the transitional phrases "consisting of" and "consisting essentially of" must be closed or semi-closed transitional phrases, respectively.

[0050] "Alkyl" or "alkyl group" refers to a fully saturated, straight-chain or branched hydrocarbon chain radical that is bonded to the remainder of the molecule by a single bond. Alkyls containing any number of carbon atoms from 1 to 12 are included. Alkyls containing up to 12 carbon atoms are C1-C 12 alkyl, and alkyls containing up to 10 carbon atoms are C1-C 10 alkyl. Alkyls containing up to 6 carbon atoms are C1-C6 alkyls, and alkyls containing up to 5 carbon atoms are C1-C5 alkyls. C1-C5 alkyls include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyls include all of the foregoing parts for C1-C5 alkyls, but also include C6 alkyl. C1-C 10 alkyl includes all of the foregoing parts for C1-C5 alkyls and C1-C6 alkyls, but also includes C7, C8, C9, and C 10 alkyl. Similarly, C1-C 12 alkyl includes all of the foregoing parts, but also includes C 11 and C 12 alkyl. C1-C 12Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated in the specification, the alkyl group may be optionally substituted.

[0051] "Alkylene" or "alkylene chain" refers to a fully saturated, straight-chain or branched-chain divalent hydrocarbon chain radical. Alkylene containing any number of carbon atoms from 1 to 12 is included. C1-C 12 Non-limiting examples of alkylene include dimethylene, ethylene, propylene, n-butylene, ethynylene, propenylene, n-butynylene, propynylene, n-butynylene, etc. The alkylene chain is bonded to the rest of the molecule via a single bond and to a radical group via a single bond. The bonding points of the alkylene chain to the rest of the molecule and the radical group can be through one carbon or any two carbons within the chain. Unless otherwise specifically stated in the specification, the alkylene chain can be optionally substituted.

[0052] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched-chain hydrocarbon chain group having 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is bonded to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are C2-C 12 is alkenyl, and alkenyl containing up to 10 carbon atoms is C2-C 10 is alkenyl, and alkenyl groups containing up to 6 carbon atoms are C2-C6 alkenyl, and alkenyl containing up to 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all the parts described above for C2-C5 alkenyl, but also includes C6 alkenyl. C2~C 10Alkenyl includes all of the portions described above with respect to C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9 and C 10 alkenyl. Similarly, C2-C 12 alkenyl includes all of the foregoing portions, but also includes C 11 and C 12 alkenyl. Non-limiting examples of C2-C 12 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Examples of C1-C3 alkyl include methyl, ethyl, n-propyl, and i-propyl. Examples of C1-C4 alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and sec-butyl. Unless otherwise specified herein, alkyl groups can be optionally substituted.

[0053] "Alkenylene" or "alkenylene chain" refers to a linear or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. 12 Non-limiting examples of alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or two carbons within the chain. Unless stated otherwise in the specification, an alkenylene chain can be optionally substituted.

[0054] "Alkynyl" or "alkynyl group" refers to a straight or branched hydrocarbon chain radical having from 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the remainder of the molecule by a single bond. Alkynyl groups containing any number of carbon atoms from 2 to 12 are included. Alkynyl groups containing up to 12 carbon atoms are C2-C 12 Alkynyl containing up to 10 carbon atoms is C2-C 10 An alkynyl group containing up to 6 carbon atoms is C2-C6 alkynyl, and an alkynyl group containing up to 5 carbon atoms is C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl, and C2 alkynyl. C2-C6 alkynyl includes all of the moieties listed above for C2-C5 alkynyl, but also includes C6 alkynyl. C2-C 10 Alkynyl includes all of the moieties listed above for C2-C5 alkynyl and C2-C6 alkynyl, but also includes C7, C8, C9 and C 10 Alkynyl is also included. Similarly, C2-C 12 Alkynyl includes all of the above moieties, but C 11 and C 12 Alkynyl is also included. C2-C 12 Non-limiting examples of alkenyls include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted.

[0055] "Alkynylene" or "alkynylene chain" refers to a straight-chain or branched-chain divalent hydrocarbon radical having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. C2-C 12 Non-limiting examples of alkynylene include ethynylene, propargylene, and the like. The alkynylene chain is bonded to the remainder of the molecule via a single bond and to a radical group via a single bond. The points of attachment to the remainder of the alkynylene chain and the radical group can be via one carbon or any two carbons within the chain. Unless otherwise specified in the specification, the alkynylene chain can be optionally substituted.

[0056] "Alkoxy" refers to a radical of the formula -OR a wherein R a is an alkyl, alkenyl, or alkynyl radical as defined above containing 1 to 12 carbon atoms. Unless otherwise specified in the specification, the alkoxy group can be optionally substituted.

[0057] "Alkylamino" refers to a radical of the formula -NHR a or -NR a wherein each R a is independently an alkyl, alkenyl, or alkynyl radical as defined above containing 1 to 12 carbon atoms. Unless otherwise specified in the specification, the alkylamino group can be optionally substituted.

[0058] "Alkylcarbonyl" refers to a -C(=O)R a moiety, where R a is an alkyl, alkenyl, or alkynyl radical as defined above. A non-limiting example of alkylcarbonyl is a methylcarbonyl ("acetyl") moiety. The alkylcarbonyl group can also be referred to as "Cw-Cz acyl", where w and z indicate the range of the number of carbon atoms in R a as defined above. For example, "C1-C 10 acyl" refers to an alkylcarbonyl group as defined above, where R a is C1-C 10 alkyl, C1-C10 An alkenyl, or a C1-C 10 is an alkynyl radical. Unless otherwise specified in the specification, the alkylcarbonyl group may be optionally substituted.

[0059] "Aryl" refers to a hydrocarbon ring system group containing hydrogen, 5 to 18 carbon atoms, and at least one aromatic ring. For the purposes of the present invention, the aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which may contain a fused ring system or a bridged ring system. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, sindacene, indene, indene, naphthalene, phenalene, phenanthrene, pyrene, and triphenylene. Unless otherwise specifically stated in the specification, the term "aryl" means including an aryl group which may be optionally substituted.

[0060] "Alkylene aryl" refers to a radical of the formula R b R c wherein R b is the alkylene as defined above, and R c is one or more aryl radicals as defined above. Examples include benzyl, diphenylmethyl, etc. Unless otherwise specified in the specification, the aralkyl group can be optionally substituted.

[0061] "Carbocyclic", "carbocyclic ring" or "carbon ring" refers to a ring structure, where the atoms forming the ring are each carbon. The carbocyclic ring can contain 3 to 20 carbon atoms in the ring. The carbocyclic ring includes cycloalkyl. The cycloalkenyl and cycloalkynyl as defined in the present specification are included. Unless otherwise specified in the specification, the carbocyclic group can be optionally substituted.

[0062] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms, including a condensed or bridged ring system having 3 to 20 carbon atoms, for example 3 to 10 carbon atoms, and is bonded to the rest of the molecule by a single bond. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, etc. Unless otherwise specifically described in the specification, the cycloalkyl group can be arbitrarily substituted.

[0063] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, having one or more carbon-carbon double bonds, including a condensed or bridged ring system, having 3 to 20 carbon atoms, for example 3 to 10 carbon atoms, and is bonded to the rest of the molecule by a single bond, and refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group. Monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyl groups include, for example, bicyclo[2.2.1]hept-2-enyl, etc. Unless otherwise specifically described in the specification, the cycloalkenyl group can be arbitrarily substituted.

[0064] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, having one or more carbon-carbon triple bonds, having 3 to 20 carbon atoms, for example 3 to 10 carbon atoms, and is bonded to the rest of the molecule by a single bond, and may include a condensed or bridged ring system, and refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group. Monocyclic cycloalkynyl groups include, for example, cycloheptynyl, cyclooctynyl, etc. Unless otherwise specifically described in the specification, the cycloalkynyl group can be arbitrarily substituted.

[0065] "Cycloalkylalkyl" refers to the formula R b -Rd refers to a radical, where R b is an alkylene, alkenylene, or alkynyl group as defined above, and R d is a cycloalkyl, cycloalkenyl, or cycloalkynyl radical as defined above. Unless otherwise specified in the specification, the cycloalkylalkyl group may be optionally substituted.

[0066] "Haloalkyl" refers to one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless otherwise specified in this specification, the haloalkyl group may be optionally substituted.

[0067] "Haloalkenyl" refers to an alkenyl radical substituted by one or more halo radicals as defined above, such as 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless otherwise specified in the specification, the haloalkenyl group may be optionally substituted.

[0068] "Haloalkynyl" refers to an alkynyl radical as defined above substituted by one or more halo radicals as defined above, such as 1-fluoropropynyl, 1-fluorobutynyl, and the like. Unless otherwise specified in the specification, the haloalkenyl group may be optionally substituted.

[0069] "Heterocyclyl", "heterocyclic ring" or "heterocycle" refers to a stable 3- to 20-membered non-aromatic ring group consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. A heterocyclic ring or heterocycle includes heteroaryl as defined below. Unless otherwise specified in the specification, a heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system that can include a fused ring system or a bridged ring system; the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can optionally be oxidized; the nitrogen atom can optionally be quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless otherwise specified in the specification, the heterocyclyl group can be optionally substituted.

[0070] "N-Heterocyclyl" refers to a heterocyclyl radical as defined above that contains at least one nitrogen, and the point of attachment to the remainder of the heterocyclyl radical is through a nitrogen atom in the heterocyclyl radical. Unless otherwise specified in the specification, the N-heterocyclyl group can be optionally substituted.

[0071] "Alkyleneheterocyclyl" refers to a radical of the formula R b -R e wherein R b is alkylene as defined above, and R eis a heterocyclic radical as defined above. When the heterocycle is a nitrogen-containing heterocycle, the heterocycle can be bonded to an alkyl, alkenyl, or alkynyl radical of a nitrogen atom. Unless otherwise specified in the specification, the heterocyclic alkyl group can be optionally substituted.

[0072] "Heteroaryl" refers to a 5- to 20-membered ring system group containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For the purposes of the present invention, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system including a fused ring system or a bridged ring system; the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; and the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxapinyl, dioxapinyl, 1,4-benzodioxane, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, q-vinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified in the present disclosure, the heteroaryl group may be optionally substituted.

[0073] "N - heteroaryl" refers to a heteroaryl radical as defined above that contains at least one nitrogen and has a point of attachment to the remainder of the heteroaryl radical through a nitrogen atom in the heteroaryl radical. Unless otherwise specifically described in the specification, the N - heteroaryl group can be optionally substituted.

[0074] "Alkyleneheteroaryl" refers to a radical of the formula R b -R f wherein R b is alkylene as defined above and R f is a heteroaryl radical as defined above. Unless otherwise specifically described in the specification, the heteroarylalkyl group can be optionally substituted.

[0075] "Thioalkyl" refers to a radical of the formula -SR a wherein R a is an alkyl, alkenyl, or alkynyl radical as defined above containing 1 to 12 carbon atoms. Unless otherwise specifically described in the specification, the thioalkyl group can be optionally substituted.

[0076] As used herein, the term "substituted" means any of the above radicals (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl), cycloalkylalkyl, haloalkyl, heterocyclyl, N - heterocyclyl, heterocyclylalkyl, heteroaryl, N - heteroaryl and / or heteroarylalkyl), where at least one hydrogen atom is replaced by a non - hydrogen atom such as, but not limited to, a halogen atom (e.g., F, Cl, Br, and I); an oxygen atom in a group such as a hydroxyl group, an alkoxy group, and an ester group; a sulfur atom in a group such as a thiol group, a thioalkyl group, a sulfone group, a sulfonyl group, and a sulfoxide group; a nitrogen atom in a group such as an amine, an amide, an alkylamine, a dialkylamine, an arylamine, an alkylarylamine, a diarylamine, an N - oxide, an imide, and an enamine; a silicon atom in a group such as a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, and a triarylsilyl group, and other heteroatoms of various other groups. "Substituted" also means that one or more hydrogen atoms are replaced by a higher - order bond (e.g., a double or triple bond) with a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. For example, "substituted" means that one or more hydrogen atoms are NR g C(=O)OR h 、NR g SO2R h 、OC(=O)NR g R h 、OR g 、SR g 、SOR g 、SO2R g 、OSO2R g 、SO2OR g 、=NSO2R g 、and SO2NR g R hcomprises any of the above groups replaced by. "Replaced" also means that one or more hydrogen atoms are C(=O)R g C(=O)OR g C(=O)NR g R h CH2SO2R g CH2SO2NR g R h means any of the above groups replaced by. In the foregoing, R g and R h are the same or different and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-. Heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Replaced" further means that one or more hydrogen atoms are amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or any of the above groups substituted by a bond to a heteroarylalkyl group. Further, each of the above substituents may be optionally substituted by one or more of the above substituents.

[0077] As used herein, the symbol "

[0078]

Chemical formula

[0079] " (which may hereinafter be referred to as a "bond point") denotes a bond that is a point of attachment between two chemical entities, one of which is shown as being attached to the bond point and the other of which is not shown as being attached to the bond point. For example, "

[0080] [ka]

[0081] " indicates that the chemical "XY" is attached to another chemical through a point of attachment. Furthermore, the specific point of attachment to the non-drawn chemical can be specified by inference. For example, R 3 H or "

[0082] [ka]

[0083] " The compound CH3-R 3 is R 3 If is "XY", the attachment point is R 3 is the same bond shown as being attached to CH3.

[0084] "Fused" refers to any ring structure described herein that is fused to an existing ring structure in the compounds of the invention. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring can be replaced with a nitrogen atom.

[0085] "Geminal" refers to any two substituents (e.g., those described herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.) that are attached to the same atom. In some embodiments, geminal substitutions refer to substitutions on the same carbon atom. Structure:

[0086] [Chemistry]

[0087] is an example of geminal methyl substitution of cyclohexane. In some embodiments, any substitution is geminal substitution.

[0088] "Optional" or "optionally" means that the event or situation described later may or may not occur, and the description includes both the case where the event or situation occurs and the case where it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.

[0089] The compounds of the present invention or their pharmaceutically acceptable salts can contain one or more asymmetric centers, and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms, whether or not they are specifically shown herein. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using a chiral synthon or chiral reagent, or can be separated using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include, for example, chiral synthesis from a suitable optically pure precursor using chiral high performance liquid chromatography (HPLC), or resolution of a racemate (or a racemate of a salt or derivative). When the compounds described herein contain an olefinic double bond or other center of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included.

[0090] "Stereoisomers" refer to compounds composed of the same atoms that are bonded by the same bonds but have different three-dimensional structures and are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers", which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed on each other.

[0091] "Tautomers" refer to the proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of the aforementioned compounds.

[0092] "Pharmaceutically acceptable carriers, diluents or excipients" include, but are not limited to, adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers, and are approved by the US Food and Drug Administration as acceptable for use in humans or livestock.

[0093] "Pharmaceutically acceptable salts" include both acid and base addition salts.

[0094] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic acids such as, but not limited to: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid; benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hypophosphorous acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc., which retain the biological effectiveness and properties of the free base and are not undesirable biologically or otherwise.

[0095] The term "pharmaceutically acceptable basic addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid and does not refer to those that are biologically undesirable. These salts are prepared from the addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. In some embodiments, the inorganic salts include ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and ammonia, basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine; tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc., but are not limited to these. In certain embodiments, the organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0096] Crystallization is a commonly used method for isolating reaction products, for example, one of the compounds disclosed herein, in a purified form. Often, crystallization produces solvates of the compounds of the invention. As used herein, the term "solvate" refers to an aggregate typically in a co-crystalline form that contains one or more solvent molecules and one or more molecules of a compound of the invention. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases, the compounds of the invention may simply retain adventitious water or may be a mixture of water and adventitious solvent.

[0097] The chemical nomenclature protocols and structure diagrams used herein include those of the I.U.P.A., such as using the ACD / Name version 9.07 software program, ChemDraw Ultra version 11.0.1 and / or ChemDraw Ultra version 14.0 and / or ChemDraw Professional 16.0.0.82 software nomenclature programs (CambridgeSoft). For complex chemical names used herein, substituents are named before the group to which they are attached. For example, cyclopropylethyl contains an ethyl backbone with a cyclopropyl substituent. Except as noted below, all bonds are assumed to be attached to hydrogen atoms sufficient to complete the valence, except for some carbon atoms identified in the chemical structure diagrams herein.

[0098] The invention disclosed herein also means including the in vivo metabolites of the disclosed compounds. Such products can arise primarily from enzymatic processes, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound. Accordingly, the invention includes compounds produced by a method comprising administering a compound of the invention to a mammal for a period sufficient to produce its metabolites. Such products are typically identified by administering a radiolabeled compound of the invention to an animal such as a rat, mouse, guinea pig, monkey, or human at a detectable dose, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological samples.

[0099] "Stable compound" and "stable structure" mean a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

[0100] As used herein, "subject" can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, insect, etc. The subject can have or be suspected of having cancer, for example, blood cancer, or other disease or condition. Diagnostic methods for various cancers, and the clinical depiction of cancer, are known to those of skill in the art. The subject can also be suspected of having an infectious disease or abnormal cardiovascular function.

[0101] "Mammal" includes humans, experimental animals, and domestic animals such as cats, dogs, pigs, cows, sheep, goats, horses, rabbits, etc., as well as non-domestic animals such as wild animals.

[0102] "Pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of a biologically active compound to a mammal, for example, a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor.

[0103] "Effective amount" refers to a therapeutically effective amount or a prophylactically effective amount. "Therapeutically effective amount" refers to an amount effective at dosages and for periods necessary to achieve a desired therapeutic result, such as reduction of tumor size, increased lifespan, or increased mean lifespan. The therapeutically effective amount of a compound can vary depending on factors such as the patient's condition, age, gender, and weight, as well as the ability of the compound to induce a desired response in the subject. The dosing regimen can be adjusted to obtain an optimal therapeutic response. The therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. "Prophylactically effective amount" refers to an amount effective at dosages and for periods necessary to achieve a desired prophylactic result, such as prevention of development of a smaller tumor, increased lifespan, extended survival, or prevention of progression of prostate cancer to a castration-resistant form. Typically, prophylactic dosages are used in a subject prior to or at an early stage of a disease, and as a result, the prophylactically effective amount can be less than the therapeutically effective amount.

[0104] As used herein, "treatment" or "treating" includes the treatment of a subject's disease or condition in a mammal, such as a human, having the disease or condition of interest, and includes, but is not limited to, the following: 1. In particular, preventing the occurrence of such a disease or condition in a mammal when such a mammal is predisposed to the condition but has not yet been diagnosed as having it. 2. Suppressing a disease or condition, i.e., preventing its development. 3. Alleviating a disease or condition, i.e., causing regression of the disease or condition (from reducing the severity of the disease or condition to curing the disease of the condition). Or 4. Reducing symptoms resulting from a disease or condition, i.e., reducing pain without addressing the underlying disease or condition. As used herein, the terms "disease" and "condition" can be used interchangeably, or a particular disease or condition may not have a known causative agent (and thus, the etiology has not yet been elucidated), and therefore, it is not yet recognized as a disease and is only recognized as an undesirable condition or syndrome, where a somewhat specific set of symptoms is identified by a clinician.

[0105] Throughout this specification, the terms "about" and / or "approximately" can be used with numerical values and / or ranges. The term "about" is understood to mean a value close to the recited value. For example, "about 40 [units]" means within ±25% of 40 (e.g., 30 to 50), ±20%, ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, less than ±1%, or other values or ranges of values described herein. Further, the phrases "less than about [value]" or "greater than about [value]" should be understood in view of the definition of the term "about" provided herein. The terms "about" and "substantially" can be used interchangeably.

[0106] Numerical ranges can be provided for a particular quantity. It should be understood that these ranges include all sub-ranges therein. Thus, the range "50 - 80" includes all possible ranges therein (e.g., 51 - 759, 52 - 78, 53 - 77, 54 - 76, 55 - 75, 60 - 70, etc.). Further, all values within a given range can be endpoints of ranges subsumed thereby (e.g., the range 50 - 80 includes ranges having endpoints such as 55 - 80, 50 - 75, etc.).

[0107] A more detailed description of various concepts and embodiments related to the compounds and methods of the present invention for the treatment of liver diseases and abnormal conditions of the liver is presented below. Since the disclosed concepts are not limited to specific methods of implementation, it should be understood that the various concepts introduced above and discussed in more detail below can be implemented in any of a number of ways. Examples of specific implementations and uses are provided primarily for illustrative purposes.

[0108] Compounds and Compositions In various embodiments, the present disclosure provides compounds of formula (A1), formula (A2), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof.

[0109] [Chemical Formula]

[0110] Wherein, L is alkylene, alkenylene, optionally substituted alkylene-S-, optionally substituted alkylene-O-, optionally substituted -alkylene-(NR 5 )-, optionally substituted

[0111] [Chemical Formula]

[0112] Optionally substituted

[0113] [Chemical Formula]

[0114] Optionally substituted

[0115] [Chemical Formula]

[0116] Optionally substituted

[0117] [Chemistry]

[0118] (optionally substituted)

[0119] [Chemistry]

[0120] (optionally substituted)

[0121] [Chemistry]

[0122] (optionally substituted)

[0123] [Chemistry]

[0124] [Chemistry]

[0125] is a linker selected from; T is CR 1 or N; U is S, S(O)2, or NH; V is H, OH, NR 2 N 3 or V and Y 1 together with the atoms to which they are attached, optionally form a phenyl ring or a pyridinyl ring which is substituted; W is CH or N; X is O, S, NR 6 , -CH=CH-, or -CH=N-; wherein when W is CH, T is N and X is O, S, or NR 6 ; Y 1and Y 2 are each independently CH or N; R 1 is H, OH, O-alkyl, alkyl or carbocyclic; R 2 and R 3 are each independently H, alkyl, alkenyl, or -C(O)alkyl; R 4 is carbocyclic, heterocyclic, aryl, or heteroaryl, each of which may be optionally substituted; R 5 is H, alkyl, -C(O)alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 6 is H, alkyl, carbocyclic, alkylene carbocyclic, alkylene aryl, -C(O)alkyl, or -C(O)alkenyl; R 7 is carbocyclic, heterocyclic, or heteroaryl; m is 0, 1, or 2; n is 1, 2, or 3.

[0126] In some embodiments, the present disclosure provides a compound of formula (A1), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof.

[0127]

Chemical formula

[0128] wherein L, T, U, V, W, X, Y 1 , Y 2 , and R 4 are as defined herein.

[0129] In some embodiments of the present disclosure, a compound of formula (A2), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof is provided.

[0130] [Chemical formula]

[0131] In the formula, L, T, U, V, W, X, Y 1 , Y 2 , and R 4 are as defined herein.

[0132] In some embodiments, L is alkylene, alkenylene, alkylene-(NR 5 )-,

[0133] [Chemical formula]

[0134] and each is optionally substituted. In some embodiments, L is alkylene, alkylene-(NR5)-,

[0135] [Chemical formula]

[0136] and each is optionally substituted. In some embodiments of formula (A1) and formula (A2), L is alkylene, alkenylene, alkylene-(NR 5 )-,

[0137] [Chemical formula]

[0138] and each is optionally substituted. In some embodiments, L is alkylene-(NR 5 )-,

[0139] [Chemical formula]

[0140] and each is optionally substituted. In some embodiments, L is alkylene-(NR 5 )-,

[0141]

Chemical formula

[0142] and each is optionally substituted. In some embodiments, L is alkylene-(NR 5 )-,

[0143]

Chemical formula

[0144] and each is optionally substituted. In some embodiments, L is alkylene-(NR 5 )-,

[0145]

Chemical formula

[0146] and each is optionally substituted. In some embodiments, L is alkenylene, alkylene-(NR 5 )-, optionally substituted

[0147]

Chemical formula

[0148] optionally substituted

[0149]

Chemical formula

[0150] optionally substituted

[0151]

Chemical formula

[0152] Optionally substituted [Chemical formula]

[0153] is. In some embodiments, L is alkylene-(NR 5 )-

[0154] [Chemical formula]

[0155] is, each of which is optionally substituted. In some embodiments, L is optionally substituted

[0156] [Chemical formula]

[0157] Optionally substituted

[0158] [Chemical formula]

[0159] Optionally substituted

[0160] [Chemical formula]

[0161] Optionally substituted

[0162] [Chemical formula]

[0163] is. In some embodiments, L is optionally substituted

[0164]

Chem.

[0165] Optionally substituted

[0166]

Chem.

[0167] Optionally substituted

[0168]

Chem.

[0169] is. In some embodiments, L is optionally substituted

[0170]

Chem.

[0171] Optionally substituted

[0172]

Chem.

[0173] Optionally substituted

[0174]

Chem.

[0175] is. In some embodiments, L is optionally substituted

[0176]

Chem.

[0177] Optionally substituted [Chemical formula]

[0178] is. In some embodiments, L is optionally substituted

[0179] [Chemical formula]

[0180] optionally substituted

[0181] [Chemical formula]

[0182] is. In some embodiments, L is optionally substituted

[0183] [Chemical formula]

[0184] is. In other embodiments, L is optionally substituted

[0185] [Chemical formula]

[0186] is. In some embodiments, L is optionally substituted

[0187] [Chemical formula]

[0188] is. In still other embodiments, L is optionally substituted

[0189] [Chemical formula]

[0190] is. In some embodiments, L is

[0191]

Chemical formula

[0192] is. In some embodiments, L is

[0193]

Chemical formula

[0194] is. In some embodiments, L is

[0195]

Chemical formula

[0196] is. In some embodiments, L is

[0197]

Chemical formula

[0198] is. In other embodiments, L is

[0199]

Chemical formula

[0200] is. In still other embodiments, L is

[0201]

Chemical formula

[0202] It is. In some embodiments, m is 0 and n is 1. In some embodiments, m is 0 and n is 2. In other embodiments, m is 1 and n is 1.

[0203] In some embodiments of formula (A1) and formula (A2), optionally substituted

[0204]

Chemical formula

[0205] is

[0206]

Chemical formula

[0207] wherein R 5 is H, alkyl, -C(O)alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 5a and R 5b are each independently selected from the group consisting of H, halogen, C 1-5 alkyl, C 3-6 carbocyclic, alkylene-C 3-6 carbocyclic, aryl, alkenyl, or NH2, where two C 1-5 alkyl together with the carbon atom to which they are attached form C 3-6 carbocyclic; m is 0 or 1.

[0208] In one embodiment, R 5 is H, methyl, or -C(O)Me. In some embodiments, R 5 is H. In some embodiments, R 5a is alkyl or carbocyclic and R 5b is H.

[0209] In some embodiments, when L is

[0210]

Chemical formula

[0211] R 5 and R 5a form a heterocyclyl ring together with the carbon atom to which they are attached. In some embodiments, when L is

[0212]

Chemical formula

[0213] R 5 and R 5a form a 4-, 5- or 6-membered heterocyclyl ring together with the carbon atom to which they are attached. In certain embodiments, the heterocyclyl ring is

[0214]

Chemical formula

[0215] In some embodiments of formula (A1) and formula (A2),

[0216] is selected from the group consisting of

[0217]

Chemical formula

[0218] wherein R

[0219]

Chemical formula

[0220] In some embodiments,

[0221]

Chemical formula

[0222] is

[0223]

Chemical formula

[0224] selected from the group consisting of

[0225] In some embodiments of formula (A1) and formula (A2),

[0226]

Chemical formula

[0227] is

[0228]

Chemical formula

[0229] selected from the group consisting of

[0230] In some embodiments of formula (A1) and formula (A2), optionally substituted

[0231]

Chemical formula

[0232] is

[0233]

Chemical formula

[0234] selected from the group consisting of, wherein R 5C is halogen, alkyl, haloalkyl, hydroxy, or alkoxy. In some embodiments, R 5 c is in the para position of the phenyl ring.

[0235] In some embodiments of formula (A1) and formula (A2), optionally substituted

Chemical formula

[0236]

Chemical formula

[0237] and in the formula, R 5 is H, alkyl, -C(O)alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 5a and R 5b are each independently selected from the group consisting of H, halogen, C 1-5 alkyl, C 3-6 carbocyclic, alkylene-C 3-6 carbocyclic, aryl, alkenyl, or NH2, where two C 1-5 alkyl together with the carbon atom to which they are attached form a C 3-6 carbocyclic.

[0238] In one embodiment, R 5 is H, methyl, or -C(O)Me. In one embodiment, R 5 is H, R 5a is alkyl or carbocyclic, and R 5b is H. In some embodiments, R 5 is H, R 5a is alkyl, and R 5b is H.

[0239] In some embodiments,

[0240] [Chemical formula]

[0241] is selected from the group consisting of

[0242] [Chemical formula]

[0243] In some embodiments of formula (A1) and formula (A2), L contains alkylene. In some embodiments, the alkylene is optionally substituted C

[0244] alkylene. In some embodiments, the alkylene is optionally substituted C 1-4 alkylene. In some embodiments, the alkylene is optionally substituted C 1-3 alkylene. In some embodiments, the alkylene is optionally substituted C 1-2 alkylene. In some embodiments, the alkylene is optionally substituted C 2-4 alkylene. In some embodiments, the alkylene is optionally substituted C 2-3 alkylene. In some embodiments, the alkylene is optionally substituted C 3-4 alkylene. In some embodiments, when L contains alkylene, the alkylene is C 1-4 alkylene. In some embodiments, the alkylene is C 1-3 alkylene. In some embodiments, the alkylene is C 1-2 alkylene. In some embodiments, the alkylene is C 2-4 alkylene. - In some embodiments, the alkylene is C 2-3 alkylene. - In some embodiments, the alkylene is C 3-4It is alkylene. - In some embodiments, the alkylene is methylene, ethylene, propylene, or butylene, each of which may be optionally substituted. In some embodiments, the alkylene is ethylene, propylene, or butylene, each of which may be optionally substituted. In some embodiments, the alkylene is optionally substituted methylene. In some embodiments, the alkylene is optionally substituted ethylene. In some embodiments, the alkylene is optionally substituted propylene. In some embodiments, the alkylene is optionally substituted butylene. In certain embodiments, the alkylene is methylene, ethylene, propylene, or butylene. In some embodiments, the alkylene is methylene. In some embodiments, the alkylene is ethylene. In some embodiments, the alkylene is propylene. In some embodiments, the alkylene is butylene.

[0245] In some embodiments of formula (A1) and formula (A2), L is alkylene-(NR 5 )-. In some embodiments, the alkylene is optionally substituted ethylene. In some embodiments, the optionally substituted ethylene is selected from the group consisting of.

[0246] [Chemical formula]

[0247] In some embodiments of formula (A1) and formula (A2), L is alkylene-(NR 5 )-. In some embodiments, the alkylene is optionally substituted propylene. In some embodiments, the optionally substituted propylene is

[0248] [Chemical formula]

[0249] is selected from the group consisting of.

[0250] In some embodiments of formula (A1) and formula (A2), L comprises alkenylene. In some embodiments, the alkenylene is optionally substituted C 2-4 alkenylene. In some embodiments, the alkenylene is optionally substituted C 2-3 alkenylene. In some embodiments, the alkenylene is optionally substituted C 3-4 alkenylene. In some embodiments, when L comprises alkenylene, the alkenylene is C24 alkenylene. - In some embodiments, the alkenylene is C 2-3 alkenylene. In some embodiments, the alkenylene is C 3-4 alkenylene. - In one embodiment, the alkenylene is ethynylene, propenylene, or butenylene, each of which may be optionally substituted. In some embodiments, the alkenylene is optionally substituted ethynylene. In some embodiments, the alkenylene is optionally substituted propenylene. In some embodiments, the alkenylene is optionally substituted butenylene. In some embodiments, the alkenylene is ethynylene, propenylene or butenylene. In some embodiments, the alkenylene is ethynylene. In some embodiments, the alkenylene is propenylene. In some embodiments, the alkenylene is butenylene.

[0251] In some embodiments of formula (A1) and formula (A2), any substituent is oxo, halogen, C 1-5 alkyl, C 3-6 carbocyclic, alkylene carbocyclic, aryl, heteroaryl, alkenyl, and alkylene heteroaryl. In some embodiments, any substituent is oxo, C 1-5 alkyl, and C 3-6It is selected from the group consisting of cycloalkyl. In some embodiments, any substituent is oxo and C 1-5 It is selected from the group consisting of alkyl. In some embodiments, any substituent is oxo. In other embodiments, any substituent is C 1-5 alkyl. In some embodiments, C 1-5 alkyl is methyl, ethyl, propyl or isopropyl. In certain embodiments, C 1-5 alkyl is methyl, ethyl, or isopropyl. In other embodiments, C 1-5 alkyl is methyl. In some embodiments, C 3-6 cycloalkyl is cyclopropyl or cyclohexyl. In some embodiments, aryl is phenyl. In certain embodiments, alkylenecarbocyclyl is methylenecyclopropyl or methylenecyclohexyl. In some embodiments, alkenylenyl is methylenephenyl.

[0252] In some embodiments of formula (A1) and formula (A2), m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0253] In some embodiments of formula (A1) and formula (A2), n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0254] In some embodiments of formula (A1) and formula (A2), m is 0 and n is 1. In other embodiments, m is 1 and n is 1. In still other embodiments, m is 0 and n is 2. In yet another embodiment, m is 2 and n is 1.

[0255] In some embodiments of formula (A1) and formula (A2), T is N. In other embodiments, T is CR 1 is.

[0256] In some embodiments of formula (A1) and formula (A2), U is S. In other embodiments, U is NH.

[0257] In some embodiments of formula (A1) and formula (A2), V is H, OH, NR 2 N 3 , or N=CR 2 R 3 is. In some embodiments of formula (A1) and formula (A2), V is H, OH, or NR 2 N 3 is. In some embodiments, V and Y 1 together with the atom to which they are attached form an optionally substituted phenyl ring or pyridinyl ring. In some embodiments, V is NR 2 N 3 is. In other embodiments, V is OH. In some embodiments, V is H.

[0258] In some embodiments of formula (A1) and formula (A2), W is N, and in other embodiments, W is CH.

[0259] In some embodiments of formula (A1) and formula (A2), X is O, S or NR 6 is. In some embodiments, X is O or NR 6 is. In some embodiments, X is NR 6 is. In one embodiment, X is O. In one embodiment, X is S. In one embodiment, X is -CH=CH or -CH=N-.

[0260] In some embodiments of formula (A1) and formula (A2), Y 1 or Y 2is N. In some embodiments, Y 1 and Y 2 are both N. In some embodiments, Y 1 is N and Y 2 is CH. In one embodiment, Y 1 is CH and Y 2 is N.

[0261] In some embodiments of formula (A1) and formula (A2), U is S, W is N, and X is NR 6 is. In one embodiment, V is NR 2 NR 3 is.

[0262] In some embodiments of formula (A1) and formula (A2), U is S, W is N, and X is NR 6 is. In one embodiment, Y 1 and Y 2 are each N.

[0263] In some embodiments of formula (A1) and formula (A2), U is S, W is N, and X is NR 6 is. In one embodiment, V is NR 2 NR 3 is.

[0264] In some embodiments of formula (A1) and formula (A2), U is S, W is N, X is NR 6 is, and Y 1 and Y 2 are each N. In certain embodiments, V is NR 2 NR 3 is.

[0265] In some embodiments of formula (A1) and formula (A2), U is S, W is N, and X is NR 6 is, and V is NR 2 NR 3 is. In one embodiment, Y 1 and Y 2 are each N.

[0266] In some embodiments of formula (A1) and formula (A2), when W is CH, T is N, U is S, V is H or NR 2 R 3 and X is NR 6 . In one embodiment, Y 1 and Y 2 are each N.

[0267] In some embodiments of formula (A1) and formula (A2), R 1 is H, OH, or C1-5 alkyl. In other embodiments, R 1 is H, and in some embodiments, R 1 is OH. In one embodiment, R 1 is C 1-5 alkyl. - In some embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isoamyl, and isobutyl. - In other embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, and isopropyl.

[0268] In some embodiments of formula (A1) and formula (A2), R 2 and R 3 are independently H, -C 1-5 alkyl, -CH2Ph, or -C(O)(C 1-5 alkyl). In one embodiment, R 2 and R 3 are independently H, C 1-5 alkyl, -CH2Ph, or -C(O)(CH3). In one embodiment, one of R 2 and R 3 is H. In some embodiments, R 2 and R 3 are H. In some embodiments, one of R 2 and R 3 is C 1-5 alkyl. In one embodiment, R 2 and R3 One of them is -CH2Ph. In certain embodiments, R 2 and R 3 One of them is -C(O)(CH3). In some embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, and isopropyl.

[0269] In some embodiments of formula (A1) and formula (A2), R 4 is aryl or heteroaryl, each of which is optionally substituted. In certain embodiments, R 4 is optionally substituted aryl. In certain embodiments, R 4is a heteroaryl optionally substituted. In some embodiments, the heteroaryl is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, indolyl, oxindolyl, isatinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benz, cinnolinyl, quinazolinyl, or quinoxalinyl. In some embodiments, the aryl is a 6- to 12-membered aryl and the heteroaryl is a 5- to 12-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In embodiments, the 5- to 12-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, tetrazolyl, or pyrazolyl. In some embodiments, the 5- to 12-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S is pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, the 5- to 12-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S is indolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl.

[0270] In some embodiments, R 4is aryl or heteroaryl, each of which is optionally substituted with one or more H, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, heterocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN. In other embodiments, aryl or heteroaryl is optionally substituted with one or more H, halogen, -C 1-5 alkyl, -CF3, OH, -O(C 1-5 alkyl), -OCF3, -OSO2Me, -COOH, -C(O)OMe, or -SO2Me. In some embodiments, aryl is optionally substituted phenyl. In one embodiment, heteroaryl is optionally substituted pyridinyl. In one embodiment, optionally substituted pyridinyl is selected from the group consisting of

[0271]

Chemical formula

[0272] and is selected from the group where p is 0, 1, or 2. In one embodiment, heteroaryl is optionally substituted pyrimidinyl. In one embodiment, optionally substituted pyrimidinyl is

[0273]

Chemical formula

[0274] where p is 0, 1, or 2. In some embodiments, each R 8 is independently halogen, alkyl, -OH, -Oalkyl, -CO2H or -CO2alkyl.

[0275] In some embodiments of formula (A1) and formula (A2), R 4 is

[0276]

Chem.

[0277] an optionally substituted aryl selected from the group consisting of

[0278] In some embodiments, R 4 is

[0279]

Chem.

[0280] an optionally substituted heteroaryl selected from the group consisting of

[0281] In some embodiments, R 4 is

Chem.

[0282] selected from the group consisting of, and p is an integer from 0 to 3. In some embodiments, each R 8 is independently halogen, alkyl, haloalkyl, alkenyl, -OH, -Oalkyl, -N(alkyl)2, -CO2H, -CO2alkyl, or -CN.

[0283] In some embodiments, R 4 is

[0284]

Chem.

[0285] selected from the group consisting of, wherein each R 8is independently halogen, C 1-5 alkyl, -OH, -OC 1-5 alkyl, -COOH, or -CO2C 1-5 alkyl; p is an integer from 0 to 3.

[0286] In some embodiments of formula (A1) and formula (A2), R 4 is carbocyclic. In certain embodiments, the carbocyclic is optionally substituted C 3-6 carbocyclic. In certain embodiments, the carbocyclic is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the carbocyclic is cyclohexyl.

[0287] In some embodiments of formula (A1) and formula (A2), R 4 is heterocyclic. In certain embodiments, the heterocyclic is an optionally substituted 4- to 6-membered heterocyclic containing 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, the heterocyclic is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

[0288] In some embodiments of formula (A1) and formula (A2), R 5 is H, C 1-5 alkyl, C(O)C 1-4 alkyl, C 3-6 6 carbocyclic, -CH2-aryl, or CH2-(C 3-6 carbocyclic). In certain embodiments, R 5 is H, C 1-5 alkyl, -C(O)Me, or C 3-6 carbocyclic. In certain embodiments, R 5 is H or C 1-5 alkyl. In some embodiments, C 1-5Alkyl is selected from the group consisting of methyl, ethyl, and isopropyl. In certain embodiments, C3-6 carbocyclic is cyclopropyl or cyclohexyl. In certain embodiments, R 5 is H, Me, or -C(O)Me. In certain embodiments, R 5 is H, Me, or CH2Ph. In some embodiments, R 5 is H. In some embodiments, R 5 is Me. In certain embodiments, R 5 is -C(O)Me.

[0289] In some embodiments of formula (A1) and formula (A2), R 6 is H, C 1-5 alkyl, CH2 aryl, or CH2(C 3-6 carbocyclic). In certain embodiments, R 6 is H, C 1-5 alkyl, or CH2Ph. In certain embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, and isopropyl. In some embodiments, R 6 is H.

[0290] In some embodiments of formula (A1) and formula (A2), R 7 is C 3-6 carbocyclic, 3- to 6-membered heterocyclic, or 5- to 6-membered heteroaryl. In certain embodiments, R 7 is C 3-6 carbocyclic. In certain embodiments, C 3-6 carbocyclic is cyclopropyl or cyclohexyl. In certain embodiments, R 7 is 5- to 6-membered heteroaryl. In some embodiments, R 7is a 5- to 6-membered heteroaryl. In some embodiments, the 5- to 6-membered heteroaryl is selected from the group consisting of oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, and pyrazinyl. In some embodiments, the 5- to 6-membered heteroaryl is

[0291] [Chemical formula]

[0292] selected from the group consisting of, where X 1 is NR 6 , S or O, and R 6 is H or alkyl. In one embodiment, R 7 is a 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl is

[0293] [Chemical formula]

[0294] selected from the group consisting of, where X 1 is selected from the group consisting of NR 6 , S or O. In some embodiments, the 5-membered heteroaryl is

[0295] [Chemical formula]

[0296] selected from the group consisting of, where X 1 is NR 6 , S or O. In one embodiment, R 7 is a 3- to 6-membered heterocyclyl. In some embodiments, the 3- to 6-membered heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0297] In some embodiments, each R 8 is independently halogen, alkyl, haloalkyl, alkenyl, -OH, -Oalkyl, -N(alkyl)2, -CO2H, -CO2alkyl, or -CN. In some embodiments, each R 8 is independently halogen, alkyl, haloalkyl, -OH, -Oalkyl, -Ohaloalkyl or -CO2H. In some embodiments, each R 8 is independently halogen, alkyl, -OH, -Oalkyl, or -CO2H.

[0298] In some embodiments, the compound of formula (A1) or formula (A2) has a structure according to one of the following:

[0299] [Table 1-1]

[0300] [Table 1-2]

[0301] [Table 1-3]

[0302] [Table 1-4]

[0303] [Table 1-5]

[0304] [Table 1-6]

[0305] [Table 1-7]

[0306]

Table 1-8

[0307]

Table 1-9

[0308]

Table 1-10

[0309]

Table 1-11

[0310]

Table 1-12

[0311]

Table 1-13

[0312]

Table 1-14

[0313]

Table 1-15

[0314]

Table 1-16

[0315]

Table 1-17

[0316]

Table 1-18

[0317]

Table 1-19

[0318]

Table 1-20

[0319]

Table 1-21

[0320]

Table 1-22

[0321]

Table 1-23

[0322]

Table 1-24

[0323]

Table 1-25

[0324]

Table 1-26

[0325]

Table 1-27

[0326]

Table 1-28

[0327]

Table 1-29

[0328]

Table 1-30

[0329]

Table 1-31

[0330]

Table 1-32

[0331]

Table 1-33

[0332]

Table 1-34

[0333]

Table 1-35

[0334]

Table 1-36

[0335]

Table 1-37

[0336]

Table 1-38

[0337]

Table 1-39

[0338]

Table 1-40

[0339]

Table 1-41

[0340]

Table 1-42

[0341]

Table 1-43

[0342] has, or is a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

[0343] In some embodiments, the compound of formula (A1) or formula (A2) is a compound provided in Table 2, Table 3 or Table 4 below.

[0344] In some embodiments, the compound of formula (A2) is a compound of formula (X).

[0345] In various embodiments, the present disclosure provides a compound of formula (X), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof:

[0346]

Chemical formula

[0347] In the formula, L is alkylene, alkenylene, optionally substituted alkylene-S-, optionally substituted alkylene-O-, optionally substituted -alkylene-(NR 5 )-, optionally substituted

[0348] [Chemical formula]

[0349] optionally substituted

[0350] [Chemical formula]

[0351] optionally substituted

[0352] [Chemical formula]

[0353] optionally substituted

[0354] [Chemical formula]

[0355] optionally substituted

[0356] [Chemical formula]

[0357] [Chemical formula]

[0358] optionally substituted

[0359] [Chemical formula]

[0360] is a linker selected arbitrarily;

[0361] [Chem.]

[0362] and is a linker selected from; U is S, S(O)2, or NH; V is OH, NR 2 N 3 or V and Y 1 and together with the atoms to which they are attached form an optionally substituted phenyl or pyridinyl ring; W is CH or N; X is O, S, NR 6 , -CH=CH-, or -CH=N-; Y 1 and Y 2 are each independently CH or N; R 1 is H, OH, O-alkyl, alkyl or carbocyclic; R 2 and R 3 are each independently H, alkyl, alkenyl, or -C(O)alkyl; R 4 is carbocyclic, heterocyclic, aryl, or heteroaryl, each of which may be optionally substituted; R 5 is H, alkyl, -C(O)alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 6 is H, alkyl, carbocyclic, alkylene carbocyclic, alkylene aryl, -C(O)alkyl, or C(O)alkenyl; R 7 is carbocyclic, heterocyclic, or heteroaryl; m is 0, 1, or 2; n is 1, 2, or 3.

[0363] In various embodiments, the present disclosure provides a compound of formula (X), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof:

[0364]

Chemical formula

[0365] wherein, L is alkylene, alkenylene, optionally substituted alkylene-S-, optionally substituted alkylene-O-, optionally substituted -alkylene-(NR 5 )-, optionally substituted

[0366]

Chemical formula

[0367] optionally substituted

[0368]

Chemical formula

[0369] optionally substituted

[0370]

Chemical formula

[0371] optionally substituted

[0372]

Chemical formula

[0373] optionally substituted

[0374]

Chemical formula

[0375]

Chem.

[0376] is optionally substituted

[0377]

Chem.

[0378] is optionally substituted

[0379]

Chem.

[0380] is a linker selected from; U is S, S(O)2, or NH; V is OH, NR 2 N 3 or V and Y 1 together with the atoms to which they are attached form an optionally substituted phenyl or pyridinyl ring; W is CH or N; X is O, S, NR 6 , -CH=CH-, or -CH=N-; Y 1 and Y 2 are each independently CH or N; R 1 is H, OH, O-alkyl, alkyl or carbocyclic; R 2 and R 3 are each independently H, alkyl, alkenyl, or -C(O)alkyl; R 4 is carbocyclic, heterocyclic, aryl, or heteroaryl, each of which may be optionally substituted; R 5is H, alkyl, -C(O)alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 6 is H, alkyl, carbocyclic, alkylene carbocyclic, alkylene aryl, -C(O)alkyl, or -C(O)alkenyl; R 7 is carbocyclic, heterocyclic, or heteroaryl; m is 0, 1, or 2; n is 1, 2, or 3, provided that the compound of formula (X) is not one or more of the following:

[0381]

Chemical formula

[0382] wherein, (a)R 2 is H, and R 4 is,

[0383]

Chemical formula

[0384] or; (b)R 2 is Me, and R 4 is,

[0385]

Chemical formula

[0386] or; (c)R 2 is Et, and R 4 is,

[0387]

Chemical formula

[0388] or; or (d)R 2 is nPr, C(O)Me or CO2nBu, and R 4 is

[0389] [Chemical formula]

[0390] [Chemical formula]

[0391] [Chemical formula]

[0392] is.

[0393] In some embodiments of formula (X), L is alkylene, alkenylene, alkylene-(NR 5 )-,

[0394] [Chemical formula]

[0395] is, each of which is optionally substituted. In some embodiments, L is alkylene, alkylene-(NR 5 )-,

[0396] [Chemical formula]

[0397] is, each of which is optionally substituted. In some embodiments of formula (A1) and formula (A2), L is alkylene, alkenylene, alkylene-(NR 5 )-,

[0398] [Chemical formula]

[0399] and each is optionally substituted. In some embodiments, L is alkylene-(NR 5 )-

[0400]

Chemical formula

[0401] and each is optionally substituted. In some embodiments, L is alkylene-(NR 5 )-

[0402]

Chemical formula

[0403] and each is optionally substituted. In some embodiments, L is alkylene-(NR 5 )-

[0404]

Chemical formula

[0405] and each is optionally substituted. In some embodiments, L is alkylene-(NR 5 )-

[0406]

Chemical formula

[0407] and each is optionally substituted. In some embodiments, L is alkenylene, alkylene-(NR 5 )-, optionally substituted

[0408]

Chemical formula

[0409] Optionally substituted

[0410]

Chem.

[0411] Optionally substituted

[0412]

Chem.

[0413] Optionally substituted,

[0414]

Chem.

[0415] is. In some embodiments, L is alkylene-(NR 5 )-,

[0416]

Chem.

[0417] and each is optionally substituted. In some embodiments, L is optionally substituted

[0418]

Chem.

[0419] Optionally substituted

Chem.

[0420] Optionally substituted

[0421]

Chem.

[0422] Optionally substituted

[0423] [Chem.]

[0424] is. In some embodiments, L is optionally substituted

[0425] [Chem.]

[0426] Optionally substituted

[0427] [Chem.]

[0428] Optionally substituted

[0429] [Chem.]

[0430] is. In some embodiments, L is optionally substituted

[0431] [Chem.]

[0432] Optionally substituted at will

[0433] [Chem.]

[0434] [Chem.]

[0435] It is. In some embodiments, L is optionally substituted

[0436] [Chemical formula]

[0437] optionally substituted

[0438] [Chemical formula]

[0439] It is. In some embodiments, L is optionally substituted

[0440] [Chemical formula]

[0441] optionally substituted

[0442] [Chemical formula]

[0443] It is. In some embodiments, L is optionally substituted

[0444] [Chemical formula]

[0445] It is. In other embodiments, L is optionally substituted

[0446] [Chemical formula]

[0447] It is. In some embodiments, L is optionally substituted

[0448]

Chem.

[0449] is. In still other embodiments, L is optionally substituted

[0450]

Chem.

[0451] is. In some embodiments, L is

[0452]

Chem.

[0453] is. In some embodiments, L is

[0454]

Chem.

[0455] is. In some embodiments, L is

[0456]

Chem.

[0457] is. In some embodiments, L is

[0458]

Chem.

[0459] is. In other embodiments, L is

[0460]

Chem.

[0461] is. Further, in other embodiments, L is

[0462]

Chemical formula

[0463] is. In some embodiments, m is 0 and n is 1. In some embodiments, m is 0 and n is 2. In other embodiments, m is 1 and n is 1.

[0464] In some embodiments of formula (X), optionally substituted

[0465]

Chemical formula

[0466] is

[0467]

Chemical formula

[0468] is, wherein: R 5 is H, alkyl, -C(O)alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 5a and R 5b are each independently selected from the group consisting of H, halogen, C 1-5 alkyl, C 3-6 carbocyclic, alkylene-C 3-6 carbocyclic, aryl, alkenyl, or NH2, where two C 1-5 alkyl together with the carbon atom to which they are attached form a C 3-6 carbocyclic; m is 0 or 1.

[0469] In some embodiments of formula (X), optionally substituted

[0470]

Chemical formula

[0471] is

[0472]

Chemical formula

[0473] wherein: R 5 is H, methyl, or -C(O)Me; R 5a is alkyl or carbocyclic. R 5b is H, here, two C 1-5 alkyl together with the carbon atom to which they are attached form a C 3-6 carbocyclic; m is 0 or 1.

[0474] In some embodiments of formula (X), optionally substituted

[0475]

Chemical formula

[0476] is

[0477]

Chemical formula

[0478] wherein: R 5 is H or methyl; R 5a is fluoro or alkyl; R 5b is H, Here, two Cs 1-5 alkyl, together with the carbon atom to which they are attached, forms a C 3-6 carbocyclic ring; m is 0.

[0479] In some embodiments, when L is,

[0480]

Chemical formula

[0481] when it is, R 5 and R 5a form a heterocyclic ring together with the carbon atom to which they are attached. In some embodiments, when L is,

[0482]

Chemical formula

[0483] when it is, R 5 and R 5a form a 4-, 5- or 6-membered heterocyclic ring together with the carbon atom to which they are attached. In certain embodiments, the heterocyclic ring is,

[0484]

Chemical formula

[0485] as such.

[0486] In some embodiments of formula (X),

[0487]

Chemical formula

[0488] is,

[0489]

Chemical formula

[0490] selected from the group consisting of, R 5c is halogen, alkyl, haloalkyl, hydroxy, or alkoxy. In some embodiments, R 5c is at the para position of the phenyl ring.

[0491] In some embodiments,

[0492]

Chemical formula

[0493] is

[0494]

Chemical formula

[0495] selected from the group consisting of.

[0496] In some embodiments of formula (X),

[0497]

Chemical formula

[0498]

Chemical formula

[0499] is selected from the group consisting of.

[0500] In some embodiments of formula (X), optionally substituted

[0501]

Chemical formula

[0502]

Chem.

[0503] selected from the group consisting of, R 5c is halogen, alkyl, haloalkyl, hydroxy, or alkoxy. In some embodiments, R 5c is at the para-position of the phenyl ring.

[0504] In some embodiments of formula (X), optionally substituted

[0505]

Chem.

[0506] is

[0507]

Chem.

[0508] where: R 5 is H, alkyl, -C(O)alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 5a and R 5b are each independently selected from the group consisting of H, halogen, C 1-5 alkyl, C 3-6 carbocyclic, alkylene-C 3-6 carbocyclic, aryl, alkyleneyl, or NH2, where two C 1-5 alkyl together with the carbon atom to which they are attached form a C 3-6 carbocyclic.

[0509] In one embodiment, R 5 is H, methyl, or -C(O)Me. In one embodiment, R 5 is H, and R 5ais alkyl or carbocyclic, and R 5b is H. In some embodiments, R 5 is H, R 5a is alkyl, and R 5b is H.

[0510] In some embodiments,

[0511]

Chemical formula

[0512] is selected from the group consisting of

[0513]

Chemical formula

[0514] In some embodiments of formula (X), when L contains alkylene, the alkylene is optionally substituted C

[0515] is alkylene. In some embodiments, the alkylene is optionally substituted C 1-4 is alkylene. In some embodiments, the alkylene is optionally substituted C 1-3 is alkylene. In some embodiments, the alkylene is optionally substituted C 1-2 is alkylene. In some embodiments, the alkylene is optionally substituted C 2-4 is alkylene. In some embodiments, the alkylene is optionally substituted C 2-3 is alkylene. In some embodiments, the alkylene is optionally substituted C 3-4 is alkylene. In some embodiments, when L contains alkylene, the alkylene is C 1-4 is alkylene. In some embodiments, the alkylene is C 1-3 is alkylene. In some embodiments, the alkylene is C 1-2 is alkylene. In some embodiments, the alkylene is C 2-4It is alkylene. In some embodiments, the alkylene is C 2-3 It is alkylene. In some embodiments, the alkylene is C 3-4 It is alkylene. In some embodiments, the alkylene is methylene, ethylene, propylene, or butylene, each of which may be optionally substituted. In some embodiments, the alkylene is ethylene, propylene, or butylene, each of which may be optionally substituted. In some embodiments, the alkylene is optionally substituted methylene. In some embodiments, the alkylene is optionally substituted ethylene. In some embodiments, the alkylene is optionally substituted propylene. In some embodiments, the alkylene is optionally substituted butylene. In one embodiment, the alkylene is methylene, ethylene, propylene, or butylene. In some embodiments, the alkylene is methylene. In some embodiments, the alkylene is ethylene. In some embodiments, the alkylene is propylene. In some embodiments, the alkylene is butylene.

[0516] In some embodiments of formula (X), L is alkylene-(NR 5 )-. In some embodiments, the alkylene is optionally substituted ethylene. In some embodiments, the optionally substituted ethylene is

[0517] [Chemical formula]

[0518] selected from the group consisting of.

[0519] In some embodiments of formula (X), L is alkylene-(NR 5 )-. In some embodiments, the alkylene is optionally substituted propylene. In some embodiments, the optionally substituted propylene is

[0520] [Chemical formula]

[0521] is selected from the group consisting of.

[0522] In some embodiments of formula (X), when L contains alkenylene, the alkenylene is optionally substituted C 2-4 alkenylene. In some embodiments, the alkenylene is optionally substituted C 2-3 alkenylene. In some embodiments, the alkenylene is optionally substituted C 3-4 alkenylene. - In some embodiments, when L contains alkenylene, the alkenylene is C 2-4 alkenylene. In some embodiments, the alkenylene is C 2-3 alkenylene. In some embodiments, the alkenylene is C 3-4 alkenylene. - In one embodiment, the alkenylene is ethynylene, propenylene, or butenylene, each of which may be optionally substituted. In some embodiments, the alkenylene is optionally substituted ethynylene. In some embodiments, the alkenylene is optionally substituted propenylene. In some embodiments, the alkenylene is optionally substituted butenylene. In some embodiments, the alkenylene is ethynylene, propenylene or butenylene. In some embodiments, the alkenylene is ethynylene. In some embodiments, the alkenylene is propenylene. In some embodiments, the alkenylene is butenylene.

[0523] In some embodiments of formula (X), any substituent is oxo, halogen, C 1-5 alkyl, C 3-6It is selected from the group consisting of carbocyclicryl, alkylene carbocyclicryl, aryl, heteroaryl, alkylene aryl, and alkylene heteroaryl. - In some embodiments, any substituent is oxo, C 1-5 alkyl, and C 3-6 selected from the group consisting of cycloalkyl. In some embodiments, any substituent is selected from the group consisting of oxo and C 1-5 alkyl. - In some embodiments, any substituent is oxo. In other embodiments, any substituent is C 1-5 alkyl. In some embodiments, C 1-5 alkyl is methyl, ethyl, propyl or isopropyl. In certain embodiments, C 1-5 alkyl is methyl, ethyl, or isopropyl. In other embodiments, C 1-5 alkyl is methyl. In some embodiments, C 3-6 cycloalkyl is cyclopropyl or cyclohexyl. In some embodiments, aryl is phenyl. In certain embodiments, alkylene carbocyclicryl is methylene cyclopropyl or methylene cyclohexyl. In some embodiments, alkenylenyl is methylene phenyl.

[0524] In some embodiments of formula (X), m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0525] In some embodiments of formula (X), n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0526] In some embodiments of formula (X), m is 0 and n is 1. In other embodiments, m is 1 and n is 1. In still other embodiments, m is 0 and n is 2. In yet another embodiment, m is 2 and n is 1.

[0527] In some embodiments of formula (X), U is the United States, and in other embodiments, U is NH.

[0528] In some embodiments of formula (X), V is H, OH, NR 2 N 3 or N=CR 2 R 3 . In some embodiments of formula (X), V is H, OH, or NR 2 N 3 . In some embodiments, V and Y 1 together with the atom to which they are attached form an optionally substituted phenyl ring or pyridinyl ring. In some embodiments, V is NR 2 N 3 . In other embodiments, V is OH. In some embodiments, V is H.

[0529] In some embodiments of formula (X), W is N, and in other embodiments, W is CH.

[0530] In some embodiments of formula (X), X is O, S, or NR 6 . In some embodiments, X is O or NR 6 . In some embodiments, X is NR 6 . In one embodiment, X is O. In one embodiment, X is S. In one embodiment, X is -CH=CH or -CH=N-.

[0531] In some embodiments of formula (X), Y 1 or Y 2 is N. In some embodiments, Y 1 and Y 2Both are N. In some embodiments, Y 1 is N, and Y 2 is CH. In one embodiment, Y 1 is CH, and Y 2 is N.

[0532] In some embodiments of formula (X), U is S, W is N, and X is NR 6 is. In one embodiment, V is NR 2 NR 3 is.

[0533] In some embodiments of formula (X), U is S, W is N, and X is NR 6 is. In one embodiment, Y 1 and Y 2 are each N.

[0534] In some embodiments of formula (X), U is S, W is N, and X is NR 6 is. In one embodiment, V is NR 2 NR 3 is.

[0535] In some embodiments of formula (X), U is S, W is N, X is NR 6 is, and Y 1 and Y 2 are each N. In certain embodiments, V is NR 2 NR 3 is.

[0536] In some embodiments of formula (X), U is S, W is N, X is NR 6 is, and V is NR 2 NR 3 is. In one embodiment, Y 1 and Y 2 are each N.

[0537] In some embodiments of formula (X), R 1 is H, OH, or C 1-5is alkyl. In other embodiments, R 1 is H, and in some embodiments, R 1 is OH. In one embodiment, R 1 is C 1-5 alkyl. In some embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isoamyl, and isobutyl. In other embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, and isopropyl.

[0538] In some embodiments of formula (X), R 2 and R 3 are independently H, C 1-5 alkyl, -CH2Ph, or -C(O)(C 1-5 alkyl). In one embodiment, R 2 and R 3 are independently H, C 1-5 alkyl, -CH2Ph, or -C(O)(CH3). In one embodiment, one of R 2 and R 3 is H. In some embodiments, R 2 and R 3 are H. In some embodiments, one of R 2 and R 3 is C 1-5 alkyl. In one embodiment, one of R 2 and R 3 is -CH2Ph. In one embodiment, one of R 2 and R 3 is -C(O)(CH3). In some embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, and isopropyl.

[0539] In some embodiments of formula (X), R 4 is aryl or heteroaryl, each of which may be optionally substituted. In one embodiment, R 4is an optionally substituted aryl. In certain embodiments, R 4 is an optionally substituted heteroaryl. In some embodiments, the heteroaryl is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, indolyl, oxindolyl, isatinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothiophenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl. In some embodiments, the aryl is a 6- to 12-membered aryl and the heteroaryl is a 5- to 12-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In certain embodiments, the 5- to 12-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, tetrazolyl, or pyrazolyl. In some embodiments, the 5- to 12-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S is pyridinyl, pyrazinyl, or pyrimidinyl.

[0540] In some embodiments of formula (X), the aryl or heteroaryl is optionally substituted with one or more H, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, C(O)Oalkylenearyl, -C(O)Oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN. In other embodiments, the aryl or heteroaryl is optionally substituted with one or more H, halogen, -C 1-5 alkyl, CF3, -OH, O(C1-5 substituted with -C(O)(alkyl), -OCF3, -OSO2Me, -COOH, -C(O)OMe, or -SO2Me. In some embodiments, the aryl is optionally substituted phenyl. In certain embodiments, the heteroaryl is optionally substituted pyridinyl. In certain embodiments, the optionally substituted pyridinyl is

[0541]

Chemical formula

[0542] selected from the group consisting of, where p is 0, 1, or 2. In certain embodiments, the heteroaryl is optionally substituted pyrimidinyl. In certain embodiments, the optionally substituted pyrimidinyl is

[0543]

Chemical formula

[0544] where p is 0, 1, or 2. In some embodiments, each R 8 is independently halogen, alkyl, -OH, -Oalkyl, -CO2H, or -CO2alkyl.

[0545] In some embodiments of formula (X), R 4 is

[0546]

Chemical formula

[0547] optionally substituted aryl selected from the group consisting of.

[0548] In some embodiments, R 4 is

[0549]

Chemical formula

[0550] It is an optionally substituted heteroaryl selected from the group consisting of.

[0551] In some embodiments, R 4 is

[0552]

Chemical formula

[0553] selected from the group consisting of. In some embodiments, each R 8 is independently halogen, alkyl, haloalkyl, alkenyl, -OH, -Oalkyl, -N(alkyl)2, -CO2H, -CO2alkyl, or -CN.

[0554] In some embodiments, R 4 is

[0555]

Chemical formula

[0556] selected from the group consisting of, wherein: each R 8 is independently halogen, C 1-5 5alkyl, -OH, -OC 1-5 alkyl, -COOH, or CO2C 1-5 alkyl; p is an integer from 0 to 3.

[0557] In some embodiments of formula (X), R 4 is carbocyclic. In one embodiment, the carbocyclic is an optionally substituted C 3-6 carbocyclic. In one embodiment, the carbocyclic is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the carbocyclic is cyclohexyl.

[0558] In some embodiments of formula (X), R 4 is heterocyclyl. In certain embodiments, the heterocyclyl is an optionally substituted 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

[0559] In some embodiments of formula (X), R 5 is H, -C(O)C 1-5 alkyl, C 1-5 alkyl, C 3-6 carbocyclyl, -CH2-aryl, or CH2-(C 3-6 6carbocyclyl). In certain embodiments, R 5 is H, C(O)C 1-5 alkyl, C 1-5 alkyl, C 3-6 carbocyclyl. In certain embodiments, R 5 is H, -C(O)C 1-5 alkyl, or C 1-5 alkyl. In certain embodiments, R 5 is H or C 1-5 alkyl. In some embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, and isopropyl. In certain embodiments, C 3-6 carbocyclyl is cyclopropyl or cyclohexyl. - In certain embodiments, R 5 is H, Me, or CH2Ph. In some embodiments, R 5 is H.

[0560] In some embodiments of formula (X), R 6 is H, C 1-5 alkyl, CH2aryl, or CH2(C 3-6 carbocyclyl). In certain embodiments, R 6 is H, C 1-5is alkyl or CH2Ph. In certain embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, and isopropyl. In some embodiments, R 6 is H.

[0561] In some embodiments of formula (X), R 7 is C 3-6 6 - carbocyclic, 3 - to 6 - membered heterocyclic, or 5 - to 6 - membered heteroaryl. In certain embodiments, R 7 is C 3-6 carbocyclic. In certain embodiments, C 3-6 carbocyclic is cyclopropyl or cyclohexyl. In certain embodiments, R 7 is 5 - to 6 - membered heteroaryl. In some embodiments, the 5 - to 6 - membered heteroaryl is selected from the group consisting of oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, and pyrazinyl. In some embodiments, the 5 - to 6 - membered heteroaryl is

[0562]

Chemical formula

[0563] selected from the group consisting of, where X 1 is NR 6 S, or O, and R 6 is H or alkyl. In certain embodiments, R 7 is 5 - membered heteroaryl. In some embodiments, the 5 - membered heteroaryl is

[0564]

Chemical formula

[0565] selected from the group consisting of, where X 1 is NR 6, S, or O. In some embodiments, the 5-membered heteroaryl is selected from the group consisting of

[0566]

Chemical formula

[0567] , and X 1 is NR 6 , S, or O. In one embodiment, R 7 is a 3- to 6-membered heterocyclyl. In some embodiments, the 3- to 6-membered heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0568] In some embodiments, each R8 is independently halogen, alkyl, haloalkyl, alkenyl, -OH, -Oalkyl, -N(alkyl)2, -CO2H, -CO2alkyl, or -CN. In some embodiments, each R 8 is independently halogen, alkyl, haloalkyl, -OH, -Oalkyl, -Ohaloalkyl, or -CO2H. In some embodiments, each R 8 is independently halogen, alkyl, -OH, -Oalkyl, or -CO2H.

[0569] In some embodiments, the compound of formula (X) has a structure according to one of the following, or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof:

[0570]

Chemical formula

[0571]

Chemical formula

[0572]

Chemical formula

[0573]

Chem.

[0574]

Chem.

[0575]

Chem.

[0576]

Chem.

[0577]

Chem.

[0578] In some embodiments, the compound of formula (X) has a structure according to one of the following, or is a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof:

[0579]

Chem.

[0580]

Chem.

[0581] In some embodiments, the compound of formula (X) has a structure according to one of the following, or is a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof:

[0582]

Chem.

[0583] [Chemical formula]

[0584] In some embodiments, the compound of formula (X) is as follows:

[0585] [Chemical formula]

[0586] has a structure according to the following, or is a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

[0587] In some embodiments, the compound of formula (X) is a compound provided in Table 2, Table 3 or Table 4 below. In some embodiments, the compound of formula (X) is a compound provided in Table 2. In some embodiments, the compound of formula (X) is a compound provided in Table 3.

[0588] In some embodiments herein, the compound of formula (X) is

[0589] [Chemical formula]

[0590] not one or more of the following. Wherein: (a) R 2 is H, and R 4 is

[0591] [Chemical formula]

[0592] ; or (b) R 2 is Me, and R 4 is

[0593] [Chemical formula]

[0594] and is; or (c) R 2 is Et, and R 4 is

[0595] [Chemical formula]

[0596] and is; or (d) R 2 is nPr, C(O)Me or CO2nBu, and R 4 is

[0597] [Chemical formula]

[0598] is.

[0599] In some embodiments of the present specification, the compound of formula (X) is not one or more of the following:

[0600] [Chemical formula]

[0601] [Chemical formula]

[0602] In some embodiments of the present specification, the compound of formula (X) is not the following:

[0603] [Chemical formula]

[0604] In some embodiments of formula (X), -L-R 4 when it is -alkylene-aryl, the compound of formula (X) is not the following:

[0605]

Chemical formula

[0606] wherein: (a) R 2 is H, and R 4 is

[0607]

Chemical formula

[0608]

Chemical formula

[0609] or (b) R 2 is Me, and R 4 is

[0610]

Chemical formula

[0611] or (c) R 2 is Et, and R 4 is

[0612]

Chemical formula

[0613] or (d) R 2 is nPr, C(O)Me or CO2nBu, and R 4 is

[0614] [Chemical formula]

[0615] is.

[0616] In some embodiments of formula (X), -L-R 4 when it is -alkylene-aryl, the compound of formula (X) is not the following:

[0617] [Chemical formula]

[0618] In some embodiments of formula (X), -L-R 4 when it is -alkenylene-aryl, the compound of formula (X) is not the following:

[0619] [Chemical formula]

[0620] In some embodiments of formula (X), -L-R 4 when it is -CH2C(O)-aryl, the compound of formula (X) is not the following:

[0621] [Chemical formula]

[0622] In some embodiments of formula (X), -L-R 4 when it is -CH2C(O)N(R 5 ), -aryl, the compound of formula (X) is not the following:

[0623] [Chemical formula]

[0624] In some embodiments of formula (X), -L-R 4When it is -alkylene-heteroaryl, the compound of formula (X) is not the following:

[0625]

Chemical formula

[0626] In various embodiments of the present disclosure, the compound of formula (X) is not the compound disclosed in WO2019 / 051269 or WO2019 / 046778.

[0627] In some embodiments of the present disclosure, the compound of formula (X) is a compound of formula (XX):

[0628]

Chemical formula

[0629] or a pharmaceutically acceptable salt, hydrate, or tautomer thereof, wherein L, W, X, Y 1 , Y 2 , R 1 , R 2 , R 3 , and R 4 are as defined above for formula (X).

[0630] In some embodiments, the compound of formula (XX) is

[0631]

Chemical formula

[0632] selected from the group consisting of, wherein R 1 , R 2 , R 3 , and R 6 are as defined above for formula (X). In some embodiments, the compound of formula (XX) is

[0633] [Chemistry]

[0634] selected from the group consisting of. In some embodiments, the compound of formula (XX) is

[0635] [Chemistry]

[0636] selected from the group consisting of. In one embodiment, the compound of formula (XX) is

[0637] [Chemistry]

[0638] wherein R 1 , R 2 , R 3 , and R 6 are as defined above for formula (X).

[0639] In some embodiments of the present disclosure, the compound of formula (X) is of formula (XXa):

[0640] [Chemistry]

[0641] is a compound of or a pharmaceutically acceptable salt, hydrate, or tautomer thereof, wherein L, W, X, Y 1 , Y 2 , R 1 , R 2 , and R 3 are as defined above for formula (X), and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently CR 8 or N.

[0642] In some embodiments of formula (XXa), Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is CR 8 . In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 at least one of is N. In other embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 one of is N. In still other embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 two of are N. In some embodiments, Z 1 and Z 5 are N, and Z 2 -Z 4 is CR 8 . In some embodiments, Z 5 is N, and Z 1 -Z 4 is CR 8 .

[0643] In some embodiments of formula (XXa), each R 8 is, independently, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO2NH2, SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN. In some embodiments, each R 8 is, independently, H, halogen, -C 1-5Alkyl, CF3, -OH, O(C 1-5 alkyl), -OCF3, -OSO2Me, -COOH, -C(O)OMe, or -SO2Me.

[0644] In some embodiments of formula (XXa),

[0645]

Chem.

[0646] is

[0647]

Chem.

[0648] selected from the group consisting of.

[0649] In some embodiments of formula (XXa),

[0650]

Chem.

[0651] is

[0652]

Chem.

[0653] selected from the group consisting of, wherein p is 0, 1, or 2.

[0654] In some embodiments of formula (XXa),

[0655]

Chem.

[0656] is

[0657] [Chemical formula]

[0658] selected from the group consisting of, and p is 0, 1, or 2.

[0659] In some embodiments of the present disclosure, the compound of formula (X) is of formula (XXb):

[0660] [Chemical formula]

[0661] a compound of or a pharmaceutically acceptable salt, hydrate, or tautomer thereof, wherein L, W, X, Y 1 , Y 2 , R 1 , R 2 , R 3 , R 5 , m, and as defined above for formula (X), and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 is each independently CR 8 or N.

[0662] In some embodiments of formula (XXb), Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is CR 8 . In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 at least one of is N. In other embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 one of is N. Z 1 , Z2 , Z 3 , Z 4 , and Z 5 Two of them are N. In some embodiments, Z 1 and Z 5 are N, and Z 2 -Z 4 is CR 8 In some embodiments, Z 5 is N, and Z 1 -Z 4 is CR 8 In some embodiments of formula (XXb), each R

[0663] is, independently, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO2NH2, SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN. In some embodiments, each R 8 is, independently, H, halogen, -C 8 alkyl, CF3, -OH, O(C 1-5 alkyl), -OCF3, -OSO2Me, -COOH, -C(O)OMe, or -SO2Me. 1-5 alkyl), -OCF3, -OSO2Me, -COOH, -C(O)OMe, or -SO2Me.

[0664] In some embodiments of (XXb),

[0665]

Chemical formula

[0666] is

[0667]

Chemical formula

[0668] is selected from the group consisting of.

[0669] In some embodiments of formula (XXb),

[0670]

Chemical formula

[0671] is

Chemical formula

[0672] selected from the group consisting of, and p is 0, 1, or 2.

[0673] In some embodiments of formula (XXb),

Chemical formula

[0674]

Chemical formula

[0675] selected from the group consisting of, and p is 0, 1, or 2.

[0676] In some embodiments of the present disclosure, the compound of formula (X), formula (XXa), or formula (XXb) is

[0677]

Chemical formula

[0678] selected from the group consisting of, wherein R 1 , R 2 , R 3 , R 5 , R 6 , m and n are as defined above for formula (X), and Z 1 , Z2 , Z 3 , Z 4 , Z 5 is each as defined above for formula (XXa) and independently is CR 8 or N.

[0679] In some embodiments of the present disclosure, the compounds of formula (X), formula (XXa), or formula (XXb) are

[0680]

Chemical formula

[0681] selected from the group consisting of.

[0682] selected from the group consisting of, and R 1 , R 2 , R 3 , R 5 , R 5a , R 5b , and R 6 are as defined above for formulas (A1), (A2), and (X), and Z 1 , Z 2 , Z 3 , Z 4 , Z 5 are each independently CR as defined above for formula (XXa) 8 or N.

[0683] In some embodiments of formula (XXc), formula (XXd), formula (XXe), and formula (XXf), Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 each is CR 8 . In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 at least one of is N. In other embodiments, Z 1 , Z 2 , Z 3 , Z4 and Z 5 One of them is N. Z 1 Z 2 Z 3 Z 4 and Z 5 Two of them are N. In some embodiments, Z 1 and Z 5 are N, and Z 2 -Z 4 is CR 8 In some embodiments, Z 5 is N, and Z 1 -Z 4 is CR 8 In some embodiments of Formula (XXc), Formula (XXd), Formula (XXe), and Formula (XXf), each R

[0684] is, independently, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN. In some embodiments, each R 8 is, independently, H, halogen, -C 8 alkyl, CF3, -OH, -O(C 1-5 alkyl), -OCF3, -OSO2Me, COOH, -C(O)OMe, or -SO2Me. 1-5 alkyl), -OCF3, -OSO2Me, COOH, -C(O)OMe, or -SO2Me.

[0685] In some embodiments of Formula (XXc), Formula (XXd), Formula (XXe), and Formula (XXf),

[0686]

Chemical Formula

[0687] is

[0688]

Chem.

[0689] selected from the group consisting of.

[0690] In some embodiments of formula (XXc), formula (XXd), formula (XXe), and formula (XXf),

[0691]

Chem.

[0692] is

[0693]

Chem.

[0694] selected from the group consisting of, wherein p is 0, 1, or 2.

[0695] In some embodiments of formula (XXc), formula (XXd), formula (XXe), and formula (XXf),

[0696]

Chem.

[0697] is

[0698]

Chem.

[0699] selected from the group consisting of, wherein p is 0, 1, or 2.

[0700] In some embodiments, the present disclosure provides a compound of formula (Y), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof:

[0701]

Chem.

[0702] In the formula, U is C or N, Here, When U is C, Y is

[0703]

Chem.

[0704] or When U is N, Y is

[0705]

Chem.

[0706] and V is N or CR 10 and W is CH or N; X is S, O, N-L-R 11 , or NR 12 and L is alkylene, alkenylene, optionally substituted -alkylene-(NR 12 )-, optionally substituted

[0707]

Chem.

[0708] optionally substituted

[0709]

Chem.

[0710] optionally substituted

[0711]

Chem.

[0712] optionally substituted

Chem.

[0713] optionally substituted

[0714]

Chem.

[0715]

Chem.

[0716] selected from, R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, alkylenecarbocyclic, -O-L-R 11 , -SLR 11 , -N(R 12 )-L-R 11 , -L-R 11 ; R 11 is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl, each of which may be optionally substituted; R 12 are each independently H, alkyl, alkylenecarbocyclic, or carbocyclic, where two R 12 groups, when combined with the carbon atoms to which they are attached, can form a heterocyclic ring; R 14 is carbocyclic, heterocyclic, or heteroaryl; R 15is H, alkyl, carbocyclic, alkylenecarbocyclic, or alkylenearyl; Z 1 , Z 2 , Z 3 , and Z 4 are each independently CR 13 or N; R 13 is H, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, C(O)Oalkylenearyl, -C(O)Oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN, and two R13s, together with the atoms to which they are attached, form carbocyclic, heterocyclic, or heteroaryl, each being optionally substituted; m is 0, 1, or 2; n is 1, 2, or 3. Provided that when X is N-L-R 11 or R 10 , either is -O-L-R 11 , -S-L-R 11 , -N(R 12 )-L-R 11 or -L-R 11 .

[0717] In certain embodiments, X is N-L-R 11 , and R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, or alkylenecarbocyclic. In other embodiments, X is S, O, or NR 12 , and R 10 is -O-L-R 11 , -S-L-R 11 , -N(R 12 )-L-R 11 , or -L-R 11 .

[0718] In some embodiments, the present disclosure provides a compound of formula (Y), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof:

[0719]

Chemical formula

[0720] Wherein: U is C or N; Here, When U is C, Y is,

[0721]

Chemical formula

[0722] or When U is N, Y is,

[0723]

Chemical formula

[0724] ; V is N or CR 10 ; W is CH or N; X is S, O, N-L-R 11 , or NR 12 ; L is alkylene, alkenylene, optionally substituted -alkylene-(NR 12 ), optionally substituted

[0725]

Chemical formula

[0726] optionally substituted

[0727]

Chemical formula

[0728] Optionally substituted

[0729] [Chem.]

[0730] Optionally substituted

[0731] [Chem.]

[0732] Optionally substituted

[0733] [Chem.]

[0734] [Chem.]

[0735] selected from: R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, alkylenecarbocyclic, -O-L-R 11 , -S-L-R 11 , -N(R 12 )-L-R 11 , -L-R 11 ; R 11 is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl, each of which may be optionally substituted; R 12 are each independently H, alkyl, alkylenecarbocyclic, or carbocyclic, where two R 12 groups, together with the carbon atom to which they are attached, can combine to form a heterocyclic ring; R14 is a carbocyclic, heterocyclic, or heteroaryl; R 15 is H, alkyl, carbocyclic, alkylenecarbocyclic, or alkylene aryl; wherein when X is N-L-R 11 V is N or CR 10 wherein R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, or alkylenecarbocyclic; when X is S, O, NR 12 ; V is CR 10 wherein R 10 is -O-L-R 11 -S-L-R 11 -N(R 12 )-L-R 11 or -L-R 11 ; when U is N, V is CR 10 wherein R 10 is -O-L-R 11 -S-L-R 11 -N(R 12 )-L-R 11 or -L-R 11 ; Z 1 Z 2 Z 3 and Z 4 are each independently CR 13 or N; R 13is H, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, C(O)Oalkylenearyl, -C(O)Oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN, and two R13s, together with the atoms to which they are attached, form carbocyclic, heterocyclic, or heteroaryl, each optionally substituted; m is 0, 1, or 2; n is 1, 2, or 3.

[0736] In some embodiments of formula (Y), U is C. In other embodiments, U is N.

[0737] In some embodiments of formula (Y), when U is C, Y is

[0738]

Chemical formula

[0739] as follows. In other embodiments, when U is N, Y is

[0740]

Chemical formula

[0741] as follows.

[0742] In some embodiments of formula (Y), V is N, and in other embodiments, V is CR 10 as follows.

[0743] In some embodiments of formula (Y), W is N. In other embodiments, W is CH.

[0744] In some embodiments of formula (Y), when X is S, O, or NH, V is CR 10 wherein R 10 is -O-L-R 11 , -S-L-R 11 , -N(R 12 )-L-R 11 , or -L-R 11 . In some embodiments, when X is S or O, V is CR 10 wherein R 10 is -O-L-R 11 , -S-L-R 11 , -N(R 12 )-L-R 11 , or -L-R 11 . In one embodiment, when X is S, O, or NH, V is CR 10 wherein R 10 is -S-L-R 11 or -N(R 12 )-L-R 11 . In one embodiment, when X is S, O, or NH, V is CR 10 wherein R 10 is -S-L-R 11 . In one embodiment, when X is S or O, V is CR 10 wherein R 10 is -S-L-R 11 or -N(R 12 )-L-R 11 . In one embodiment, when X is S or O, V is CR 10 wherein R 10 is -S-L-R 11 . In one embodiment, when X is NH, V is CR 10 wherein R 10 is -O-L-R 11 , -S-L-R 11 , -N(R 12 )-L-R 11 , or -L-R 11 . In one embodiment, when X is NH, V is CR 10 wherein R 10-S-L-R 11 or -N(R 12 )L-R 11 is. In certain embodiments, when X is NH, V is CR 10 , where R 10 is -S-L-R 11 .

[0745] In some embodiments of formula (Y), X is N-L-R 11 and V is N. In some embodiments, X is N-L-R 11 and V is CR 10 , where R 10 is H, alkyl, -O-alkyl, or -S-alkyl. In certain embodiments, X is N-L-R 11 and V is CR 10 , where R 10 is H, -O-alkyl, or -S-alkyl. In certain embodiments, X is N-L-R 11 and CR 10 , where R 10 is H. In some embodiments of formula (Y), X is N-L-R 11 and V is CR 10 , where R 10 is H, alkyl, -O-alkyl, or -S-alkyl.

[0746] In some embodiments of formula (Y), L is -alkylene-(NR 12 )-

[0747]

Chemical formula

[0748] and each is optionally substituted. In some embodiments, L is optionally substituted

[0749]

Chemical formula

[0750] Optionally substituted

[0751] [Chemical formula]

[0752] Optionally substituted

[0753] [Chemical formula]

[0754] Optionally substituted

[0755] [Chemical formula]

[0756] Optionally substituted

[0757] [Chemical formula]

[0758] Optionally substituted

[0759] [Chemical formula]

[0760] is. In some embodiments, L is optionally substituted

[0761] [Chemical formula]

[0762] Optionally substituted

[0763] [Chemical formula]

[0764] Arbitrarily substituted

[0765] [Chem.]

[0766] Arbitrarily substituted

[0767] [Chem.]

[0768] is. In some embodiments, L is arbitrarily substituted

[0769] [Chem.]

[0770] Arbitrarily substituted

[0771] [Chem.]

[0772] Arbitrarily substituted

[0773] [Chem.]

[0774] is. In some embodiments, L is arbitrarily substituted or arbitrarily substituted

[0775] [Chem.]

[0776] [Chem.]

[0777] is. In some embodiments, L is optionally substituted

[0778]

Chemical formula

[0779] is. In other embodiments, L is optionally selected

[0780]

Chemical formula

[0781] is. In still other embodiments, L is optionally substituted

[0782]

Chemical formula

[0783] In yet other embodiments, L is optionally substituted

[0784]

Chemical formula

[0785] is. In another embodiment, L is optionally substituted

[0786]

Chemical formula

[0787] is. In yet another embodiment, L is optionally substituted

[0788]

Chemical formula

[0789] is. In some embodiments, L is

[0790]

Chem.

[0791] is. In some embodiments, L is

[0792]

Chem.

[0793] is. In some embodiments, L is

[0794]

Chem.

[0795] is. In some embodiments, L is

[0796]

Chem.

[0797] is. In some embodiments, L is

[0798]

Chem.

[0799] is. In other embodiments, L is

[0800]

Chem.

[0801] is. In still other embodiments, L is

[0802]

Chem.

[0803] is. Further, in other embodiments, L is

[0804]

Chemical formula

[0805] is. In another embodiment, L is

[0806]

Chemical formula

[0807] is. Further, in yet another embodiment, L is

[0808]

Chemical formula

[0809] is.

[0810] In some embodiments of formula (Y), L is

[0811]

Chemical formula

[0812] wherein: R 15 is as defined above for formula (Y); R 15a and R 15b are each independently selected from the group consisting of H, halogen, C 1-5 alkyl, C 3-6 carbocyclic, alkylene-C 3-6 carbocyclic, aryl, alkenylenyl, or NH2, where two C 1-5 alkyl together with the carbon atom to which they are attached form a C 3-6 carbocyclic; m is 0 or 1.

[0813] In some embodiments of formula (Y), L is

[0814]

Chemical formula

[0815] selected from the group consisting of

[0816] In some embodiments of formula (Y), L is

[0817]

Chemical formula

[0818] selected from the group consisting of

[0819] In some embodiments of formula (Y), when L contains alkylene, the alkylene is optionally substituted C 1-4 alkylene. In some embodiments, the alkylene is optionally substituted C 1-3 alkylene. In some embodiments, the alkylene is optionally substituted C 1-32 alkylene. In some embodiments, the alkylene is optionally substituted C 2-4 alkylene. In some embodiments, the alkylene is optionally substituted C 2-3 alkylene. In some embodiments, the alkylene is optionally substituted C 3-4 alkylene. In some embodiments, when L contains alkylene, the alkylene is C 1-4 alkylene. In some embodiments, the alkylene is C 1-3 alkylene. In some embodiments, the alkylene is C 1-2 alkylene. In some embodiments, the alkylene is C 2-4It is alkylene. In some embodiments, the alkylene is C 2-3 It is alkylene. In some embodiments, the alkylene is C 3-4 It is alkylene. In some embodiments, the alkylene is methylene, ethylene, propylene, or butylene, each of which may be optionally substituted. In some embodiments, the alkylene is ethylene, propylene, or butylene, each of which may be optionally substituted. In some embodiments, the alkylene is optionally substituted methylene. In some embodiments, the alkylene is optionally substituted ethylene. In some embodiments, the alkylene is optionally substituted propylene. In some embodiments, the alkylene is optionally substituted butylene. In certain embodiments, the alkylene is methylene, ethylene, propylene, or butylene. In some embodiments, the alkylene is methylene. In some embodiments, the alkylene is ethylene. In some embodiments, the alkylene is propylene. In some embodiments, the alkylene is butylene.

[0820] In some embodiments of formula (Y), when L contains alkenylene, the alkenylene is optionally substituted C 2-4 It is alkenylene. In some embodiments, the alkenylene is optionally substituted C 2-3 It is alkenylene. In some embodiments, the alkenylene is optionally substituted C 3-4 It is alkenylene. In some embodiments, when L contains alkenylene, the alkenylene is C 2-4 It is alkenylene. In some embodiments, the alkenylene is C 2-3 It is alkenylene. In some embodiments, the alkenylene is C 3-4It is alkenylene. In certain embodiments, the alkenylene is ethynylene, propenylene, or butenylene, each of which may be optionally substituted. In some embodiments, the alkenylene is optionally substituted ethynylene. In some embodiments, the alkenylene is optionally substituted propenylene. In some embodiments, the alkenylene is optionally substituted butenylene. In some embodiments, the alkenylene is ethynylene, propenylene or butenylene. In some embodiments, the alkenylene is ethynylene. In some embodiments, the alkenylene is propenylene. In some embodiments, the alkenylene is butenylene.

[0821] In some embodiments of formula (Y), any substituent is selected from the group consisting of oxo, halogen, C15 alkyl, C 3-6 carbocyclic, alkylene carbocyclic, aryl, heteroaryl, alkylene aryl, and alkylene heteroaryl. In some embodiments, any substituent is selected from the group consisting of oxo, C 1-5 alkyl, and C 3-6 cycloalkyl. In some embodiments, any substituent is selected from the group consisting of oxo and C 1-5 alkyl. In some embodiments, any substituent is oxo. In other embodiments, any substituent is C 1-5 alkyl. In some embodiments, C 1-5 alkyl is methyl, ethyl, propyl or isopropyl. In certain embodiments, C 1-5 alkyl is methyl, ethyl, or isopropyl. In other embodiments, C 1-5 alkyl is methyl. In some embodiments, C 3-6The cycloalkyl is cyclopropyl or cyclohexyl. In some embodiments, the aryl is phenyl. In certain embodiments, the alkylene carbocyclyl is methylenecyclopropyl or methylenecyclohexyl. In some embodiments, the alkenylenyl is methylenephenyl.

[0822] In some embodiments of formula (Y), R 11 is heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted. In certain embodiments, R 11 is aryl or heteroaryl, each of which may be optionally substituted. In certain embodiments, R 11 is optionally substituted aryl. In certain embodiments, the aryl is optionally substituted 6- to 12-membered aryl. In some embodiments, the aryl is optionally substituted phenyl. In some embodiments of formula (Y), the optionally substituted phenyl is selected from the group consisting of:

[0823]

Chemical formula

[0824] selected from the group consisting of.

[0825] In certain embodiments, R 11is a heteroaryl optionally substituted. In some embodiments, the heteroaryl is a 5- to 12-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heteroaryl is an optionally substituted 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from S, O, and N. In some embodiments, the 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments, the optionally substituted heteroaryl is the following:

[0826] [Chemical formula]

[0827] selected from the group consisting of. In one embodiment, the heteroaryl is an optionally substituted pyridinyl. In one embodiment, the optionally substituted pyridinyl is

[0828] [Chemical formula]

[0829] selected from the group consisting of, and p is 0, 1, or 2.

[0830] In some embodiments, aryl or heteroaryl is optionally substituted with one or more H, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, C(O)Oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, N(H)SO2alkyl, -N(H)SO2aryl, or -CN. In some embodiments, aryl or heteroaryl is optionally substituted with one or more H, halogen, -C 1-5 alkyl, CF3, -OH, -O(C 1-5 alkyl), OCF3, -OSO2Me, -COOH, -C(O)OMe, or -SO2Me.

[0831] In certain embodiments, R 11 is optionally substituted heterocyclyl. In some embodiments, heterocyclyl is a 4- to 6-membered heterocyclyl which is substituted when having 1 or 2 heteroatoms selected from S, O, and N. In some embodiments, heterocyclyl is a 3- to 6-membered heterocyclyl which is substituted when having a maximum of 2 nitrogen atoms. In certain embodiments, heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

[0832] In some embodiments of formula (Y), R 12 are each independently H, C 1-5 alkyl, CH2aryl, or CH2(C 3-6 carbocyclic). In certain embodiments, R 12 are each independently H, C 1-5 alkyl, or CH2Ph. In some embodiments of formula (Y), R 12 are each independently H or C 1-5 alkyl. In certain embodiments, C1-5 Alkyl is selected from the group consisting of methyl, ethyl, and isopropyl. In some embodiments, each R 12 is independently H.

[0833] In some embodiments of formula (Y), R 14 is heterocyclyl or heteroaryl. In certain embodiments, R 14 is heteroaryl. In some embodiments, the heteroaryl is an optionally substituted 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from S, O, and N. In some embodiments, the heteroaryl is

[0834]

Chemical formula

[0835] selected from the group consisting of, wherein X 1 is NR 16 S, or O; R 16 is H or alkyl. In some embodiments of formula (Y), R 14 is heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl which is substituted when having 1, 2, or 3 heteroatoms selected from S, O, and N. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl which is substituted when having a maximum of 2 nitrogen atoms. In some embodiments, the heterocyclyl is

[0836]

Chemical formula

[0837] selected from the group consisting of.

[0838] In some embodiments of formula (Y), R 15is H or alkyl. In some embodiments, the alkyl is C 1-5 alkyl. In certain embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isoamyl, and isobutyl. In other embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, and isopropyl.

[0839] In some embodiments of formula (Y), Z 1 , Z 2 , Z 3 , and Z 4 each is CR 13 . In some embodiments, at least one of Z 1 , Z 2 , Z 3 , and Z 4 is N. In some embodiments, one of Z 1 , Z 2 , Z 3 , and Z 4 is N. In some embodiments, two of Z 1 , Z 2 , Z 3 , and Z 4 are N. In certain embodiments, Z 1 is N and Z 2 , Z 3 , and Z 4 are CR 13 . In other embodiments, Z 2 is N and Z 1 , Z 3 , and Z 4 are CR 13 . In yet other embodiments, Z 3 is N and Z 1 , Z 2 , and Z 4 are CR 13 . In yet other embodiments, Z 4 is N and Z 1 , Z 2 , and Z 3 are CR 13 . In another embodiment, Z1 and Z 4 are each N, and Z 2 and Z 3 is CR 13 is. In yet another embodiment, Z 1 and Z 3 are each N, and Z 2 and Z 4 is CR 13 is. In yet another embodiment, Z 2 and Z 4 are each N, and Z 1 and Z 3 is CR 13 is.

[0840] In some embodiments of formula (Y), each R 13 is, independently, H, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, OSO2NH2, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, C(O)Oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, N(H)SO2alkyl, -N(H)SO2aryl, or -CN. In other embodiments, each R 13 is, independently, H, halogen, -C 1-5 alkyl, CF3, -OH, -O(C 1-5 alkyl), -OCF3, -OSO2Me, -COOH, -C(O)OMe, or -SO2Me. In some embodiments, two Rs 13 when taken together with the atoms to which they are attached, can form a carbocyclic, heterocyclic, or heteroaryl, each of which may be optionally substituted.

[0841] In some embodiments of formula (Y), m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0842] In some embodiments of formula (Y), n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0843] In some embodiments of formula (Y), m is 0 and n is 1. In other embodiments, m is 1 and n is 1. In still other embodiments, m is 0 and n is 2. In yet other embodiments, m is 2 and n is 1.

[0844] In some embodiments, the compound of formula (Y) is

[0845]

Chemical formula

[0846] selected from the group consisting of, or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof, wherein: L, R 11 , and R 13 are as defined above for formula (Y); o is an integer from 1 to 3.

[0847] In some embodiments, the compound of formula (Y) is

[0848]

Chemical formula

[0849] or a pharma- ceutically acceptable salt, tautomer, solvate, or hydrate thereof, wherein: L, R 10 , R 11 , and R 13 is as defined above for formula (Y); o is an integer from 1 to 3.

[0850] In some embodiments, the present disclosure provides a compound having the following structure:

[0851] [ka]

[0852] [ka]

[0853] [ka]

[0854] [ka]

[0855] or a pharma- ceutically acceptable salt, tautomer, solvate, or hydrate thereof.

[0856] In other embodiments, the present disclosure provides a compound having the following structure:

[0857] [ka]

[0858] [ka]

[0859] A compound of formula (Y) having one of the following, or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof.

[0860] In other embodiments, the present disclosure provides the following structure:

[0861]

Chem.

[0862]

Chem.

[0863] In yet another embodiment, the present disclosure provides the following structure:

[0864]

Chem.

[0865] A compound of formula (Y) having one of the following, or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof.

[0866] In various embodiments of the present disclosure, the compound of formula (Y) is not a compound disclosed in the following publications: (a) Chang, L., et al. J. Med. Chem. 2014, 57 (23), 10080 - 10100; (b) Vankayalapati, H., et al., US20109 / 0031655.

[0867] In some embodiments of the present disclosure, the compound of formula (Y) is a compound of formula (YY), or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof:

[0868]

Chem.

[0869] and in the formula, V, W, X, Z 1 , Z 2 , Z 3 , and Z 4 are as defined above for formula (Y).

[0870] In some embodiments of the present disclosure, the compound of formula (Y) is a compound of formula (YYa), or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof:

[0871]

Chem.

[0872] and in the formula: R 10 is H, alkyl, alkylenecarboxicyclic, carboxicyclic, -O-alkyl, -S-alkyl; L, R 11 , Z 1 , Z 2 , Z 3 , and Z 4 are as defined above for formula (Y).

[0873] In some embodiments of formula (YYa), alkyl is C 1-5 alkyl. In certain embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isoamyl, butyl, and isobutyl. In other embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, and isopropyl.

[0874] In some embodiments of formula (YYa), alkylene is optionally substituted C 1-4It is alkylene. In some embodiments, the alkylene is optionally substituted C 1-3 It is alkylene. In some embodiments, the alkylene is optionally substituted C 1-2 It is alkylene. In some embodiments, the alkylene is optionally substituted C 2-4 It is alkylene. In some embodiments, the alkylene is optionally substituted C 2-3 It is C3 alkylene. In some embodiments, the alkylene is optionally substituted C 3-4 It is alkylene. In some embodiments, when L contains alkylene, the alkylene is C 1-4 It is alkylene. In some embodiments, the alkylene is C 1-3 It is alkylene. In some embodiments, the alkylene is C 1-2 It is alkylene. In some embodiments, the alkylene is C 2-4 It is alkylene. In some embodiments, the alkylene is C 2-3 It is alkylene. - In some embodiments, the alkylene is C 3-4 It is alkylene. In some embodiments, the alkylene is methylene, ethylene, propylene, or butylene, each of which may be optionally substituted. In some embodiments, the alkylene is ethylene, propylene, or butylene, each of which may be optionally substituted. In some embodiments, the alkylene is optionally substituted methylene. In some embodiments, the alkylene is optionally substituted ethylene. In some embodiments, the alkylene is optionally substituted propylene. In some embodiments, the alkylene is optionally substituted butylene. In one embodiment, the alkylene is methylene, ethylene, propylene, or butylene. In some embodiments, the alkylene is methylene. In some embodiments, the alkylene is ethylene. In some embodiments, the alkylene is propylene. In some embodiments, the alkylene is butylene.

[0875] In some embodiments of formula (YYa), the carbocyclic ring is C 3-6 a carbocyclic ring. In certain embodiments, C 3-6 the carbocyclic ring is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0876] In some embodiments of the present disclosure, the compound of formula (Y) is a compound of formula (YYb), or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof:

[0877]

Chemical formula

[0878] wherein: X is O, S, or NR 12 ; R 10 is -O-L-R 11 , -S-L-R 11 , -N(R 12 )-L-R 11 , -L-R 11 ; R 11 , R 12 , L, Z 1 , Z 2 , Z 3 , and Z 4 are as defined above for formula (Y).

[0879] In some embodiments, the present disclosure provides a compound of formula (Z), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof:

[0880]

Chemical formula

[0881] wherein: Z 1 , Z 2 , Z 3 , Z4 , Z 5 , Z 6 , and Z 7 is each independently N or CR 22 , provided that (a) One of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is -L-R 18 -; (b) Two or less of Z 1 , Z 2 , Z 3 or Z 4 are N; and (c) Either Z 6 or Z 7 is N; Wherein: L is a linker selected from -N(R 19 ), -alkylene-(NR 19 ),

[0882]

Chemical formula

[0883] and each is optionally selected; R 18 is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl, each of which may be optionally substituted; R 19 is H, alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 20 is H, alkyl, alkylene carbocyclic, alkylene aryl; R 21 is carbocyclic, heterocyclic, or heteroaryl; R 22is, independently of one another, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, C(O)Oalkylenearyl, -C(O)oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN; m is 0, 1, or 2; n is 1, 2, or 3.

[0884] In some embodiments of formula (Z), Z 1 , Z 2 , Z 3 , and Z 4 each is, independently, N or CR 22 . In some embodiments, Z 1 , Z 2 , Z 3 , or Z 4 two of which are N. In some embodiments, Z 1 , Z 2 , Z 3 , or Z 4 one of which is N. In some embodiments, Z 1 , Z 2 , Z 3 , and Z 4 are each CR 22 . In one embodiment, Z 1 is N and Z 2 , Z 3 , and Z 4 are CR 22 . In other embodiments, Z 2 is N and Z 1 , Z 3 , and Z 4 are CR 22 . In yet other embodiments, Z 3 is N and Z 1 , Z 2 , and Z 4 are CR 13is. In yet another embodiment, Z 4 is N, and Z 1 , Z 2 , and Z 3 is CR 22 . In another embodiment, Z 1 and Z 4 are each N, and Z 2 and Z 3 is CR 22 . In yet another embodiment, Z 1 and Z 3 are each N, and Z 2 and Z 4 is CR 22 . In yet another embodiment, Z 2 and Z 4 are each N, and Z 1 and Z 3 is CR 22 .

[0885] In some embodiments of formula (Z), Z 6 is N, and one of Z 1 , Z 5 , or Z 7 is -L-R 18 -. In some embodiments, Z 6 is N, and one of Z 5 or Z 7 is -L-R 18 -. In other embodiments, Z 6 is N, Z 7 is CR 22 , and Z 5 is -L-R 18 -.

[0886] In some embodiments of formula (Z), Z 7 is N, and one of Z 1 , Z 5 , or Z 6 is -L-R 18 -. In some embodiments, Z 7 is N, and one of Z 5 or Z 6 is -L-R 18 -. In other embodiments, Z7 is N, and Z 6 is CR 22 and Z 5 is -L-R 18 -.

[0887] In some embodiments of formula (Z), L is

[0888]

Chemical formula

[0889] and each is optionally substituted. In some embodiments, L is

[0890]

Chemical formula

[0891] and each is optionally substituted. In other embodiments, L is

[0892]

Chemical formula

[0893] and each is optionally substituted. In other embodiments, L is

[0894]

Chemical formula

[0895] is

[0896] In some embodiments of formula (Z), L is the following:

[0897]

Chemical formula

[0898] selected from the group consisting of

[0899] In some embodiments of formula (Z), when L contains alkylene, the alkylene is optionally substituted C 1-4 alkylene. In some embodiments, the alkylene is optionally substituted C 1-3 alkylene. In some embodiments, the alkylene is optionally substituted C 1-2 alkylene. In some embodiments, the alkylene is optionally substituted C 2-4 alkylene. In some embodiments, the alkylene is optionally substituted C 2-3 alkylene. In some embodiments, the alkylene is optionally substituted C 3-4 alkylene. In some embodiments, when L contains alkylene, the alkylene is C 1-4 alkylene. In some embodiments, the alkylene is C 1-3 alkylene. In some embodiments, the alkylene is C 1-2 alkylene. In some embodiments, the alkylene is C 2-4 alkylene. In some embodiments, the alkylene is C 2-3 alkylene. In some embodiments, the alkylene is C 3-4It is alkylene. In some embodiments, the alkylene is methylene, ethylene, propylene, or butylene, each of which may be optionally substituted. In some embodiments, the alkylene is ethylene, propylene, or butylene, each of which may be optionally substituted. In some embodiments, the alkylene is optionally substituted methylene. In some embodiments, the alkylene is optionally substituted ethylene. In some embodiments, the alkylene is optionally substituted propylene. In some embodiments, the alkylene is optionally substituted butylene. In certain embodiments, the alkylene is methylene, ethylene, propylene, or butylene. In some embodiments, the alkylene is methylene. In some embodiments, the alkylene is ethylene. In some embodiments, the alkylene is propylene. In some embodiments, the alkylene is butylene.

[0900] In some embodiments of formula (Z), any substituent is selected from the group consisting of oxo, halogen, C15 alkyl, C 3-6 carbocyclic, alkylenecarbocyclic, aryl, heteroaryl, alkylenearyl, and alkyleneheteroaryl. In some embodiments, any substituent is selected from the group consisting of oxo, C 1-5 alkyl, and C 3-6 cycloalkyl. In some embodiments, any substituent is selected from the group consisting of oxo and C 1-5 alkyl. In some embodiments, any substituent is oxo. In other embodiments, any substituent is C 1-5 alkyl. In some embodiments, C 1-5 alkyl is methyl, ethyl, propyl or isopropyl. In certain embodiments, C 1-5 alkyl is methyl, ethyl, or isopropyl. In other embodiments, C 1-5 alkyl is methyl. In some embodiments, C 3-6The cycloalkyl is cyclopropyl or cyclohexyl. In some embodiments, the aryl is phenyl. In certain embodiments, the alkylene carbocyclyl is methylenecyclopropyl or methylenecyclohexyl. In some embodiments, the alkenylenyl is methylenephenyl.

[0901] In some embodiments of formula (Z), R 18 is alkyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted.

[0902] In some embodiments of formula (Z), R 18 is alkyl. In some embodiments, the alkyl is C 1-5 alkyl. In certain embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isoamyl, butyl, and isobutyl. In other embodiments, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, and isopropyl.

[0903] In certain embodiments, R 18 is aryl or heteroaryl, each of which may be optionally substituted. In certain embodiments, R 18 is optionally substituted aryl. In some embodiments, the optionally substituted aryl is 6- to 12-membered aryl. In certain embodiments, the aryl is optionally substituted 6- to 12-membered aryl. In some embodiments, the aryl is optionally substituted phenyl. In some embodiments of formula (Z), the optionally substituted phenyl is selected from the group consisting of optionally substituted phenyls,

[0904] [Chemical formula]

[0905] selected from the group consisting of.

[0906] In certain embodiments, R 18 is optionally substituted heteroaryl. In some embodiments, the optionally substituted heteroaryl is a 5- to 12-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heteroaryl is an optionally substituted 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from S, O, and N. In some embodiments, N, O, and S are oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyrazinyl. In certain embodiments, the optionally substituted heteroaryl is

[0907]

Chemical formula

[0908] selected from the group consisting of. In certain embodiments, the heteroaryl is optionally substituted pyridinyl. In certain embodiments, the optionally substituted pyridinyl is

[0909]

Chemical formula

[0910] selected from the group consisting of, and p is 0, 1, or 2.

[0911] In some embodiments, aryl or heteroaryl is optionally substituted with one or more H, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, C(O)Oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, N(H)SO2alkyl, -N(H)SO2aryl, or -CN. In some embodiments, aryl or heteroaryl is optionally substituted with one or more H, halogen, -C 1-5 alkyl, CF3, -OH, -O(C 1-5 alkyl), OCF3, -OSO2Me, -COOH, -C(O)OMe, or -SO2Me.

[0912] In some embodiments, heterocyclyl is an optionally substituted 3- to 12-membered heterocyclic ring having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, heterocyclyl is an optionally substituted 3- to 6-membered heterocyclyl having 1 or 2 nitrogen atoms. In some embodiments, the 3- to 6-membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In some embodiments, the 3- to 6-membered heterocyclyl is optionally substituted pyrrolidinyl, piperidinyl, or piperazinyl. In other embodiments, the 3- to 6-membered heterocyclyl is optionally substituted piperidinyl. -

[0913] In some embodiments of formula (Z), R 19 is H or alkyl. In some embodiments, alkyl is C 1-5 alkyl. In one embodiment, C 1-5 alkyl is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isoamyl, butyl, and isobutyl. In other embodiments, C1-5 Alkyl is selected from the group consisting of methyl, ethyl, and isopropyl. In some embodiments, R 19 is H.

[0914] In some embodiments of formula (Z), R 20 is H, -C 1-5 alkyl, -C 3-6 carbocyclic, -CH2-aryl, or -CH2-(C 3-6 carbocyclic). In certain embodiments, R 20 is H, Me, or -CH2Ph. In other embodiments, R 20 is H.

[0915] In some embodiments of formula (Z), R 21 is heterocyclyl or heteroaryl.

[0916] In some embodiments of formula (Z), heteroaryl is an optionally substituted 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from S, O, and N. In certain embodiments, heteroaryl is

[0917]

Chemical formula

[0918] selected from the group consisting of, and X 1 is NR 16 , S, or O; and R 16 is H or alkyl

[0919] In some embodiments of formula (Z), heterocyclyl is a 3- to 12-membered heterocyclyl which is substituted when having 1, 2, or 3 heteroatoms selected from S, O, and N. In some embodiments, heterocyclyl is a 5- or 6-membered heterocyclyl which is substituted when having a maximum of 2 nitrogen atoms. In certain embodiments, heterocyclyl is

[0920] [Chemical formula] selected from the group consisting of.

[0921] In some embodiments of formula (Z), m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0922] In some embodiments of formula (Z), n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0923] In some embodiments of formula (Z), m is 0 and n is 1. In other embodiments, m is 1 and n is 1. In still other embodiments, m is 0 and n is 2. In yet another embodiment, m is 2 and n is 1.

[0924] In some embodiments, the present disclosure has the following structure:

[0925] [Chemical formula]

[0926] [Chemical formula]

[0927] provides a compound of formula (Z) having one of the following:

[0928] In some embodiments of the present disclosure, the compound of formula (Z) has the formula (ZZ):

[0929]

Chem.

[0930] is a compound, wherein: L, R 18 , Z 1 , Z 2 , Z 3 , and Z 4 are as defined above for formula (Z).

[0931] In some embodiments of the present disclosure, the compound of formula (Z) is of formula (ZZa):

[0932]

Chem.

[0933] is a compound, wherein: L, R 18 , and Z 1 are as defined above for formula (Z); p is 0, 1, or 2.

[0934] In various embodiments, the compounds of formula (Z), formula (ZZ), and formula (ZZa) exclude the compounds disclosed in WO2019 / 051269.

[0935] Formulas (X), (XX), (XXa), (XXb), (XXc), (XXd), (XXe), (XXf), (XXd1), (XXf1), (Y), (YY), (YYa), (YYb), (Z), (ZZ), and (ZZa) mean that, whether or not they are specifically shown herein, they include all racemic mixtures, all individual enantiomers or combinations thereof, and all diastereomers or combinations thereof when two or more stereocenters are present.

[0936] Therapeutic methods The present disclosure provides compounds and compositions useful for treating cancers and other conditions associated with ENPP1 deficiency. Thus, in some embodiments, the compounds disclosed herein are inhibitors of ENPP1. In some embodiments, the compounds of the present disclosure are cell-permeable inhibitors of ENPP1.

[0937] In some embodiments, the methods of the invention are useful for treating disorders of uncontrolled cell proliferation in a subject in need thereof, and comprise administering to the subject a therapeutically effective amount of a compound disclosed herein (e.g., of formula (A1), formula (A2), formula (X), formula (XX), formula (XXa), formula (XXb), formula (XXc), formula (XXd), formula (XXe), formula (XXf), formula (XXd1), formula (XXf1), formula (Y), formula (YY), formula (YYa), formula (YYb), formula (Z), formula (ZZ), and formula (ZZa)), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, or a composition thereof. In certain embodiments, the disorder of uncontrolled cell proliferation is cancer or a tumor. In certain embodiments, the disorder or uncontrolled cell proliferation is associated with ENPP1 deficiency, e.g., a deficiency caused by a mutation in ENPP1.

[0938] In some embodiments, the present disclosure also provides a method of reducing ENPP1 activity in a subject, the method comprising administering to the subject an effective amount of a compound or composition disclosed herein. In some embodiments, the compounds of the present disclosure are cell-permeable.

[0939] In some embodiments, the present disclosure also provides a method of inhibiting ENPP1 activity in a subject by administering to the subject an effective amount of a compound or composition disclosed herein. In some embodiments, ENPP1 activity is inhibited by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% (including all ranges and values therebetween).

[0940] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, or a composition thereof. In certain embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from adrenal, liver, kidney, bladder, breast, colon, stomach, ovary, cervical, uterine, esophageal, colorectal, prostate, pancreas, lung (both small cell and non-small cell), thyroid, cancer tumor, sarcoma, glioblastoma, melanoma, and various head and neck tumors. In some embodiments, the solid tumor is breast cancer, lung cancer, or glioblastoma.

[0941] In some embodiments of the present disclosure, the cancer is a hematological malignancy. In certain embodiments, the hematological malignancy is leukemia, lymphoma, or myeloma. In some embodiments, the hematological malignancy is a B-cell malignancy. In certain embodiments, the hematological malignancy is multiple myeloma.

[0942] In some embodiments of the present disclosure, the cancer is a recurrent or refractory cancer. In some embodiments of the present disclosure, the cancer is a metastatic cancer.

[0943] In some embodiments, the present disclosure provides a method of treating a bacterial infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, or a composition thereof. In some embodiments, the bacterial infection is a Gram-positive infection. In other embodiments, the bacterial infection is a Gram-negative infection. In some embodiments, the Gram-positive infection is an infection caused by Staphylococcus aureus (e.g., methicillin-sensitive or methicillin-resistant) or E. faecium. In other embodiments, the Gram-negative bacterial infection is an infection caused by Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, or A. baumannii. In some embodiments, the bacterial infection is multi-drug resistant. In some embodiments, the bacterial infection is caused by Mycobacterium tuberculosis. Accordingly, in various embodiments, the compounds and compositions of the present disclosure are effective in the treatment of tuberculosis.

[0944] In some embodiments, the present disclosure provides a method of treating a viral infection in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a compound disclosed herein, a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, or a composition thereof. In some embodiments, the viral infection is caused by a DNA virus. In some embodiments, the viral infection is by a herpes virus. In certain embodiments, the herpes virus is herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human herpesvirus 6A (HHV-6A), human herpesvirus 6B (HHV-6B), human herpesvirus 7 (HHV-7), and Kaposi's sarcoma-associated herpesvirus (in certain embodiments, the herpes virus is herpes simplex virus 1 (HSV-1). In some embodiments of the present disclosure, the viral infection is by a retrovirus. In certain embodiments, the retrovirus is human immunodeficiency virus. In some embodiments, the viral infection is by a hepatitis virus. In certain embodiments, the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV). In certain other specific embodiments, the viral infection is caused by vaccinia virus (VACV), adenovirus, or human papillomavirus (HPV). In some embodiments of the present disclosure, the viral infection is by an RNA virus. In certain embodiments, the viral infection is caused by dengue virus, yellow fever virus, Ebola virus, Marburg virus, Venezuelan equine encephalitis virus, or Zika virus.

[0945] Compound formulation In some embodiments, the present disclosure is directed to an effective amount of formula (A1), formula (A2), formula (X), formula (XX), formula (XXa), formula (XXb), formula (XXc), formula (XXd), formula (XXe), formula (XXf), formula (XXd1), formula (XXf1), formula (Y), formula (YYa), formula (YYb), formula (Z), formula (ZZ), or formula (ZZa), or a pharmaceutically acceptable salt, tautomer, solvate, or hydrate thereof. The pharmaceutical compositions provided herein can include one or more pharmaceutically acceptable carriers or excipients.

[0946] In various embodiments, the pharmaceutical compositions of the present disclosure can be formulated for administration by various means including oral, parenteral, inhalation spray, topical, or rectal in formulations containing pharmaceutically acceptable carriers, adjuvants, and vehicles. As used herein, the term parenteral includes subcutaneous, intravenous, intramuscular, and intraarterial injection using various injection techniques. Intraarterial and intravenous injection as used herein includes administration via a catheter.

[0947] An effective amount of a compound of the present disclosure, including pharmaceutically acceptable salts, esters, prodrugs, hydrates, solvates, and isomers thereof, or pharmaceutical compositions thereof, can be determined by one of ordinary skill in the art based on known methods.

[0948] In one embodiment, a pharmaceutical composition or formulation includes a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, and / or excipient. Pharmaceutically acceptable carriers, diluents, or excipients include, but are not limited to, adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifying agents approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0949] In one embodiment, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents, and sterile aqueous or organic solutions. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, about 0.01 to about 0.1 M, such as 0.05 M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.

[0950] Examples of aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcohol / aqueous solutions, glycerol, saline, and emulsions or suspensions containing buffer media. Oral carriers can be elixirs, syrups, capsules, tablets, etc.

[0951] Liquid carriers suitable for use in the present application can be used in the preparation of solutions, suspensions, emulsions, syrups, elixirs, and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, both, or a mixture of pharmaceutically acceptable oils and fats. The liquid carrier can include other suitable pharmaceutical additives such as solubilizing agents, emulsifying agents, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, or osmotic pressure regulators.

[0952] Suitable liquid carriers for use in this application include, but are not limited to, water (e.g., cellulose derivatives such as sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols such as glycols) and their derivatives, and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also include oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form containing compounds for parenteral administration. The liquid carrier for the pressurized compounds disclosed herein can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0953] Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol, etc. The solid carrier can further contain one or more substances that act as flavoring agents, lubricants, solubilizing agents, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrants, and can also be an encapsulating material. In powders, the carrier can be a finely divided solid mixed with a finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in appropriate proportions and compressed into the desired shape and size. Powders and tablets contain, for example, up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting wax, and ion exchange resins. Tablets can be manufactured by compression or molding, optionally using one or more auxiliary components. Compressed tablets can be prepared by compressing, in a suitable machine, a free-flowing form of the active ingredient such as a powder or granules, optionally with a binder (e.g., povidone, gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), surfactant or dispersing agent. Molded tablets can be manufactured by molding, in a suitable machine, a mixture of a powdered compound moistened with an inert liquid diluent. Tablets can be optionally coated or scored and formulated, for example, using hydroxypropylmethylcellulose in various proportions to provide a slow or controlled release of the active ingredient therein to provide the desired release profile. Tablets can optionally be provided with an enteric coating to provide release in parts of the intestine other than the stomach.

[0954] Suitable parenteral carriers for use in this application include, but are not limited to, sodium chloride solution, Ringer's glucose, dextrose and sodium chloride, lactated Ringer's, and fixed oils. Intravenous carriers include fluids and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, etc. For example, preservatives and other additives such as antibacterial agents, antioxidants, chelating agents, inert gases, etc. can also be present.

[0955] The carriers suitable for use in this application can be mixed with disintegrants, diluents, granulating agents, lubricants, binders, etc. using conventional techniques known in the art, as necessary. The carriers can also be sterilized using methods that do not react detrimentally with the compounds, as is generally known in the art.

[0956] Diluents can be added to the formulations of the present invention. Diluents can increase the bulk of solid pharmaceutical compositions and / or combinations and make the pharmaceutical dosage forms containing the compositions and / or combinations easier for patients and caregivers to handle. Diluents for solid compositions and / or combinations include, for example, microcrystalline cellulose (e.g., Avicel), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugars, dextrates, dextrins, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (e.g., EUDRAGIT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0957] The pharmaceutical composition of the present invention can be prepared into any type of formulation and drug delivery system by using any of the conventional methods well-known in the art. The pharmaceutical composition of the present invention can be formulated into an injectable preparation that can be administered by a route including intrathecal, intraventricular, intravenous, intraperitoneal, intranasal, intraocular, intramuscular, subcutaneous or intraosseous. Also, it may be administered orally or parenterally through the rectal, intestinal or intranasal mucosa (see Gennaro, A. R., ed. (1995) Remington's Pharmaceutical Sciences). In certain embodiments, the composition is administered locally rather than enterally. For example, the composition can be injected or delivered via a targeted drug delivery system such as a reservoir formulation or a sustained release formulation.

[0958] The pharmaceutical formulations of the present invention can be prepared by any method well-known in the art, such as mixing, dissolving, granulating, tablet coating, levigation, emulsifying, encapsulating, enclosing, or freeze-drying processes. As described above, the compositions of the present invention may include one or more physiologically acceptable carriers, such as excipients and adjuvants that facilitate the processing of the active molecule into a preparation for pharmaceutical use.

[0959] The appropriate formulation depends on the selected route of administration. For injection, for example, the composition can be formulated in an aqueous solution such as in a physiologically compatible buffer such as Hank's solution, Ringer's solution, or saline buffer. For transmucosal or nasal administration, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art. In one embodiment of the present invention, the compounds of the present invention can be prepared as oral formulations. For oral administration, the compounds can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier known in the art. Such carriers enable the disclosed compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by a subject. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

[0960] Pharmaceutical preparations for oral use are obtained as solid excipients, and if desired, the resulting mixture is comminuted and, if desired, after adding suitable adjuvants, the mixture of granules can be processed to obtain tablets or dragee cores. Suitable excipients can be, in particular, fillers such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP) preparations. Disintegrants such as cross-linked polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate can also be used. Also, wetting agents such as sodium dodecyl sulfate may be added.

[0961] The dredging core is provided with an appropriate coating. For this purpose, a concentrated sugar solution can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and an appropriate organic solvent or solvent mixture. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of the active compound dosages.

[0962] Although various inventive embodiments are described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions and / or results and / or one or more of the advantages described herein, and each such variation and / or modification is to be regarded as within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily understand that all parameters, dimensions, materials, and configurations described herein are exemplary, and that the actual parameters, dimensions, materials, and / or configurations depend on the particular application or applications for which the teachings of the invention are used. Those skilled in the art will be able to recognize or confirm many equivalents to the specific inventive embodiments described herein using only routine experimentation. Accordingly, the above-described embodiments are presented by way of example only, and it is to be understood that within the scope of the appended claims and their equivalents, inventive embodiments may be practiced other than as specifically described and claimed. The inventive embodiments of the present disclosure relate to each individual feature, system, article, material, kit, and / or method described herein. Further, any combination of two or more of such functions, systems, articles, materials, kits, and / or methods is included within the scope of the invention of the present disclosure if such functions, systems, articles, materials, kits, and / or methods do not mutually conflict.

[0963] The above-described embodiments can be implemented in any of a number of ways. Also, various inventive concepts can be embodied as one or more methods, and examples thereof are provided. The acts performed as part of the method can be ordered in any suitable way. Accordingly, the embodiments, notwithstanding that they may be shown in exemplary embodiments as sequential acts, may be configured to perform some acts simultaneously, or acts may be performed in an order different from that shown, and may include performing some acts in parallel.

[0964] All cited references are hereby incorporated by reference in their entirety for all purposes.

Example

[0965] The various derivatives of the above formula can be prepared from appropriate starting materials and intermediates using the general methods described herein. Representative synthetic schemes are provided as follows.

[0966] Synthesis of Compounds

[0967] Example 1: Compound 3

[0968]

Chemical Formula

[0969] Step 1: 2-Chloro-N-(3,4-dimethoxyphenyl)acetamide Procedure: To a stirred solution of 3,4-dimethoxyaniline (5 g, 32.64 mmol) in acetone (50 mL) was added potassium carbonate (9 g, 65.28 mmol) at 0 °C. After 30 minutes, chloroacetyl chloride (3.5 mL, 48.96 mmol) was added thereto. The reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated to dryness. The crude residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude residue. Purification was performed by flash chromatography using hexane:ethyl acetate as the elution system. Yield: 4 g (54%).

[0970] Step 2: N-(3,4-Dimethoxyphenyl)-2-((5-methoxy-1H-benzo[d]imidazol-2-yl)amino)acetamide Procedure: To a stirred solution of sodium hydride (24.5 mg, 0.61 mmol) in dimethylformamide (2 mL) was added 5-methoxy-1H-benzo[d]imidazol-2-amine (0.1 g, 0.61 mmol) at 0 °C. After 30 minutes, 2-chloro-N-(3,4-dimethoxyphenyl)acetamide (0.154 g, 0.67 mmol) was added thereto. The reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude residue. Purification was carried out by flash chromatography using dichloromethane:methanol as the elution system. Yield: 20 mg (9.15%)

[0971] Example 2: Compound 10

[0972] [Chemical formula]

[0973] Step 1: 2-Bromo-N-(3,4-dimethoxyphenyl)acetamide Procedure: To a stirred solution of 3,4-dimethoxyaniline (1 g, 6.52 mmol) in dichloromethane (10 mL) was added potassium carbonate (1.35 g, 9.78 mmol) at 0 °C. After 30 minutes, bromoacetyl bromide (0.8 mL, 8.48 mmol) was added thereto. The reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude residue. Purification was carried out by flash chromatography using hexane:ethyl acetate as the elution system. Yield: 1.7 g (98%).

[0974] Step 2: N-(3,4-Dimethoxyphenyl)-2-(2-methyl-1H-benzo[d]imidazol-1-yl)acetamide Procedure: To a stirred solution of 2-methyl-1H-benzo[d]imidazole (0.1 g, 0.75 mmol) in acetone (5 mL) was added potassium carbonate (0.15 g, 1.13 mmol) at 0 °C. After 30 minutes, 2-bromo-N-(3,4-dimethoxyphenyl)acetamide (0.23 g, 0.83 mmol) was added thereto. The reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated to dryness. The crude residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude residue. Purification was carried out by flash chromatography using dichloromethane:methanol as the elution system. Yield: 0.4 g (16.25%).

[0975] Example 3: Compound 37

[0976] [Chemical formula]

[0977] Step 1: Ethyl 2-((6,7-dimethoxyquinoxalin-2-yl)thio)acetate Procedure: To a stirred solution of sodium hydride (0.04 g, 1.59 mmol) in tetrahydrofuran (3 mL) was added ethyl 2-mercaptoacetate (0.18 mL, 1.46 mmol) at 0 °C. The reaction mixture was refluxed for 30 minutes. 2-Chloro-6,7-dimethoxyquinoxaline (0.3 g, 1.33 mmol) was added thereto. The reaction mixture was stirred at the reflux temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The crude residue was purified by flash chromatography using hexane:ethyl acetate as the elution system. Yield 340 mg (82.7%).

[0978] Step 2: 2-((6,7-Dimethoxyquinoxalin-2-yl)thio)acetic acid Procedure: To a stirred solution of ethyl 2-(6,7-dimethoxyquinoxalin-2-yl)thio)acetate (0.34 g, 1.10 mmol) in THF:H2O (1:1, 5 mL) was added lithium hydroxide monohydrate (0.07 g, 1.65 mmol) at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The crude residue was dissolved in water and neutralized with 2N HCl. After neutralization, it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give the pure compound. Yield: 0.25 g (83%).

[0979] Step 3: N-(3,4-Dimethoxyphenyl)-2-((6,7-dimethoxyquinoxalin-2-yl)thio)acetamide Procedure: To a stirred solution of 2-((6,7-dimethoxyquinoxalin-2-yl)thio)acetic acid (0.05 g, 0.17 mmol) in ethyl acetate (5 mL) were added 3,4-dimethoxyaniline (0.025 g, 0.16 mmol) and pyridine (0.043 mL, 0.53 mmol) at 0 °C. After 30 minutes, T3P (0.22 mL, 50% in ethyl acetate, 0.71 mmol) was added thereto. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude residue. Purification was carried out by flash chromatography using dichloromethane:methanol as the elution system. Yield: 0.20 g (27%).

[0980] Example 4: Compound 46

[0981]

Chemical Structure

[0982] Step 1: 2-Chloro-N-(3,4-dimethoxyphenyl)acetamide Procedure: Potassium carbonate (9 g, 65.28 mmol) was added to a stirred solution of 3,4-dimethoxyaniline (5 g, 32.64 mmol) in acetone (50 mL) at 0 °C. After 30 minutes, chloroacetyl chloride (3.5 mL, 48.96 mmol) was added thereto. The reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated to dryness. The crude residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude residue. Purification was carried out by flash chromatography using hexane:ethyl acetate as the elution system. Yield: 4 g (54%).

[0983] Step 2: 2-(((2-Amino-7H-purin-6-yl)thio)-N-(3,4-dimethoxyphenyl)acetamide Procedure: Potassium carbonate (0.25 g, 1.79 mmol) was added to a stirred solution of 2-amino-1,7-dihydro-6H-purine-6-thione (0.1 g, 0.59 mmol) in dimethylformamide (3 mL) at 0 °C. After 30 minutes, 2-chloro-N-(3,4-dimethoxyphenyl)acetamide (0.15 g, 0.65 mmol) was added thereto. The reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated to dryness. The crude residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude residue. Purification was carried out by flash chromatography using hexane:ethyl acetate as the elution system. Yield: 0.6 g (27.9%).

[0984] Example 5: Compound 148

[0985]

Chemical Structure

[0986] Step 1: Ethyl (3,4-dimethoxybenzoyl)glycinate Procedure: To a stirred solution of 3,4-dimethoxybenzoic acid (1 g, 5.48 mmol) and glycine ethyl ester hydrochloride (0.76 g, 5.48 mmol) in dimethylformamide (10 mL) was added diisopropylethylamine (3.35 mL, 19.2 mmol) at 0 °C. After 30 minutes, HATU (3.1 g, 8.23 mmol) was added thereto. The reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, cold water was added. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude residue. Purification was carried out by flash chromatography using hexane:ethyl acetate as the elution system. Yield: 1.34 g (91%).

[0987] Step 2: N-(2-Hydroxyethyl)-3,4-dimethoxybenzamide Procedure: To a stirred solution of ethyl (3,4-dimethoxybenzoyl)glycinate (1.32 g, 4.93 mmol) in methanol (20 mL) was added sodium borohydride in fraction (0.93 g, 24.6 mmol) at 0 °C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a crude residue. Purification was carried out by flash chromatography using hexane:ethyl acetate as the elution system. Yield: 0.61 g (54.4%)

[0988] Step 3: N-(2-Chloroethyl)-3,4-dimethoxybenzamide Procedure: Triethylamine (0.76 mL, 5.37 mmol) was added to a stirred solution of N-(2-hydroxyethyl)-3,4-dimethoxybenzamide (0.6 g, 2.68 mmol) in dichloromethane (10 mL) at 0 °C. After 30 minutes, methanesulfonyl chloride (0.42 mL, 5.37 mmol) was added thereto. The reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude residue. Purification was carried out by flash chromatography using hexane:ethyl acetate as the elution system. Yield: 0.27 g (40.6%). da Step 4: N-(2-((2-Amino-7H-purin-6-yl)thio)ethyl)-3,4-dimethoxybenzamide Procedure: Potassium carbonate (0.165 g, 1.19 mmol) was added to a stirred solution of 2-amino-1,7-dihydro-6H-purine-6-thione (0.1 g, 0.59 mmol) in dimethylformamide (3 mL) at 0 °C. After 30 minutes, N-(2-chloroethyl)-3,4-dimethoxybenzamide (0.159 g, 0657 mmol) was added thereto. The reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated to dryness. The crude residue was purified by flash chromatography using dichloromethane:methanol as the elution system. Yield: 0.045 g (20.1%).

[0989] Table 1. Characteristic data of the synthesized compounds

[0990]

Table 2-1

[0991]

Table 2-2

[0992]

Table 2-3

[0993] Table 2-4

[0994] Table 2-5

[0995] Table 2-6

[0996] Table 2-7

[0997] Table 2-8

[0998] Table 2-9

[0999] Table 2-10

[1000] Table 2-11

[1001] Table 2-12

[1002] Table 2-13

[1003] Biological evaluation

[1004] Example 6: Colorimetric NPP assay using p-nitrophenyl-5-TMP as substrate Ectonucleotide pyrophosphatase (ENPP1) belongs to the ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family. ENPP1 is a type II transmembrane glycoprotein that hydrolyzes nucleotides and nucleotide derivatives to produce nucleotide-5'-monophosphate. A colorimetric assay using thymidine 5'-monophosphate p-nitrophenyl ester (5'-TMP-pNP) as substrate was used to synthesize ENPP1 inhibitors and evaluate their inhibitory potency. ENPP1 hydrolyzes 5'-TMP-pNP to produce the chromogenic product p-nitrophenolic acid. The amount of p-nitrophenolic acid produced is directly proportional to the ENPP1 enzyme activity and was measured using the absorbance at 405 nm.

[1005] The enzyme inhibition assay was performed in a clear 96-well microplate. The reaction mixture contained different concentrations of ENPP1 inhibitor and 20 ng of human ENPP1 in 1 mM CaCl2, 200 μM ZnCl2, 50 mM Tris, pH 9.0. The reaction mixture was pre-incubated at 37 °C for 10 minutes, and the absorbance was measured at 405 nm as a pre-read using a microplate reader. Then, the 5'-TMP-pNP substrate was added at a final concentration of 400 μM to initiate the reaction, and after incubation at 37 °C for 20 minutes, the enzyme reaction was stopped by adding 20 μL of 1.0 N NaOH. The amount of released p-nitrophenolate was measured at 405 nm (as a post-read). Appropriate controls for the test samples and each blank control were taken to remove the background absorbance. The incubation and operating conditions were the same as those described above. The inhibition rate was measured for various concentrations of the test inhibitor by comparing the absorbance of the inhibitor with that of the blank.

[1006] IC 50The value was determined by plotting the percentage of inhibitor concentration against the inhibitor concentration curve using a three-parameter non-linear regression curve fit in GraphPad Prism® software. The Ki value was derived from the IC 50 value using the Cheng-Prusoff equation. Ki = IC 50 / (1 + [TMP-pNP] / Km) where [TMP-pNP] = the Michaelis’ Menten constant (Km) of 5’-TMP-pN is usually 222 μM.

[1007] Example 7: NPP assay based on capillary electrophoresis using ATP as substrate ENPP1 is a eukaryotic protein with broad substrate specificity and can hydrolyze nucleotides, such as ATP, to AMP. Here, a capillary electrophoresis-based method was used to determine the IC50 value of an ENNP1 inhibitor against the ENNP1 protein.

[1008] The synthesized inhibitor was evaluated for its ability to inhibit ENPP1 against the natural substrate ATP. The enzyme inhibition assay was performed at different inhibitor concentrations in 10 mM 2-(N-cyclohexylamino)-ethanesulfonic acid (CHES) buffer (pH 10.0) containing 1 mM MgCl2, 2 mM CaCl2, and 400 μM ATP. The reaction mixture was incubated with 20 ng of human NPP1 at 37 °C for 30 min with a final volume of 100 μL, and the reaction was stopped by heating at 90 °C for 3 min. Finally, the reaction mixture was directly measured by capillary electrophoresis (CE). The CE measurement and operating conditions were as follows: a P / ACE MDQ capillary electrophoresis system (Beckman Instruments, Fullerton, CA, USA) equipped with a DAD detection system, a polyacrylamide-coated capillary with an effective length of 40 cm × 50 μm (id) obtained from CS Chromatographie GmbH (Langerwehe, Germany), 50 mM phosphate buffer (pH 6.5) as the running buffer, hydrodynamic injection (-6 kV, 60 s), and a separation voltage of -15 kV. The amount of generated AMP was measured at 260 nm. Data collection and peak area analysis were performed using 32 Karat software obtained from Beckman Coulter (Fullerton, CA, USA).

[1009] The IC 50 values of the test compounds were calculated by plotting the data of Prism 5.0 program, and the Ki values were calculated from the IC 50 values using the Cheng-Prusoff equation (Table 2-4). Ki = IC 50 / (1 + [ATP] / Km) where [ATP] = 400 μM and the Michaelis-Menten constant (Km) of ATP is 8.17 μM.

[1010]

Table 3-1

[1011]

Table 3-2

[1012]

Table 3-3

[1013]

Table 3-4

[1014]

Table 3-5

[1015] Table 3. In Vitro Data of the Evaluated Compounds

[1016]

Table 4-1

[1017]

Table 4-2

[1018]

Table 4-3

[1019]

Table 4-4

[1020]

Table 5-1

[1021]

Table 5-2

[1022] Example 8: In Vivo Efficacy Evaluation of Compound 155, Compound 173, and Compound 174 in Combination with Anti-PD-1 Antibody, CD279, in LLC1 Syngeneic Tumor Model

[1023]

Chemical Structure

[1024] Test Summary The antitumor effects of Compounds 155, 173, and 174 were evaluated in combination with an anti-PD-1 antibody (checkpoint inhibitor) in the LLC1 syngeneic tumor model. The compounds were orally administered once a day at a dose of 100 mg / kg. The intravenous administration dose of the compounds was 10 mg / kg twice a week or Q3D (2 mg / Kg intravenous injection of Compound 155). The anti-PD-1 antibody was administered via the IP route at a dose of 200 μg / animal on Days 1, 5, and 9 (Table 5).

[1025] Test Design 0.2 × 106 LLC1 cells (ATCC® CRL-1642™) were subcutaneously implanted into C57BL / 6 mice (female, 7 - 8 weeks old), and tumor growth in the mouse Lewis lung cancer model was evaluated. The tumor-bearing animals were randomly assigned to eight different treatment groups based on a tumor size criterion of approximately 50 - 60 mm 3 and administered according to the schedule in Table 5.

[1026]

Table 6

[1027] Administration Protocol: The frequency of oral administration was once a day, intravenous administration was twice a week for two weeks, and the anti-PD-1 antibody was administered via the IP route on Days 1, 5, and 9.

[1028] Tumor Measurement: Tumor growth was measured three times a week using a digital Vernier caliper. The tumor volume was calculated as follows: Tumor Volume (TV) = [Length (L) × Width (W)2] / 2 (Length is the maximum diameter, and width is the minimum diameter of the tumor).

[1029] Final evaluation items: To analyze cytokine concentrations (IFN-β and IP-10) in serum, animals were bled 2 weeks after treatment. At the end of the study, tumor samples were collected from 4 / 8 animals in each treatment group for analysis of TIL by flow cytometry.

[1030] Efficacy evaluation: Tumor growth inhibition (TGI) was calculated as follows:

[1031]

Number

[1032] Data analysis: Statistical analysis of the data was performed by one-way ANOVA, followed by Dunnett's test using GraphPad Prism (version 5.03).

[1033] Results Antitumor effect of compound 155 Oral administration: Once-daily oral administration of compound 155 for 2 weeks resulted in 33% TGI compared to the control group, which was statistically significant (p < 0.0001). The combination of compound 155 (PO) and anti-PD-1 antibody resulted in a significant (p < 0.0001) 44% tumor growth inhibition (TGI) (Figure 2).

[1034] Intravenous administration: Twice-weekly intravenous administration of compound 155 resulted in a significant (p < 0.0001) 47% tumor growth inhibition (TGI). The combination of compound 155 (IV) and anti-PD-1 antibody resulted in a significant (p < 0.0001) 57% tumor growth inhibition (TGI) (Figure 3).

[1035] As shown in Figure 4, PO and IV administration of compound 155 alone or in combination with anti-PD-1 antibody decreased tumor volume in the mouse Lewis lung cancer model, and IV administration of compound 155 provided the greatest decrease in combination with anti-PD-1 antibody.

[1036] Antitumor effect of compound 173 Oral administration: Once-daily oral administration of Compound 173 for 2 weeks resulted in a 37% TGI, which was statistically significant (p < 0.0001) compared to the control group. The combination of Compound 173 (PO) and the anti-PD-1 antibody resulted in a significant (p < 0.0001) 47% tumor growth inhibition (TGI) (Figure 5).

[1037] Intravenous administration: Twice-weekly intravenous administration of Compound 173 resulted in a significant (p < 0.0001) 48% tumor growth inhibition (TGI). The combination of Compound 173 (IV) and the anti-PD-1 antibody resulted in a significant (p < 0.0001) 53% tumor growth inhibition (TGI) (Figure 6).

[1038] As shown in Figure 7, administration of Compound 173 alone or in combination with the anti-PD-1 antibody at 7, PO, and IV doses decreased tumor volume in the mouse Lewis lung cancer model, and the greatest decrease was obtained with intravenous administration of Compound 173 in combination with the anti-PD-1 antibody.

[1039] Antitumor effect of Compound 174 Oral administration: Once-daily oral administration of Compound 174 for 2 weeks resulted in a 52% TGI, which was statistically significant (p < 0.0001) compared to the control group. The combination of Compound 174 (PO) and the anti-PD-1 antibody resulted in a significant (p < 0.0001) 60% tumor growth inhibition (TGI) (Figure 8).

[1040] Intravenous administration: Twice-weekly intravenous administration of Compound 174 resulted in a significant (p < 0.0001) 48% tumor growth inhibition (TGI). The combination of Compound 174 (IV) and the anti-PD-1 antibody resulted in a significant (p < 0.0001) 57% tumor growth inhibition (TGI) (Figure 9).

[1041] As shown in Figure 10, administration of Compound 173 alone or in combination with the anti-PD-1 antibody at 10, PO, and IV doses decreased tumor volume in the mouse Lewis lung cancer model, and the greatest decrease was obtained with intravenous administration of Compound 174 in combination with the anti-PD-1 antibody.

[1042]

Table 7

[1043] The invention is further illustrated by the following numbered embodiments. 1. Formula (X):

[1044]

Chemical formula

[1045] [wherein, L is alkylene, alkenylene, alkylene-S-, alkylene-O-, optionally substituted -alkylene-(NR 5 )-, optionally substituted

[1046]

Chemical formula

[1047] optionally substituted

[1048]

Chemical formula

[1049] optionally substituted

[1050]

Chemical formula

[1051] optionally substituted

[1052]

Chemical formula

[1053] optionally substituted

[1054] [Chemistry]

[1055] (optionally substituted)

[1056] [Chemistry]

[1057] (optionally substituted)

[1058] [Chemistry]

[1059] [Chemistry]

[1060] a linker selected from; U is S or NH; V is OH, NR 2 N 3 or V and Y 1 and together with the atom to which they are attached form an optionally substituted phenyl or pyridinyl ring; W is CH or N; X is O, S, NR 6 , -CH=CH-, or -CH=N-; Y 1 and Y 2 are each independently CH or N; R 1 is H, OH, O-alkyl, alkyl or carbocyclic; R 2 and R 3 are each independently H, alkyl, alkenyl, or -C(O)alkyl; R 4 is carbocyclic, heterocyclic, aryl, or heteroaryl, each of which may be optionally substituted; R 5 is H, alkyl, -C(O)alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 6 is H, alkyl, carbocyclic, alkylene carbocyclic, alkylene aryl, -C(O)alkyl, or -C(O)oalkenyl; R 7 is carbocyclic, heterocyclic, or heteroaryl; m is 0, 1, or 2; n is 1, 2, or 3] or a pharmaceutically acceptable salt, hydrate or tautomer thereof.

[1061] 2. L is each optionally substituted

Chemical formula

[1062] The compound according to Embodiment 1, which is

[1063] 2a. Optionally substituted

[1064]

Chemical formula

[1065] wherein

[1066]

Chemical formula

[1067] is as follows, wherein R 5 is H, alkyl, -C(O)alkyl, carbocyclic, alkylene carbocyclic, or alkylene aryl; R 5a and R 5b are each H, halogen, C 1-5 alkyl, C3-6 Carbocyclic, alkylene-C 3-6 Independently selected from the group consisting of carbocyclic, aryl, alkenyl, or NH2, wherein two C 1-5 Alkyl, together with the carbon atom to which they are attached, forms C 3-6 The compound according to embodiment 2, which forms a carbocyclic.

[1068] 2b.

[1069]

Chemical formula

[1070] is

[1071]

Chemical formula

[1072] selected from the group consisting of, wherein in the formula R 5 is H, Me, or -C(O)alkyl; R 5c is halogen, alkyl, haloalkyl, hydroxy or alkoxy, the compound according to embodiment 2a.

[1073] 2c.

[1074]

Chemical formula

[1075] is

[1076]

Chemical formula

[1077] selected from the group consisting of, wherein in the formula R 1 is H, Me, or -C(O)alkyl, the compound according to embodiment 2a

[1078] 3. The compound according to any one of Embodiments 1 to 2c, wherein U is S.

[1079] 4. The compound according to any one of Embodiments 1 to 3, wherein V is NR 2 R 3 wherein R is as defined above.

[1080] 5. The compound according to any one of Embodiments 1 to 4, wherein W is N.

[1081] 6. The compound according to any one of Embodiments 1 to 5, wherein X is NR 6 wherein R is as defined above.

[1082] 7. Y 1 and Y 2 are both N, the compound according to any one of claims 1 to 6.

[1083] 8. R 1 is H, OH, or C 1-5 alkyl, the compound according to any one of Embodiments 1 to 7.

[1084] 9. R 2 and R 3 are independently H, C 1-5 alkyl, -CH2Ph, or -C(O)(C 1-5 alkyl), the compound according to any one of Embodiments 1 to 8.

[1085] 10. R 4 is each independently optionally substituted aryl or heteroaryl, the compound according to any one of claims 1 to 9.

[1086] 10a. R 4 is

[1087]

Chemical formula

[1088] selected from the group consisting of, wherein each R 8 is independently halogen, C 1-5 alkyl, -C 1-5 alkenyl, -OH, -OC 1-5 alkyl, -COOH, or -CO2C 1-5 alkyl; p is an integer from 0 to 3, the compound according to any one of Embodiments 1 to 10.

[1089] 10b. R 4 is

[1090]

Chemical formula

[1091] selected from the group consisting of, wherein each R 8 is independently halogen, C 1-5 alkyl, -OH, -OC 1-5 alkyl, -COOH, or -CO2C 1-5 alkyl; p is an integer from 0 to 3, the compound according to any one of Embodiments 1 to 10.

[1092] 11. R 5 is H, -C 1-5 alkyl, -C(O)C 1-5 alkyl, -C 3-6 carbocyclic, -CH2-aryl, or -CH2-(C 3-6 carbocyclic), the compound according to any one of Embodiments 1 to 10.

[1093] 12. R 6 is H, -C 1-5 alkyl, -CH2aryl, or CH2(C 3-6 carbocyclic), the compound according to any one of Embodiments 1 to 11.

[1094] 13. R 7 is C 3-6The compound according to any one of Embodiments 1 to 12, which is carbocyclic, a 3- to 6-membered heterocyclic ring, or a 5- to 6-membered heteroaryl ring.

[1095] 14. The compound according to any one of Embodiments 1 to 13, wherein m is 0 or 1.

[1096] 15. The compound according to any one of Embodiments 1 to 14, wherein n is 1 or 2.

[1097] 16. The following structure:

[1098] [Table 8-1]

[1099] [Table 8-2]

[1100] [Table 8-3]

[1101] [Table 8-4]

[1102] [Table 8-5]

[1103] The compound according to Embodiment 1, or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof, having one of the following:

[1104] 17. Formula (Y):

[1105] [Chemical formula]

[1106] [wherein, U is C or N, here when U is C, Y is,

[1107] [Chemical formula]

[1108] or; or when U is N, Y is,

[1109] [Chemical formula]

[1110] and, V is N or CR 10 and; W is CH or N; X is S, O, N-L-R 11 , or NR 12 and; L is alkylene, alkenylene, optionally substituted -alkylene-(NR 12 ), optionally substituted

[1111] [Chemical formula]

[1112] optionally substituted

[1113] [Chemical formula]

[1114] optionally substituted

[1115] [Chemical formula]

[1116] Optionally substituted

[1117]

Chem.

[1118] Optionally substituted

[1119]

Chem.

[1120]

Chem.

[1121] selected from, R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, alkylenecarbocyclic, -O-L-R 11 , SLR 11 , -N(R 12 )-L-R 11 , -L-R 11 ; R 11 is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl, each optionally substituted; R 12 is independently H, alkyl, alkylenecarbocyclic, or carbocyclic, where two R 12 groups, together with the carbon atom to which they are attached, can combine to form a heterocyclic ring; R 14 is carbocyclic, heterocyclic, or heteroaryl; R 15 is H, alkyl, carbocyclic, alkylenecarbocyclic, or alkylenearyl; here, when X is N-L-R 11 , V is N or CR 10 , where R 10is H, alkyl, -O-alkyl, S-alkyl, carbocyclic, or alkylene carbocyclic; where X is S, O, NR 12 ; V is CR 10 and R 10 is -O-L-R 11 , -S-L-R 11 , N(R 12 )-L-R 11 , or -L-R 11 ; when U is N, V is CR 10 and R 10 is -O-L-R 11 , -S-L-R 11 , N(R 12 )LR 11 , or -L-R 11 ; Z 1 , Z 2 , Z 3 , and Z 4 are each independently CR 13 or N; R 13 is H, halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylene aryl, -C(O)oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN, where two R 13 may together with the atom to which they are attached form a carbocyclic, heterocyclic, or heteroaryl, each optionally substituted; m is 0, 1, or 2; n is 1, 2, or 3] compound, or a pharmaceutically acceptable salt, hydrate or tautomer thereof.

[1122] 18. The compound according to embodiment 17, wherein U is C.

[1123] The compound according to embodiment 17 or 18, wherein W is N.

[1124] 20. When X is S, O, or NH, V is CR 10 and R 10 is -O-L-R 11 -S-L-R 11 -N(R 12 )-L-R 11 or -L-R 11 The compound according to any one of embodiments 17 to 19.

[1125] 21. When X is N-L-R 11 and V is CR 10 and R 10 is H, alkyl, -O-alkyl, or -S-alkyl, the compound according to any one of embodiments 17 to 20.

[1126] 22. L is -alkylene-(NR 12 ), each of which is optionally substituted

[1127]

Chemical formula

[1128] The compound according to any one of embodiments 17 to 22.

[1129] 23. R 11 is heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted, the compound according to any one of embodiments 17 to 22.

[1130] 24. R 12 is independently H or C 1-5 alkyl, the compound according to any one of embodiments 17 to 23.

[1131] 25. R 14The compound according to any one of Embodiments 17 to 24, wherein is heterocyclic or heteroaryl.

[1132] 26.R 15 The compound according to any one of Embodiments 17 to 25, wherein is H or alkyl.

[1133] 27.Z 1 , Z 2 , Z 3 , and Z 4 each of which is CR 13 The compound according to any one of Embodiments 17 to 26.

[1134] 28.Z 1 , Z 2 , Z 3 , and Z 4 The compound according to any one of Embodiments 17 to 26, wherein at least one of is N.

[1135] 29. The compound according to any one of Embodiments 17 to 28, wherein m is 0 or 1.

[1136] 30. The compound according to any one of Embodiments 17 to 29, wherein n is 1 or 2.

[1137] 31. The following structure:

[1138]

Chemical formula

[1139]

Chemical formula

[1140]

Chemical formula

[1141]

Chemical formula

[1142] The compound according to embodiment 17 having one of the following, or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof.

[1143] 32. Formula (Z):

[1144] [Chemical formula]

[1145] [In the formula, (a) One of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 is -L-R 18 -; (b) Two or less of Z 1 , Z 2 , Z 3 or Z 4 are N; and (c) Either Z 6 or Z 7 is N Under the condition that Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and Z 7 are each independently N or CR 22 ; Here, L is a linker selected from -N(R 19 ), -alkylene-(NR 19 ),

[1146] [Chemical formula]

[1147] and each is optionally substituted; R18 is alkyl, carbocyclic, heterocyclic, aryl, or heteroaryl, each of which is optionally substituted; R 19 is H, alkyl, carbocyclic, alkylenecarbocyclic, or alkylenearyl; R 20 is H, alkyl, alkylenecarbocyclic, alkylenearyl; R 21 is carbocyclic, heterocyclic, or heteroaryl; R 22 is each independently halogen, alkyl, alkene, alkyne, haloalkyl, carbocyclic, OH, O-alkyl, O-haloalkyl, O-carbocyclic, OSO2-alkyl, OSO2-aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO2NH2, -SO2NHalkyl, -SO2NH(alkyl)2-, -NH2, -NHalkyl, -N(alkyl)2, -N(H)SO2alkyl, -N(H)SO2aryl, or -CN; m is 0, 1, or 2; n is 1, 2, or 3] a compound of, or a pharmaceutically acceptable salt, hydrate or tautomer thereof.

[1148] 33.Z 1 Z 2 Z 3 and Z 4 are each independently N or CR 22 is a compound according to embodiment 32.

[1149] 34.Z 6 is N and one of Z 1 Z 5 or Z 7 is -L-R 18 - is a compound according to embodiment 32 or 33.

[1150] 35.Z 7 is N and Z 1 Z5 or Z 6 One of which is -L-R 18 - is the compound according to Embodiment 32 or 33.

[1151] 36. L is each optionally substituted with

[1152]

Chemical formula

[1153] is the compound according to any one of Embodiments 32 to 35.

[1154] 37. R 18 is alkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted, the compound according to any one of Embodiments 32 to 36.

[1155] 38. R 19 is H or alkyl, the compound according to any one of Embodiments 32 to 37.

[1156] 39. R 20 is H, -C 1-5 alkyl, C 3-6 carbocyclic, -CH2-aryl, or -CH2-(C 3-6 carbocyclic), the compound according to any one of Embodiments 32 to 38.

[1157] 40. R 21 is heterocyclyl or heteroaryl, the compound according to any one of Embodiments 32 to 39.

[1158] 41. m is 0 or 1, the compound according to any one of Embodiments 32 to 40.

[1159] 42. n is 1 or 2, the compound according to any one of Embodiments 32 to 41.

[1160] The following structure:

[1161] [Chem.]

[1162] [Chem.]

[1163] A compound according to embodiment 32 having one of the following, or a pharmaceutically acceptable salt, tautomer, hydrate, or solvate thereof.

[1164] 44. The following structure:

[1165] [Chem.]

[1166] A compound according to embodiment 48 having one of the following.

Claims

1. Formula (X): 【Chemical 1】 [wherein, L is optionally substituted alkylene-(NR ５ )-, optionally substituted [Chemical 2] a linker selected arbitrarily; 【Chemical Formula 3】 a linker selected arbitrarily; 【Chemical Formula 4】 is a linker selected from; U is S; V is NR₂R₃; W is N; X is NR ６ and; Y １ and Y ２ are each independently N; R １ is H; R ２ and R ３ are each independently H; R ４ is 【Chemical Formula 5】 is selected from the group consisting of, wherein each R₈ is independently halogen, -C₁₋₅ alkyl, -C₁₋₅ alkenyl, -OH, -OC₁₋₅ alkyl, -COOH, or -CO₂C₁₋₅ alkyl; and p is an integer from 0 to 3; R ５ is H; R ６ is H; m is 0, 1, or 2; n is 1, 2, or 3]] a compound of or a pharmaceutically acceptable salt, hydrate or tautomer thereof.

2. L is each arbitrarily substituted 【Chemical Formula 6】 the compound according to claim 1.

3. arbitrarily substituted [Chemical Formula 7] is 【Chemical 8】 wherein, R ５ is H; R ５ａ and R ５ｂ are each independently selected from the group consisting of H, C １－５ alkyl, C ３－６ carbocyclic, aryl, or alkenylenyl, where two C １－５ alkyls together with the carbon atom to which they are attached form a C ３－６ carbocyclic, the compound according to claim 2.

4. 【Fig. 9】 is 【Chemical Formula 10】 is selected from the group consisting of, wherein, R ５ is H; R ５ｃ The compound according to claim 3, wherein R is hydrogen.

5. 【Fig. 11】 is 【Chemical 12】 is selected from the group consisting of, wherein, R₅ is H, the compound according to claim 3.

6. U is S, the compound according to any one of claims 1 to 5.

7. V is NR ２ R ３ The compound according to any one of claims 1 to 5, wherein this is the case.

8. W is N, the compound according to any one of claims 1 to 5.

9. X is NR ６ The compound according to any one of claims 1 to 5, wherein X is NR

10. Y １ and Y ２ The compound according to any one of claims 1 to 5, wherein both are N.

11. R １ The compound according to any one of claims 1 to 5, wherein R is H.

12. R ２ and R ３ is independently H, the compound according to claim 1.

13. R ４ is 【Chemical 13】 selected from the group consisting of, wherein, Each R ８ is independently halogen, C １－５ alkyl, -OH, -OC １－５ alkyl, -COOH, or -CO ２ C １－５ alkyl; p is an integer from 0 to 3, the compound according to claim 1.

14. R ５ The compound according to any one of claims 1 to 5, wherein R is H.

15. R ６ The compound according to claim 1, wherein R is H.

16. m is 0 or 1, the compound according to any one of claims 1 to 5.

17. n is 1 or 2, the compound according to any one of claims 1 to 5.

18. the following structure: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 having one of, the compound according to claim 1, or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

19. Structure: 【Chemical 14】 the compound according to claim 1 having, or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

20. the compound, having the structure: 【Chemical Formula 15】 the compound according to claim 19 having, or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

21. (i) an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof, and (ii) one or more pharmaceutically acceptable excipients, a pharmaceutical composition.

22. The pharmaceutical composition according to claim 21 for use in the treatment of cancer.

23. The pharmaceutical composition according to claim 22, wherein the cancer is a cancer associated with ENPP1 dysfunction.

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