2-Amino-S6-substituted thiopurine compounds as inhibitors of ENPP1 protein

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-pyrophosphodiesterase (ENPP1) dysfunction.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to Indian Provisional Application No. 201941037291 filed on September 16, 2019 and Indian Provisional Application No. 202041017699 filed on April 24, 2020, which are incorporated herein by reference in their entirety for all purposes. Background Art

[0003] Members of the ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family include seven isoforms, ENPP1-7, which are type II transmembrane glycoproteins or exoenzymes. One isoform, ENPP1 (plasmacyte membrane glycoprotein-1, PC-1), is associated with many physiological processes, such as development, formation, and transport, as well as with pathophysiological conditions. Abnormal ENPP1 expression has been detected in breast cancer relative to normal mammary epithelium, and there is evidence that it has potential in the development of bone metastasis (occurring in about 80% of cases), Hodgkin lymphoma, hepatocellular carcinoma, follicular lymphoma, glioblastoma, and other malignant tumor tissues. In addition, mutations in ENPP1 are associated with several conditions, including infantile arterial calcification (systemic arterial calcification of infants or GACI), ossification of the posterior longitudinal ligament of the spine, and insulin signaling and resistance. ENPP1 is highly expressed in bones and cartilage and is associated with pulmonary and renal fibrosis. A correlation was also found between the expression of ENPP1 and the grade of astrocytic tumors. Another study reported that ENPP1 is required for maintaining the undifferentiated and proliferative state of glioblastoma stem-like cells. Therefore, ENPP1 appears to be a viable target for the development of novel anticancer, cardiovascular, diabetes, obesity, and antifibrotic therapies. In addition, ENPP1 activity has also been implicated in diseases caused by bacteria and / or viruses, so modulators of ENPP1 could be used to treat bacterial and / or viral diseases and conditions. Summary of the invention

[0004] Various embodiments are described herein involving compounds, compositions, and methods useful for treating diseases and conditions associated with ENPP1 dysfunction. In some embodiments, the compounds disclosed herein are inhibitors of ENPP1.

[0005] In some embodiments, the present disclosure provides a compound of formula (X) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0006]

[0007] in:

[0008] L is a linker selected from the group consisting of alkylene, alkenylene, alkylene-S-, alkylene-O-, optionally substituted-alkylene-(NR5 )-, optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted

[0009] U is S or NH;

[0010] 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 pyridyl ring;

[0011] W is CH or N;

[0012] X is O, S, NR 6 , -CH=CH- or -CH=N-;

[0013] Y 1 and Y 2 are each independently CH or N;

[0014] R 1 is H, OH, O-alkyl, alkyl or carbocyclyl;

[0015] R 2 and R 3 are each independently H, alkyl, alkylenearyl or -C(O)alkyl;

[0016] R 4 is carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted;

[0017] R 5 is H, alkyl, -C(O)alkyl, carbocyclyl, alkylenecarbocyclyl, or alkylenearyl;

[0018] R 6 is H, alkyl, carbocyclyl, alkylenecarbocyclyl, alkylenearyl, -C(O)alkyl, or -C(O)Oalkylenearyl;

[0019] R 7 is a carbocyclyl, heterocyclyl or heteroaryl;

[0020] m is 0, 1 or 2; and

[0021] n is 1, 2 or 3.

[0022] In a further embodiment, the present disclosure provides a compound of formula (Y) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0023]

[0024] in:

[0025] U is C or N;

[0026] in,

[0027] When U is C, Y is or

[0028] When U is N, Y is

[0029] V is N or CR 10 ;

[0030] W is CH or N;

[0031] X is S, O, NLR 11 or NR 12 ;

[0032] L is selected from alkylene, alkenylene, optionally substituted -alkylene-(NR 12 )-, optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted

[0033] R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, alkylenecarbocyclic, -OLR 11 , -SLR 11 、-N(R 12 )-LR 11 , -LR 11 ;

[0034] R 11 is alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted;

[0035] R 12 Each independently represents H, alkyl, alkylene carbocyclic group or carbocyclic group, wherein two R 12 The groups together with the carbon atoms to which they are attached are capable of forming a heterocyclic group;

[0036] R 14 is a carbocyclyl, heterocyclyl or heteroaryl;

[0037] R 15 is H, alkyl, carbocyclyl, alkylenecarbocyclyl or alkylenearyl;

[0038] in:

[0039] When X is NLR 11 When V is N or CR 10 , where R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclyl or alkylenecarbocyclyl;

[0040] When X is S, O, or NR 12 When V is CR 10 , where R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 ;or

[0041] When U is N, V ​​is CR 10 , where R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 ;

[0042] Z 1 , Z 2 , Z 3 , and Z 4 Each independently is CR 13 or N;

[0043] R 13 is H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 Aryl or -CN, where both R 13 together with the atoms to which they are attached are capable of forming a carbocyclyl, heterocyclyl or heteroaryl group, each of which is optionally substituted;

[0044] m is 0, 1 or 2; and

[0045] n is 1, 2 or 3.

[0046] In yet further embodiments, the present disclosure provides a compound of formula (ZZ) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0047]

[0048] in:

[0049] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 Each independently is N or CR 22 , the condition is:

[0050] (a) Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 One of them is –LR 18 -;

[0051] (b) Z 1 , Z 2 , Z 3 or Z 4 No more than two of them are N; and

[0052] (c)Z 6 or Z 7 One is N;

[0053] in:

[0054] L is a linker selected from the group consisting of: -N(R 19 )-、-alkylene-(NR 19 )-、

[0055] R 18 is alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted;

[0056] R 19 is H, alkyl, carbocyclyl, alkylenecarbocyclyl or alkylenearyl;

[0057] R 20 is H, alkyl, alkylene carbocyclyl, alkylene aryl;

[0058] R 21 is a carbocyclyl, heterocyclyl or heteroaryl;

[0059] R 22 Each is independently halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 Aryl or -CN;

[0060] m is 0, 1 or 2; and

[0061] n is 1, 2 or 3. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Those skilled in the art will appreciate that the drawings are primarily for illustration purposes and are not intended to limit the scope of the inventive subject matter described herein.

[0063] Figure 1 The role of ENPP1 inhibitors in helping to regulate the cGAS-cGAMP-STING pathway, an innate immune pathway activated during infection or by pathophysiological conditions (eg, cancer, autoimmune disorders, etc.) is shown.

[0064] Figure 2 Provided are graphs of tumor growth kinetics in the LLC1 syngeneic tumor model following treatment with Compound 155 administered intravenously (IV) alone or in combination with an anti-PD-1 antibody.

[0065] Figure 3 Provided are graphs of tumor growth kinetics in the LLC1 syngeneic tumor model following treatment with Compound 155 administered orally (PO) alone or in combination with an anti-PD-1 antibody.

[0066] Figure 4 Provided are graphs comparing IV and PO dosing of Compound 155 on tumor growth kinetics in the LLC1 syngeneic tumor model when given alone or in combination with an anti-PD-1 antibody.

[0067] Figure 5Provided are graphs of tumor growth kinetics in the LLC1 syngeneic tumor model following treatment with compound 173 administered intravenously (IV) alone or in combination with an anti-PD-1 antibody.

[0068] Figure 6 Provided are graphs of tumor growth kinetics in the LLC1 syngeneic tumor model following treatment with Compound 173 administered orally (PO) alone or in combination with an anti-PD-1 antibody.

[0069] Figure 7 Provided are graphs comparing IV and PO dosing of Compound 173 on tumor growth kinetics in the LLC1 syngeneic tumor model when given alone or in combination with an anti-PD-1 antibody.

[0070] Figure 8 Provided are graphs of tumor growth kinetics in the LLC1 syngeneic tumor model following treatment with Compound 174 administered intravenously (IV) alone or in combination with an anti-PD-1 antibody.

[0071] Fig. 9 Provided are graphs of tumor growth kinetics in the LLC1 syngeneic tumor model following treatment with Compound 174 administered orally (PO) alone or in combination with an anti-PD-1 antibody.

[0072] Fig.10 Provided are graphs comparing IV and PO dosing of Compound 174 on tumor growth kinetics in the LLC1 syngeneic tumor model when given alone or in combination with an anti-PD-1 antibody. DETAILED DESCRIPTION

[0073] All definitions, as defined and used herein, should be understood to be limited to dictionary definitions, definitions in documents incorporated by reference, and / or the ordinary meanings of the defined terms. The use of flow charts is not meant to limit the order in which operations are performed for all embodiments. Unless expressly indicated to the contrary, the indefinite articles "a" and "an" used in the specification and claims should be understood to mean "at least one".

[0074] References throughout the specification to "one embodiment" or "an embodiment" and the like mean that a particular feature, structure, or characteristic described in conjunction with that embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout the specification do not necessarily all refer to the same embodiment. In addition, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. In addition, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense that includes "and / or" unless the content clearly dictates otherwise.

[0075] As used herein in the specification and claims, the phrase "at least one" referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows that elements other than the elements specifically identified in the list of elements referred to by the phrase "at least one" may optionally be present, whether or not related to those specifically identified elements. Thus, as a 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 refer to: in one embodiment, at least one (optionally including more than one) A, no B (and optionally including elements other than B); in another embodiment, at least one (optionally including more than one) B, no A (and optionally including elements other than A); in yet another embodiment, at least one (optionally including more than one) A, and at least one (optionally including more than one) B (and optionally including other elements); and so on.

[0076] In the claims and the foregoing specification, all transitional phrases, such as "comprising," "including," "carrying," "having," "containing," "involving," "having," "consisting of," etc., shall be understood as open-ended, i.e., meaning including but not limited to. As provided in Section 2111.03 of the U.S. Patent Office Manual of Patent Examining Procedures, only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively.

[0077] "Alkyl" or "alkyl group" refers to a fully saturated straight or branched hydrocarbon chain radical that is attached to the rest of the molecule by a single bond. Alkyl groups containing any number of carbon atoms from 1 to 12 are included. Alkyl groups containing up to 12 carbon atoms are C 1 -C 12Alkyl groups, containing up to 10 carbon atoms, are C 1 -C 10 Alkyl groups, containing up to 6 carbon atoms, are C 1 -C 6 Alkyl and alkyl groups containing up to 5 carbon atoms are C 1 -C 5 Alkyl. C 1 -C 5 Alkyl groups include C 5 Alkyl, C 4 Alkyl, C 3 Alkyl, C 2 Alkyl and C 1 Alkyl (i.e. methyl). 1 -C 6 The alkyl group includes the above C 1 -C 5 All parts of the alkyl group, but also including C 6 Alkyl. C 1 -C 10 The alkyl group includes the above C 1 -C 5 Alkyl and C 1 -C 6 All parts of the alkyl group, but also including C 7 , C 8 , C 9 and C 10 Similarly, C 1 -C 12 Alkyl groups include all of the above moieties, but also include C 11 and C 12 Alkyl. C 1 -C 12 The limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Unless specifically stated otherwise in the specification, alkyl groups may be optionally substituted.

[0078] "Alkylene" or "alkylene chain" refers to a fully saturated straight or branched divalent hydrocarbon chain group. It includes alkylene groups containing any number of carbon atoms from 1 to 12. 1 -C 12The limiting examples of alkylidene group include methylene, ethylene, propylene, n-butylene, vinylidene, propenylene, n-butylene, propyne, n-butylene etc. The alkylidene chain is connected to the rest of the molecule by a single bond and is connected to the free radical group by a single bond. The connection point of the alkylidene chain with the rest of the molecule and the free radical group can be through a carbon or any two carbons in the chain. Unless specifically stated otherwise in the specification, the alkylidene chain can be optionally substituted.

[0079] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain radical having from 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached 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 C 2 -C 12 Alkenyl, alkenyl containing up to 10 carbon atoms is C 2 -C 10 Alkenyl. Alkenyl groups containing up to 6 carbon atoms are C 2 -C 6 Alkenyl and alkenyl containing up to 5 carbon atoms are C 2 -C 5 Alkenyl. C 2 -C 5 Alkenyl includes C 5 Alkenyl, C 4 Alkenyl, C 3 Alkenyl and C 2 Alkenyl. C 2 -C 6 Alkenyl includes the above C 2 -C 5 All parts of alkenyl, but also including C 6 Alkenyl. C 2 -C 10 Alkenyl includes the above C 2 -C 5 Alkenyl and C 2 -C 6 All parts of alkenyl, but also including C 7 , C 8 , C 9 and C 10 Similarly, C 2 -C 12 Alkenyl includes all of the above moieties, but also includes C 11 and C 12 Alkenyl. C 2 -C 12Non-limiting examples of alkenyl groups include ethylidene (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 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. C 1 -C 3 Examples of alkyl groups include methyl, ethyl, n-propyl and isopropyl. 1 -C 4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and sec-butyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted.

[0080] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. 2 -C 12 The limiting examples of alkenylene include ethylene, propylene, butylene etc. The alkenylene chain is connected to the rest of the molecule by a single bond and is connected to the free radical group by a single bond. The connection point of the alkenylene chain to the rest of the molecule and the free radical group can be through a carbon or any two carbons in the chain. Unless specifically stated otherwise in the specification, the alkenylene chain can be optionally substituted.

[0081] "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 rest 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 C 2 -C12 Alkynyl. Alkynyl containing up to 10 carbon atoms is C 2 -C 10 Alkynyl. Alkynyl groups containing up to 6 carbon atoms are C 2 -C 6 Alkynyl and alkynyl groups containing up to 5 carbon atoms are C 2 -C 5 Alkynyl. C 2 -C 5 Alkynyl groups include C 5 Alkynyl, C 4 Alkynyl, C 3 Alkynyl and C 2 Alkynyl. C 2 -C 6 Alkynyl groups include the above C 2 -C 5 All parts of the alkynyl group, but also including C 6 Alkynyl. C 2 -C 10 Alkynyl groups include the above C 2 -C 5 Alkynyl and C 2 -C 6 All parts of the alkynyl group, but also including C 7 , C 8 , C 9 and C 10 Similarly, C 2 -C 12 Alkynyl groups include all of the above moieties, but also include C 11 and C 12 Alkynyl. C 2 -C 12 Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted.

[0082] "Alkyne" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain radical having 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. 2 -C 12 The limiting examples of alkynylene include ethynylene, propynylene etc. The alkynylene chain is connected to the rest of the molecule by a single bond and is connected to the radical group by a single bond. The connection point of the alkynylene chain to the rest of the molecule and the radical group can be through one carbon or any two carbons in the chain. Unless otherwise specifically stated in the specification, the alkynylene chain can be optionally substituted.

[0083] "Alkoxy" refers to a group of the formula -OR a A group in which R ais an alkyl, alkenyl or alkynyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.

[0084] "Alkylamino" refers to a group of the formula -NHR a or -NR a R a A group in which R a Each is independently an alkyl, alkenyl or alkynyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group may be optionally substituted.

[0085] "Alkylcarbonyl" refers to -C(=O)R a Part, of which R a is an alkyl, alkenyl or alkynyl group as defined above. A non-limiting example of an alkylcarbonyl group is a methylcarbonyl ("acetal") moiety. An alkylcarbonyl group may also be referred to as a "Cw-Cz acyl group," where w and z describe R a The carbon number range in the formula is as defined above. For example, "C 1 -C 10 "Acyl" means an alkylcarbonyl group as defined above, wherein R a is C as defined above 1 -C 10 Alkyl, C 1 -C 10 Alkenyl or C 1 -C 10 Alkynyl groups. Unless stated otherwise specifically in the specification, an alkylcarbonyl group may be optionally substituted.

[0086] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 5 to 18 carbon atoms and at least one aromatic ring. For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl groups include, but are not limited to, aryl groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, Fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene and triphenylene. Unless otherwise specifically stated in the specification, the term "aryl" is intended to include optionally substituted aryl groups.

[0087] "Alkylenaryl" refers to a group of the formula -R b -R c A group in which R bis an alkylene group as defined above and R c is one or more aryl groups as defined above. Examples include benzyl, diphenylmethyl, etc. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

[0088] "Carbocyclyl", "carbocyclic ring" or "carbocycle" refers to a ring structure in which the atoms forming the ring are each carbon. The carbocyclic ring may contain 3 to 20 carbon atoms in the ring. Carbocyclic rings include cycloalkyl, cycloalkenyl and cycloalkynyl as defined herein. Unless otherwise specifically stated in the specification, a carbocyclyl group may be optionally substituted.

[0089] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include a fused ring or bridged ring system having 3 to 20 carbon atoms, for example, 3 to 10 carbon atoms, and is connected 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]heptyl, etc. Unless otherwise specifically stated in the specification, cycloalkyl groups may be optionally substituted.

[0090] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical with one or more carbon-carbon double bonds consisting only of carbon atoms and hydrogen atoms, which can include a fused ring or bridged ring system with 3 to 20 carbon atoms, for example, with 3 to 10 carbon atoms, and is connected to the rest of the molecule by a single bond. 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 specifically stated otherwise in the specification, cycloalkenyl groups can be optionally substituted.

[0091] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon atoms and hydrogen atoms with one or more carbon-carbon triple bonds, which may include a fused ring or bridged ring system having 3 to 20 carbon atoms, for example, 3 to 10 carbon atoms, and is connected to the remainder of the molecule by a single bond. Monocyclic cycloalkynyl groups include, for example, cycloheptynyl, cyclooctynyl, etc. Unless specifically stated otherwise in the specification, cycloalkynyl groups may be optionally substituted.

[0092] "Cycloalkylalkyl" refers to a group of the formula -R b -R d A group in which R b is an alkylene, alkenylene or alkynylene group as defined above, and R dis a cycloalkyl, cycloalkenyl, cycloalkynyl group as defined above. Unless stated otherwise specifically in the specification, a cycloalkylalkyl group may be optionally substituted.

[0093] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halogen groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group may be optionally substituted.

[0094] "Haloalkenyl" refers to an alkenyl group as defined above substituted with one or more halo groups as defined above, for example 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless stated otherwise specifically in the specification, a haloalkenyl group may be optionally substituted.

[0095] "Haloalkynyl" refers to an alkynyl group as defined above substituted with one or more halo groups as defined above, for example 1-fluoropropynyl, 1-difluorobutynyl, etc. Unless stated otherwise specifically in the specification, a haloalkenyl group may be optionally substituted.

[0096] "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 nitrogen, oxygen and sulfur. Heterocyclyl or heterocyclic ring includes heteroaryl as defined below. Unless otherwise specifically stated in the specification, the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclyl group can be optionally oxidized; the nitrogen atom can be optionally quaternized; the heterocyclyl group can be partially or fully saturated. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl [1,3] dithienyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithienyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the heterocyclyl group may be optionally substituted.

[0097] "N-heterocyclyl" refers to a heterocyclyl group as defined above that contains at least one nitrogen and wherein the point of attachment of the heterocyclyl group to the rest of the molecule is through the nitrogen atom in the heterocyclyl group. Unless otherwise specifically stated in the specification, an N-heterocyclyl group may be optionally substituted.

[0098] "Alkylene heterocyclic group" refers to a group of the formula -R b -R e A group in which R b is an alkylene group as defined above, R e is a heterocyclyl group as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the nitrogen atom of an alkyl, alkenyl or alkynyl group. Unless specifically stated otherwise in the specification, an alkylene heterocyclyl group may be optionally substituted.

[0099] "Heteroaryl" refers to a 5- to 20-membered ring system radical containing hydrogen atoms, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. For the purposes of the present invention, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxazolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazine oxide substituted, 1- phenyl-1H-pyrrolyl ...

[0100] "N-heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. Unless otherwise specifically stated in the specification, an N-heteroaryl group may be optionally substituted.

[0101] "Alkylene heteroaryl" refers to a group of the formula -R b -R f A group in which R b is an alkylene group as defined above and R f is a heteroaryl group as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.

[0102] "Thioalkyl" refers to a group of the formula -SR a A group in which R a is an alkyl, alkenyl or alkynyl group as defined above containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.

[0103] As used herein, the term "substituted" refers to any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, alkylthio, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, such as, but not limited to, a halogen atom, such as F, Cl, Br and I; such as hydroxyl. The term "substituted" refers to any of the above groups, wherein one or more hydrogen atoms are replaced by a higher bond (e.g., a double bond or a triple bond) connected to a heteroatom, such as oxygen atoms in oxo, carbonyl, carboxyl, and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituted" also refers to any of the above groups, wherein one or more hydrogen atoms are replaced by a higher bond (e.g., a double bond or a triple bond) connected to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups, wherein one or more hydrogen atoms are replaced by -NR g C(=O)OR h 、-NR g SO 2 R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-SOR g 、-SO 2 R g 、-OSO 2 R g 、-SO 2 OR g , =NSO 2 R g , and -SO 2 NR g R h "Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by -C(=O)R g、-C(=O)OR g 、-C(=O)NR g R h 、-CH 2 SO 2 R g 、-CH 2 SO 2 NR g R h In the above, R g and R h Identical or different and independently be hydrogen, alkyl, alkenyl, alkynyl, alkoxyl, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic radical, N-heterocyclic radical, heterocyclic radical alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl. "Substituted" further means any of the above-mentioned groups, wherein one or more hydrogen atoms are replaced by the key connected to the following groups: amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxyl, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic radical, N-heterocyclic radical, heterocyclic radical alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl groups. In addition, each of the above-mentioned substituents can also be optionally substituted by one or more of the above-mentioned substituents.

[0104] As used herein, the symbol (hereinafter referred to as a "point of attachment bond") is a bond that represents a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other chemical entity is not depicted as being attached to the point of attachment bond. For example, Indicates that the chemical entity "XY" is bonded to another chemical entity via a point of attachment bond. In addition, specific points of attachment to chemical entities not depicted can be indicated by inference. For example, the compound CH 3 -R 3 , where R 3 is H or This means that when R 3 When it is "XY", connect the point key with R 3 Depicted with CH 3 The bonds are the same.

[0105] "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 the fused heteroaryl ring may be replaced by a nitrogen atom.

[0106] "Geminal" refers to any two substituents attached to the same atom (e.g., those described herein, such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.). In some embodiments, geminal substitution refers to substitution on the same carbon atom. The structure Geminal methyl substitution on cyclohexane is exemplified. In some embodiments, the optional substitution is geminal substitution.

[0107] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes substituted aryl groups and aryl groups without substitution.

[0108] The compounds of the present invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may 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 described herein. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0109] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but with different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0110] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of the described compounds.

[0111] "Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0112] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts.

[0113] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases which are not biologically or otherwise undesirable and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; and organic acids such as, but not limited to, 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, acid), dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptanoic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric 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.

[0114] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acid which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. In some embodiments, inorganic salts include ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines, cyclic amines), and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hepamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. In specific embodiments, the organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0115] Crystallization is a method commonly used to separate a reaction product (e.g., one of the compounds disclosed herein) in a purified form. Typically, crystallization produces a solvate of the compounds of the present invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compounds of the present invention and one or more solvent molecules, which is typically in the form of co-crystallization. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may only retain exogenous water or a mixture of water and some exogenous solvents.

[0116] The chemical naming scheme and structure diagram used herein are modified forms of the IUPAC naming system using 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 naming program (CambridgeSoft) etc. For the complex chemical names used herein, the substituent is named before the group to which it is connected. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent. Except as described below, all bonds are identified in the chemical structure diagrams herein, except for some carbon atoms, assuming that they are bonded to enough hydrogen atoms to complete valence.

[0117] The invention disclosed herein is also intended to encompass in vivo metabolites of the disclosed compounds. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Therefore, the present invention includes compounds produced by a method comprising administering a compound of the present invention to a mammal for a period of time sufficient to produce its metabolites. Such products are typically obtained by administering a detectable dose of a radiolabeled compound of the present invention to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating its conversion products from urine, blood, or other biological samples.

[0118] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0119] As used herein, a "subject" can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, insect, etc. The subject may be suspected of having or being at risk of having cancer, such as blood cancer, or another disease or condition. Methods for diagnosing various cancers and clinical descriptions of cancer are known to those of ordinary skill in the art. The subject may also be suspected of having an infection or cardiovascular dysfunction.

[0120] "Mammal" includes humans and domestic animals such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and non-domestic animals such as wild animals, among others.

[0121] "Pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (eg, a human). Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0122] "Effective amount" refers to a therapeutically effective amount or a preventive effective amount. "Therapeutically effective amount" refers to an amount that effectively achieves the desired therapeutic result within the necessary time period and dosage, such as a reduced tumor size, an increased life span, or an increased life expectancy. The therapeutically effective amount of a compound can vary according to factors such as the disease state, age, sex, and weight of the subject, as well as the ability of the compound to elicit the desired response in the subject. The dosage regimen can be adjusted to provide the best therapeutic response. A therapeutically effective amount is also an amount in which the therapeutic beneficial effect exceeds any toxic or deleterious effect of the compound. "Preventive effective amount" refers to an amount that effectively achieves the desired preventive result within the necessary time period and dosage, such as a smaller tumor, an increased life span, an increased life expectancy, or prevention of prostate cancer from progressing to a castration-resistant form. Typically, a preventive dose is used in a subject before the disease or in the early stages of the disease, so that the preventive effective amount can be less than the therapeutically effective amount.

[0123] As used herein, "in treatment" or "treatment" encompasses the treatment of a disease or condition of interest in a mammal (e.g., a human) suffering from the disease or condition of interest, and includes, but is not limited to:

[0124] 1. Preventing the disease or condition from occurring in a mammal, particularly when the mammal is susceptible to the condition but has not yet been diagnosed as having the condition;

[0125] 2. To inhibit a disease or condition, that is, to prevent its development;

[0126] 3. alleviate the disease or condition, i.e., cause regression of the disease or condition (ranging from reducing the severity of the disease or condition to curing the condition); or

[0127] 4. Relieve symptoms caused by a disease or condition, i.e., relieve pain without addressing the underlying disease or condition. As used herein, the terms "disease" and "condition" may be used interchangeably, or may be different, in that a particular disease or condition will not have a known pathogen (and thus a cause has not yet been determined) and therefore is still not yet considered a disease, but rather an adverse condition or syndrome for which clinicians have identified a group of more or less specific symptoms.

[0128] Throughout this specification, the term "about" and / or "approximately" can be used in conjunction with numerical value and / or range. The term "about" is understood to refer to those values ​​close to the listed values. For example, "about 40 [units]" can refer to within ± 25% (e.g., 30 to 50) of 40, within ± 20%, ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, less than ± 1% or any other value or value herein. In addition, the phrase "less than about [value]" or "greater than about [value]" should be understood according to the definition of the term "about" provided herein. The terms "about" and "approximately" can be used interchangeably.

[0129] Numerical ranges can be provided for certain amounts. It should be understood that these ranges include all subranges therein. Therefore, the range "50 to 80" includes all possible ranges therein (e.g., 51 to 79, 52 to 78, 53 to 77, 54 to 76, 55 to 75, 60 to 70, etc.). In addition, all values ​​in a given range can be the endpoints of the range thus covered (e.g., the range 50 to 80 includes a range with endpoints, such as 55 to 80, 50 to 75, etc.).

[0130] The following is a more detailed description of various concepts and embodiments related to the compounds and methods of the present invention for treating liver diseases and liver abnormalities. It should be understood that the various concepts introduced above and discussed in more detail below can be implemented in any of a variety of ways, as the disclosed concepts are not limited to any particular implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes.

[0131] Compounds and compositions

[0132] In various embodiments, the present disclosure provides a compound of formula (A1), formula (A2), or a pharmaceutically acceptable salt, hydrate, or tautomer thereof:

[0133]

[0134] in:

[0135] L is a linker selected from the group consisting of alkylene, alkenylene, optionally substituted alkylene-S-, optionally substituted alkylene-O-, optionally substituted -alkylene-(NR 5 )-, optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted

[0136] T is CR1 or N;

[0137] U is S, S(O) 2 or NH;

[0138] V is H, 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 pyridyl ring;

[0139] W is CH or N;

[0140] X is O, S, NR 6 , -CH=CH- or -CH=N-;

[0141] in:

[0142] When W is CH, T is N and X is O, S or NR 6 ;

[0143] Y 1 and Y 2 are each independently CH or N;

[0144] R 1 is H, OH, O-alkyl, alkyl or carbocyclyl;

[0145] R 2 and R 3 are each independently H, alkyl, alkylenearyl or -C(O)alkyl;

[0146] R 4 is carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted;

[0147] R 5 is H, alkyl, -C(O)alkyl, carbocyclyl, alkylenecarbocyclyl, or alkylenearyl;

[0148] R 6 is H, alkyl, carbocyclyl, alkylenecarbocyclyl, alkylenearyl, -C(O)alkyl, or -C(O)Oalkylenearyl;

[0149] R 7 is a carbocyclyl, heterocyclyl or heteroaryl;

[0150] m is 0, 1 or 2; and

[0151] n is 1, 2 or 3.

[0152] In some embodiments, the present disclosure provides a compound of formula (A1) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0153]

[0154] Among them L, T, U, V, W, X, Y 1 , Y 2 and R 4 As defined herein.

[0155] In some embodiments of the present disclosure, there is provided a compound of formula (A2) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0156]

[0157] Among them L, T, U, V, W, X, Y 1 , Y 2 and R 4 As defined herein.

[0158] In some embodiments, L is alkylene, alkenylene, alkylene-(NR 5 )-、 In some embodiments, L is each optionally substituted alkylene, alkylene-(NR 5 )-、 In some embodiments of Formula (A1) and Formula (A2), L is an alkylene, alkenylene, alkylene-(NR 5 )-、 In some embodiments, L is each optionally substituted alkylene-(NR 5 )-、 In some embodiments, L is each optionally substituted alkylene-(NR 5 )-、 In some embodiments, L is each optionally substituted alkylene-(NR 5 )-、 In some embodiments, L is each optionally substituted alkylene-(NR 5 )-、 In some embodiments, L is alkenylene, alkylene-(NR 5 )-, optionally substituted Optional Substituted Optional Substituted or optionally substituted In some embodiments, L is each optionally substituted alkylene-(NR 5 )-、 In some embodiments, L is optionally substituted Optional Substituted Optional Substituted or optionally substituted In some embodiments, L is optionally substituted Optional Substituted or optionally substituted In some embodiments, L is optionally substituted Optional Substituted or optionally substituted In some embodiments, L is optionally substituted or optionally substituted In some embodiments, L is optionally substituted or optionally substituted In some embodiments, L is optionally substituted In other embodiments, L is optionally substituted In some embodiments, L is optionally substituted In yet other embodiments, L is optionally substituted In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In other embodiments, L is In yet other embodiments, L 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.

[0159] In some embodiments of Formula (A1) and Formula (A2), the optionally substituted yes

[0160] in:

[0161] R 5 is H, alkyl, -C(O)alkyl, carbocyclyl, alkylenecarbocyclyl, or alkylenearyl;

[0162] R 5a and R 5b are each independently selected from H, halogen, C 1-5 Alkyl, C 3-6 Carbocyclic group, alkylene-C 3-6 Carbocyclic, aryl, alkylene aryl or NH 2 ; Two of the C 1-5 The alkyl groups together with the carbon atom to which they are attached form a C3-6 Carbocyclyl; and

[0163] m is 0 or 1.

[0164] In some embodiments, R 5 is H, methyl or -C(O)Me. 5 is H. In some embodiments, R 5a is an alkyl group or a carbocyclic group and R 5b It's H.

[0165] In some embodiments, when L is When R 5 and R 5a Together with the carbon atoms to which they are attached, they form a heterocyclyl ring. When R 5 and R 5a Together with the carbon atoms to which they are attached, they form a 4-, 5-, or 6-membered heterocyclyl ring.

[0166] In some embodiments of Formula (A1) and Formula (A2), Selected from:

[0167] Where R 5c is halogen, alkyl, haloalkyl, hydroxyl or alkoxy. 5c In the para position of the benzene ring.

[0168] In some embodiments, Selected from:

[0169]

[0170] In some embodiments of Formula (A1) and Formula (A2), Selected from:

[0171]

[0172] In some embodiments of Formula (A1) and Formula (A2), the optionally substituted Selected from:

[0173] Where R 5c is halogen, alkyl, haloalkyl, hydroxyl or alkoxy. 5c In the para position of the benzene ring.

[0174] In some embodiments of Formula (A1) and Formula (A2), the optionally substituted yes in:

[0175] R 5 is H, alkyl, -C(O)alkyl, carbocyclyl, alkylenecarbocyclyl, or alkylenearyl; and

[0176] R 5a and R 5b are each independently selected from H, halogen, C 1-5 Alkyl, C 3-6 Carbocyclic group, alkylene-C 3-6 Carbocyclic, aryl, alkylene aryl or NH 2 ; Two of the C 1-5 The alkyl groups together with the carbon atom to which they are attached form a C 3-6 Carbocyclic group.

[0177] In some embodiments, R 5 is H, methyl or -C(O)Me. 5 Yes H, R 5a is an alkyl group or a carbocyclic group, and R 5b is H. In some embodiments, R 5 Yes H, R 5a is an alkyl group, and R 5b It's H.

[0178] In some embodiments, Selected from:

[0179]

[0180] In some embodiments of Formula (A1) and Formula (A2), L comprises an alkylene group. In some embodiments, the alkylene group is an optionally substituted C 1-4 In some embodiments, the alkylene group is an optionally substituted C 1-3 In some embodiments, the alkylene group is an optionally substituted C 1-2 In some embodiments, the alkylene group is an optionally substituted C 2-4 In some embodiments, the alkylene group is an optionally substituted C 2-3 In some embodiments, the alkylene group is an optionally substituted C 3-4 In some embodiments, when L comprises an alkylene group, the alkylene group is C 1-4 In some embodiments, the alkylene group is C 1-3 In some embodiments, the alkylene group is C 1-2 In some embodiments, the alkylene group is C2-4 In some embodiments, the alkylene group is C 2-3 In some embodiments, the alkylene group is C 3-4 Alkylene. In some embodiments, alkylene is methylene, ethylene, propylene or butylene, each of which is optionally substituted. In some embodiments, alkylene is ethylene, propylene or butylene, each of which is optionally substituted. In some embodiments, alkylene is an optionally substituted methylene. In some embodiments, alkylene is an optionally substituted ethylene. In some embodiments, alkylene is an optionally substituted propylene. In some embodiments, alkylene is an optionally substituted butylene. In some embodiments, alkylene is methylene, ethylene, propylene or butylene. In some embodiments, alkylene is methylene. In some embodiments, alkylene is ethylene. In some embodiments, alkylene is propylene. In some embodiments, alkylene is butylene.

[0181] In some embodiments of Formula (A1) and Formula (A2), L is an alkylene-(NR 5 )-. In some embodiments, the alkylene group is an optionally substituted ethylene group. In some embodiments, the optionally substituted ethylene group is selected from:

[0182]

[0183] In some embodiments of Formula (A1) and Formula (A2), L is an alkylene-(NR 5 )-. In some embodiments, the alkylene group is an optionally substituted propylene group. In some embodiments, the optionally substituted propylene group is selected from:

[0184]

[0185] In some embodiments of Formula (A1) and Formula (A2), L comprises an alkenylene group. In some embodiments, the alkenylene group is an optionally substituted C 2-4 In some embodiments, alkenyl is an optionally substituted C 2-3 In some embodiments, alkenylene is an optionally substituted C 3-4 In some embodiments, when L comprises an alkenylene group, the alkenylene group is C 2-4 In some embodiments, alkenylene is C 2-3 In some embodiments, the alkenylene group is C 3-4In some embodiments, the alkenylene is an optionally substituted vinylene, propenylene or butenylene. In some embodiments, the alkenylene is an optionally substituted vinylene. In some embodiments, the alkenylene is an optionally substituted propenylene. In some embodiments, the alkenylene is an optionally substituted butenylene. In some embodiments, the alkenylene is an optionally substituted vinylene, propenylene or butenylene. In some embodiments, the alkenylene is an vinylene. In some embodiments, the alkenylene is propenylene. In some embodiments, the alkenylene is butenylene.

[0186] In some embodiments of formula (A1) and formula (A2), the optional substituents are selected from oxo, halogen, C 1-5 Alkyl, C 3-6 In some embodiments, the optional substituents are selected from oxo, C 1-5 Alkyl and C 3-6 In some embodiments, the optional substituents are selected from oxo and C 1-5 In some embodiments, the optional substituent is oxo. In other embodiments, the optional substituent is C 1-5 In some embodiments, C 1-5 Alkyl is methyl, ethyl, propyl or isopropyl. 1-5 Alkyl is methyl, ethyl or isopropyl. In other embodiments, C 1-5 In some embodiments, C 3-6 Cycloalkyl is cyclopropyl or cyclohexyl. In some embodiments, aryl is phenyl. In some embodiments, alkylene carbocyclyl is methylenecyclopropyl or methylenecyclohexyl. In some embodiments, alkylenearyl is methylenephenyl.

[0187] 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.

[0188] 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.

[0189] In some embodiments of Formula (A1) and Formula (A2), m is 0 or and n is 1. In other embodiments, m is 1 and n is 1. In yet other embodiments, m is 0 and n is 2. In yet another embodiment, m is 2 and n is 1.

[0190] In some embodiments of Formula (A1) and Formula (A2), T is N. In other embodiments, T is CR 1 .

[0191] In some embodiments of Formula (A1) and Formula (A2), U is S. In other embodiments, U is NH.

[0192] In some embodiments of Formula (A1) and Formula (A2), V is H, OH, NR 2 N 3 Or N = CR 2 R 3 In some embodiments of Formula (A1) and Formula (A2), V is H, OH or NR 2 N 3 In some embodiments, V and Y 1 Together with the atoms to which they are attached, they form an optionally substituted phenyl or pyridyl ring. 2 N 3 In other embodiments, V is OH. In some embodiments, V is H.

[0193] In some embodiments of Formula (A1) and Formula (A2), W is N. In other embodiments, W is CH.

[0194] In some embodiments of Formula (A1) and Formula (A2), X is O, S or NR 6 In some embodiments, X is O or NR 6 In some embodiments, X is NR 6 In some embodiments, X is O. In some embodiments, X is S. In some embodiments, X is -CH=CH- or -CH=N-.

[0195] In some embodiments of Formula (A1) and Formula (A2), Y 1 or Y 2 is N. In some embodiments, Y 1 and Y 2 are all N. In some embodiments, Y 1 N and Y 2 In some embodiments, Y 1 CH and Y 2 is N.

[0196] In some embodiments of Formula (A1) and Formula (A2), U is S, W is N, and X is NR 6 In certain embodiments, V is NR 2 NR 3 .

[0197] In some embodiments of Formula (A1) and Formula (A2), U is S, W is N, and X is NR 6 In certain embodiments, Y 1 and Y 2 Each is N.

[0198] In some embodiments of Formula (A1) and Formula (A2), U is S, W is N, and X is NR 6 In certain embodiments, V is NR 2 NR 3 .

[0199] In some embodiments of formula (A1) and formula (A2), U is S, W is N, and X is NR 6 , and Y 1 and Y 2 Each is N. In certain embodiments, V is NR 2 NR 3 .

[0200] In some embodiments of formula (A1) and formula (A2), U is S, W is N, and X is NR 6 , and V is NR 2 NR 3 In certain embodiments, Y 1 and Y 2 Each is N.

[0201] In some embodiments of formula (A1) and formula (A2), when W is CH, T is N, U is S, and V is H or NR 2 R 3 , and X is NR 6 In certain embodiments, Y 1 and Y 2 Each is N.

[0202] In some embodiments of Formula (A1) and Formula (A2), R 1 is H, OH or C 1-5 In other embodiments, R 1 is H. In some embodiments, R 1 is OH. In some embodiments, R 1 It is C 1-5 In some embodiments, C 1-5The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopentyl and isobutyl. 1-5 The alkyl group is selected from methyl, ethyl and isopropyl.

[0203] In some embodiments of Formula (A1) and Formula (A2), R 2 and R 3 are independently H, -C 1-5 Alkyl, -CH 2 Ph or –C(O)(C 1-5 In some embodiments, R 2 and R 3 are independently H, -C 1-5 Alkyl, -CH 2 Ph or –C(O)(CH 3 ). In some embodiments, R 2 and R 3 One of is H. In some embodiments, R 2 and R 3 is H. In some embodiments, R 2 and R 3 One of them is -C 1-5 In some embodiments, R 2 and R 3 One of them is -CH 2 Ph. In some embodiments, R 2 and R 3 One of them is –C(O)(CH 3 ). In some embodiments, C 1-5 The alkyl group is selected from methyl, ethyl and isopropyl.

[0204] In some embodiments of Formula (A1) and Formula (A2), R 4 is each optionally substituted aryl or heteroaryl. 4 is an optionally substituted aryl. 4It is an optionally substituted heteroaryl. In some embodiments, heteroaryl is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, indolyl, oxindolyl, isatinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl or quinoxalinyl. In some embodiments, aryl is 6 to 12 yuan of aryl and heteroaryl is 5 to 12 yuan of heteroaryl with 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, the 5- to 12-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from N, O, and S is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, tetrazolyl, or pyrazolyl. In some embodiments, the 5- to 12-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from N, O, and S is pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, the 5- to 12-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from N, O, and S is indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, and quinoxalinyl.

[0205] In some embodiments, R 4 is aryl or heteroaryl, each optionally substituted with one or more of the following: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, heterocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 In other embodiments, the aryl or heteroaryl groups are replaced by one or more H, halogen, -C 1-5 Alkyl, -CF 3 、-OH、-O(C 1-5 Alkyl), -OCF 3 、-OSO 2 Me, -COOH, -C(O)OMe, or -SO 2Me is optionally substituted. In some embodiments, aryl is optionally substituted phenyl. In some embodiments, heteroaryl is optionally substituted pyridyl. In certain embodiments, optionally substituted pyridyl is selected from wherein p is 0, 1 or 2. In some embodiments, heteroaryl is optionally substituted pyrimidinyl. In certain embodiments, optionally substituted pyrimidinyl is wherein p is 0, 1 or 2. In some embodiments, R 8 Each is independently halogen, alkyl, -OH, -Oalkyl, -CO 2 H or -CO 2 alkyl.

[0206] In some embodiments of Formula (A1) and Formula (A2), R 4 is an optionally substituted aryl group selected from:

[0207]

[0208] In some embodiments, R 4 is an optionally substituted heteroaryl selected from:

[0209]

[0210] In some embodiments, R 4 Selected from:

[0211]

[0212] wherein p is an integer from 0 to 3. In some embodiments, R 8 are independently halogen, alkyl, haloalkyl, alkenyl, -OH, -Oalkyl, -N(alkyl) 2 , -CO 2 H, -CO 2 Alkyl or -CN.

[0213] In some embodiments, R 4 Selected from:

[0214]

[0215] in:

[0216] R 8 are independently halogen, C 1-5 Alkyl, -OH, -OC 1-5 Alkyl, -COOH or -CO 2 C 1-5 an alkyl group; and p is an integer from 0 to 3.

[0217] In some embodiments of Formula (A1) and Formula (A2), R 4 In some embodiments, the carbocyclyl group is an optionally substituted C 3-6 In some embodiments, the carbocyclyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the carbocyclyl is cyclohexyl.

[0218] In some embodiments of Formula (A1) and Formula (A2), R 4 is a heterocyclyl. In some 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.

[0219] In some embodiments of Formula (A1) and Formula (A2), R 5 It is H, C 1-5 Alkyl, -C(O)C 1-4 Alkyl, -C 3-6 Carbocyclic group, -CH 2 -Aryl or -CH 2 -(C 3-6 In some embodiments, R 5 It is H, C 1-5 Alkyl, -C(O)Me or -C 3-6 In some embodiments, R 5 H or C 1-5 In some embodiments, C 1-5 The alkyl group is selected from the group consisting of methyl, ethyl and isopropyl. 3-6 Carbocyclyl is cyclopropyl or cyclohexyl. 5 is H, Me or -C(O)Me. 5 is H, Me or CH 2 Ph. In some embodiments, R 5 is H. In some embodiments, R 5 is Me. In some embodiments, R 5 It’s -C(O)Me.

[0220] In some embodiments of Formula (A1) and Formula (A2), R 6 It is H, C 1-5 Alkyl, CH 2 Aryl or CH 2 -(C 3-6 In some embodiments, R 6 H, C 1-5 Alkyl or CH2 Ph. In some embodiments, C 1-5 The alkyl group is selected from methyl, ethyl and isopropyl. 6 It's H.

[0221] In some embodiments of Formula (A1) and Formula (A2), R 7 It is C 3-6 In some embodiments, R 7 C 3-6 In some embodiments, C 3-6 Carbocyclyl is cyclopropyl or cyclohexyl. 7 is a 5- to 6-membered heteroaryl. In some embodiments, the 5- to 6-membered heteroaryl is selected from oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl and pyrazinyl. In some embodiments, the 5- to 6-membered heteroaryl is selected from Where X 1 NR 6 , S or O, and R 6 is H or alkyl. In some embodiments, R 7 is a 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl is selected from Where X 1 NR 6 , S or O. In some embodiments, the 5-membered heteroaryl is selected from In some embodiments, R 7 is a 3- to 6-membered heterocyclic group. In some embodiments, the 3- to 6-membered heterocyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0222] In some embodiments, R 8 are independently halogen, alkyl, haloalkyl, alkenyl, -OH, -Oalkyl, -N(alkyl) 2 , -CO 2 H, -CO 2 In some embodiments, R 8 Each is independently halogen, alkyl, haloalkyl, -OH, -Oalkyl, -Ohaloalkyl or -CO 2 H. In some embodiments, R 8 Each is independently halogen, alkyl, -OH, -Oalkyl or -CO 2 H.

[0223] In some embodiments, the compound of Formula (A1) or Formula (A2) has a structure according to one of the following:

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

[0266] In some embodiments, the compound of Formula (A1) or Formula (A2) is a compound provided in Table 2, Table 3, or Table 4 below.

[0267] In some embodiments, the compound of formula (A2) is a compound of formula (X).

[0268] In various embodiments, the present disclosure provides a compound of formula (X) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0269]

[0270] in:

[0271] L is a linker selected from the group consisting of alkylene, alkenylene, optionally substituted alkylene-S-, optionally substituted alkylene-O-, optionally substituted -alkylene-(NR 5)-, optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted

[0272] U is S, S(O) 2 or NH;

[0273] 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 pyridyl ring;

[0274] W is CH or N;

[0275] X is O, S, NR 6 , -CH=CH- or -CH=N-;

[0276] Y 1 and Y 2 are each independently CH or N;

[0277] R 1 is H, OH, O-alkyl, alkyl or carbocyclyl;

[0278] R 2 and R 3 are each independently H, alkyl, alkylenearyl or -C(O)alkyl;

[0279] R 4 is carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted;

[0280] R 5 is H, alkyl, -C(O)alkyl, carbocyclyl, alkylenecarbocyclyl, or alkylenearyl;

[0281] R 6 is H, alkyl, carbocyclyl, alkylenecarbocyclyl, alkylenearyl, -C(O)alkyl, or -C(O)Oalkylenearyl;

[0282] R 7 is a carbocyclyl, heterocyclyl or heteroaryl;

[0283] m is 0, 1 or 2; and

[0284] n is 1, 2 or 3.

[0285] In various embodiments, the present disclosure provides a compound of formula (X) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0286]

[0287] in:

[0288] L is a linker selected from the group consisting of alkylene, alkenylene, optionally substituted alkylene-S-, optionally substituted alkylene-O-, optionally substituted -alkylene-(NR 5 )-, optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted

[0289] U is S, S(O) 2 or NH;

[0290] 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 pyridyl ring;

[0291] W is CH or N;

[0292] X is O, S, NR 6 , -CH=CH- or -CH=N-;

[0293] Y 1 and Y 2 are each independently CH or N;

[0294] R 1 is H, OH, O-alkyl, alkyl or carbocyclyl;

[0295] R 2 and R 3 are each independently H, alkyl, alkylenearyl or -C(O)alkyl;

[0296] R 4 is carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted;

[0297] R 5 is H, alkyl, -C(O)alkyl, carbocyclyl, alkylenecarbocyclyl, or alkylenearyl;

[0298] R 6 is H, alkyl, carbocyclyl, alkylenecarbocyclyl, alkylenearyl, -C(O)alkyl, or -C(O)Oalkylenearyl;

[0299] R 7 is a carbocyclyl, heterocyclyl or heteroaryl;

[0300] m is 0, 1 or 2; and

[0301] n is 1, 2 or 3.

[0302] Provided that the compound of formula (X) is not one or more of the following:

[0303] in:

[0304] (a)R 2 is H, and R 4 yes or

[0305] (b)R 2 is Me, and R 4 yes or

[0306] (c)R 2 is Et, and R 4 yes or

[0307] (d) R 2 is nPr, C(O)Me or CO 2 nBu, and R 4 yes or

[0308]

[0309]

[0310] In some embodiments of Formula (X), L is an alkylene, alkenylene, alkylene-(NR 5 )-、 In some embodiments, L is each optionally substituted alkylene, alkylene-(NR 5 )-、 In some embodiments of Formula (A1) and Formula (A2), L is an alkylene, alkenylene, alkylene-(NR 5 )-、 In some embodiments, L is each optionally substituted alkylene-(NR 5 )-、 In some embodiments, L is each optionally substituted alkylene-(NR 5 )-、 In some embodiments, L is each optionally substituted alkylene-(NR 5 )-、 In some embodiments, L is each optionally substituted alkylene-(NR 5 )-、 In some embodiments, L is alkenylene, alkylene-(NR 5 )-, optionally substituted Optional Substituted Optional Substituted or optionally substituted In some embodiments, L is each optionally substituted alkylene-(NR 5 )-、 In some embodiments, L is optionally substituted Optional Substituted Optional Substituted or optionally substituted In some embodiments, L is optionally substituted Optional Substituted or optionally substituted In some embodiments, L is optionally substituted Optional Substituted or optionally substituted In some embodiments, L is optionally substituted or optionally substituted In some embodiments, L is optionally substituted or optionally substituted In some embodiments, L is optionally substituted In other embodiments, L is optionally substituted In some embodiments, L is optionally substituted In yet other embodiments, L is optionally substituted In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In other embodiments, L is In yet other embodiments, L 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.

[0311] In some embodiments of Formula (X), the optionally substituted yes

[0312] in:

[0313] R 5 is H, alkyl, -C(O)alkyl, carbocyclyl, alkylenecarbocyclyl, or alkylenearyl;

[0314] R 5a and R 5b are each independently selected from H, halogen, C 1-5 Alkyl, C 3-6 Carbocyclic group, alkylene-C 3-6 Carbocyclic, aryl, alkylene aryl or NH 2 ; Two of the C 1-5 The alkyl groups together with the carbon atom to which they are attached form a C 3-6 Carbocyclyl; and

[0315] m is 0 or 1.

[0316] In some embodiments of Formula (X), the optionally substituted yes

[0317] in:

[0318] R 5 is H, methyl or -C(O)Me;

[0319] R 5a is alkyl or carbocyclyl; and

[0320] R 5b It is H.

[0321] Two of the C 1-5 The alkyl groups together with the carbon atom to which they are attached form a C 3-6 Carbocyclyl; and

[0322] m is 0 or 1.

[0323] In some embodiments of Formula (X), the optionally substituted yes

[0324] in:

[0325] R 5 is H or methyl;

[0326] R 5a is fluoro or alkyl; and

[0327] R 5b It is H.

[0328] Two of the C 1-5 The alkyl groups together with the carbon atom to which they are attached form a C 3-6 carbocyclyl; and m is 0.

[0329] In some embodiments, when L is When R 5 and R 5a Together with the carbon atoms to which they are attached, they form a heterocyclyl ring. When R 5 and R 5a Together with the carbon atoms to which they are attached, they form a 4-, 5-, or 6-membered heterocyclyl ring.

[0330] In some embodiments of Formula (X), Selected from:

[0331] Where R 5c is halogen, alkyl, haloalkyl, hydroxyl or alkoxy. 5c In the para position of the benzene ring.

[0332] In some embodiments, Selected from:

[0333]

[0334] In some embodiments of Formula (X), Selected from:

[0335]

[0336] In some embodiments of Formula (X), the optionally substituted Selected from:

[0337] Where R 5c is halogen, alkyl, haloalkyl, hydroxyl or alkoxy. 5c In the para position of the benzene ring.

[0338] In some embodiments of Formula (X), the optionally substituted yes

[0339] in:

[0340] R 5 is H, alkyl, -C(O)alkyl, carbocyclyl, alkylenecarbocyclyl, or alkylenearyl; and

[0341] R 5a and R 5b are each independently selected from H, halogen, C 1-5 Alkyl, C 3-6 Carbocyclic group, alkylene-C 3-6 Carbocyclic, aryl, alkylene aryl or NH 2 ; Two of the C 1-5 The alkyl groups together with the carbon atom to which they are attached form a C 3-6 Carbocyclic group.

[0342] In some embodiments, R 5 is H, methyl or -C(O)Me. 5 Yes H, R 5a is an alkyl group or a carbocyclic group, and R 5b is H. In some embodiments, R 5 Yes H, R 5a is an alkyl group, and R 5b It's H.

[0343] In some embodiments, Selected from:

[0344]

[0345] In some embodiments of formula (X), when L comprises an alkylene group, the alkylene group is an optionally substituted C 1-4 In some embodiments, the alkylene group is an optionally substituted C 1-3 In some embodiments, the alkylene group is an optionally substituted C 1-2 In some embodiments, the alkylene group is an optionally substituted C 2-4 In some embodiments, the alkylene group is an optionally substituted C 2-3 In some embodiments, the alkylene group is an optionally substituted C 3-4 In some embodiments, when L comprises an alkylene group, the alkylene group is C 1-4 In some embodiments, the alkylene group is C 1-3 In some embodiments, the alkylene group is C 1-2 In some embodiments, the alkylene group is C 2-4In some embodiments, the alkylene group is C 2-3 In some embodiments, the alkylene group is C 3-4 Alkylene. In some embodiments, alkylene is methylene, ethylene, propylene or butylene, each of which is optionally substituted. In some embodiments, alkylene is ethylene, propylene or butylene, each of which is optionally substituted. In some embodiments, alkylene is an optionally substituted methylene. In some embodiments, alkylene is an optionally substituted ethylene. In some embodiments, alkylene is an optionally substituted propylene. In some embodiments, alkylene is an optionally substituted butylene. In some embodiments, alkylene is methylene, ethylene, propylene or butylene. In some embodiments, alkylene is methylene. In some embodiments, alkylene is ethylene. In some embodiments, alkylene is propylene. In some embodiments, alkylene is butylene.

[0346] In some embodiments of Formula (X), L is an alkylene-(NR 5 )-. In some embodiments, the alkylene group is an optionally substituted ethylene group. In some embodiments, the optionally substituted ethylene group is selected from:

[0347]

[0348] In some embodiments of Formula (X), L is an alkylene-(NR 5 )-. In some embodiments, the alkylene group is an optionally substituted propylene group. In some embodiments, the optionally substituted propylene group is selected from:

[0349]

[0350] In some embodiments of Formula (X), when L comprises an alkenylene group, the alkenylene group is an optionally substituted C 2-4 In some embodiments, alkenylene is an optionally substituted C 2-3 In some embodiments, alkenylene is an optionally substituted C 3-4 In some embodiments, when L comprises an alkenylene group, the alkenylene group is C 2-4 In some embodiments, the alkenylene group is C 2-3 In some embodiments, the alkenylene group is C 3-4In some embodiments, the alkenylene is an optionally substituted vinylene, propenylene or butenylene. In some embodiments, the alkenylene is an optionally substituted vinylene. In some embodiments, the alkenylene is an optionally substituted propenylene. In some embodiments, the alkenylene is an optionally substituted butenylene. In some embodiments, the alkenylene is an optionally substituted vinylene, propenylene or butenylene. In some embodiments, the alkenylene is an vinylene. In some embodiments, the alkenylene is propenylene. In some embodiments, the alkenylene is butenylene.

[0351] In some embodiments of formula (X), the optional substituents are selected from oxo, halogen, C 1-5 Alkyl, C 3-6 In some embodiments, the optional substituents are selected from oxo, C 1-5 Alkyl and C 3-6 In some embodiments, the optional substituents are selected from oxo and C 1-5 In some embodiments, the optional substituent is oxo. In other embodiments, the optional substituent is C 1-5 In some embodiments, C 1-5 Alkyl is methyl, ethyl, propyl or isopropyl. 1-5 Alkyl is methyl, ethyl or isopropyl. In other embodiments, C 1-5 In some embodiments, C 3-6 Cycloalkyl is cyclopropyl or cyclohexyl. In some embodiments, aryl is phenyl. In some embodiments, alkylene carbocyclyl is methylenecyclopropyl or methylenecyclohexyl. In some embodiments, alkylenearyl is methylenephenyl.

[0352] 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.

[0353] 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.

[0354] In some embodiments of Formula (X), m is 0 and n is 1. In other embodiments, m is 1 and n is 1. In yet other embodiments, m is 0 and n is 2. In yet another embodiment, m is 2 and n is 1.

[0355] In some embodiments of Formula (X), U is S. In other embodiments, U is NH.

[0356] 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 atoms to which they are attached, they form an optionally substituted phenyl or pyridyl ring. 2 N 3 In other embodiments, V is OH. In some embodiments, V is H.

[0357] In some embodiments of Formula (X), W is N. In other embodiments, W is CH.

[0358] In some embodiments of formula (X), X is O, S or NR 6 In some embodiments, X is O or NR 6 .

[0359] In some embodiments, X is NR 6 In some embodiments, X is O. In some embodiments, X is S.

[0360] In some embodiments, X is -CH=CH- or -CH=N-.

[0361] In some embodiments of Formula (X), Y 1 or Y 2 is N. In some embodiments, Y 1 and Y 2 Both are N.

[0362] In some embodiments, Y 1 N and Y 2 In some embodiments, Y 1 CH and Y 2 is N.

[0363] In some embodiments of formula (X), U is S, W is N, and X is NR 6 In certain embodiments, V is NR 2 NR 3 .

[0364] In some embodiments of formula (X), U is S, W is N, and X is NR6 In certain embodiments, Y 1 and Y 2 Each is N.

[0365] In some embodiments of formula (X), U is S, W is N, and X is NR 6 In certain embodiments, V is NR 2 NR 3 .

[0366] In some embodiments of formula (X), U is S, W is N, and X is NR 6 , and Y 1 and Y 2 Each is N. In certain embodiments, V is NR 2 NR 3 .

[0367] In some embodiments of formula (X), U is S, W is N, and X is NR 6 , and V is NR 2 NR 3 In certain embodiments, Y 1 and Y 2 Each is N.

[0368] In one embodiment of Formula (X), R 1 H, OH or C 1-5 In other embodiments, R 1 is H. In some embodiments, R 1 is OH. In some embodiments, R 1 It is C 1-5 In some embodiments, C 1-5 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopentyl and isobutyl. 1-5 The alkyl group is selected from methyl, ethyl and isopropyl.

[0369] In some embodiments of Formula (X), R 2 and R 3 are independently H, -C 1-5 Alkyl, -CH 2 Ph or –C(O)(C 1-5 In some embodiments, R 2 and R 3 are independently H, -C 1-5 Alkyl, -CH 2 Ph or –C(O)(CH 3 ). In some embodiments, R 2 and R 3One of is H. In some embodiments, R 2 and R 3 is H. In some embodiments, R 2 and R 3 One of them is -C 1-5 In some embodiments, R 2 and R 3 One of them is -CH 2 Ph. In some embodiments, R 2 and R 3 One of them is –C(O)(CH 3 ). In some embodiments, C 1-5 The alkyl group is selected from methyl, ethyl and isopropyl.

[0370] In some embodiments of Formula (X), R 4 is each optionally substituted aryl or heteroaryl. 4 is an optionally substituted aryl. 4 It is an optionally substituted heteroaryl. In some embodiments, heteroaryl is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, indolyl, oxindolyl, isatinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl or quinoxalinyl. In some embodiments, aryl is 6 to 12 yuan of aryl and heteroaryl is 5 to 12 yuan of heteroaryl with 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, the 5- to 12-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from N, O, and S is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, tetrazolyl, or pyrazolyl. In some embodiments, the 5- to 12-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from N, O, and S is pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments, the 5- to 12-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from N, O, and S is indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuranyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, and quinoxalinyl.

[0371] In some embodiments of formula (X), the aryl or heteroaryl group is optionally substituted with one or more of the following groups: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2-aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 In other embodiments, the aryl or heteroaryl groups are replaced by one or more H, halogen, -C 1-5 Alkyl, -CF 3 、-OH、-O(C 1-5 Alkyl), -OCF 3 、-OSO 2 Me, -COOH, -C(O)OMe, or -SO 2 Me is optionally substituted. In some embodiments, aryl is optionally substituted phenyl. In some embodiments, heteroaryl is optionally substituted pyridyl. In certain embodiments, optionally substituted pyridyl is selected from wherein p is 0, 1 or 2. In some embodiments, heteroaryl is optionally substituted pyrimidinyl. In certain embodiments, optionally substituted pyrimidinyl is wherein p is 0, 1 or 2. In some embodiments, R 8 Each is independently halogen, alkyl, -OH, -Oalkyl, -CO 2 H or -CO 2 alkyl.

[0372] In some embodiments of Formula (X), R 4 is an optionally substituted aryl group selected from:

[0373]

[0374] In some embodiments, R 4 is an optionally substituted heteroaryl selected from:

[0375]

[0376] In some embodiments, R 4 Selected from:

[0377]

[0378] wherein p is an integer from 0 to 3. In some embodiments, R 8are independently halogen, alkyl, haloalkyl, alkenyl, -OH, -Oalkyl, -N(alkyl) 2 , -CO 2 H, -CO 2 Alkyl or -CN.

[0379] In some embodiments, R 4 Selected from:

[0380]

[0381] in:

[0382] R 8 are independently halogen, C 1-5 Alkyl, -OH, -OC 1-5 Alkyl, -COOH or -CO 2 C 1-5 Alkyl; and

[0383] p is an integer from 0 to 3.

[0384] In some embodiments of Formula (X), R 4 In some embodiments, the carbocyclyl group is an optionally substituted C 3-6 In some embodiments, the carbocyclyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the carbocyclyl is cyclohexyl.

[0385] In some embodiments of Formula (X), R 4 is a heterocyclyl. In some 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.

[0386] In some embodiments of Formula (X), R 5 is H, -C(O)C 1-5 Alkyl, C 1-5 Alkyl, C 3-6 Carbocyclic group, -CH 2 -Aryl or -CH 2 -(C 3-6 In some embodiments, R 5 is H, -C(O)C 1-5 Alkyl, C 1-5 Alkyl, C 3-6 In some embodiments, R 5 H, -C(O)C 1-5 Alkyl or C 1-5 In some embodiments, R5 H or C 1-5 In some embodiments, C 1-5 The alkyl group is selected from the group consisting of methyl, ethyl and isopropyl. 3-6 Carbocyclyl is cyclopropyl or cyclohexyl. 5 is H, Me or CH 2 Ph. In some embodiments, R 5 It's H.

[0387] In some embodiments of Formula (X), R 6 It is H, C 1-5 Alkyl, CH 2 Aryl or CH 2 -(C 3-6 In some embodiments, R 6 H, C 1-5 Alkyl or CH 2 Ph. In some embodiments, C 1-5 The alkyl group is selected from methyl, ethyl and isopropyl. 6 It's H.

[0388] In some embodiments of Formula (X), R 7 It is C 3-6 In some embodiments, R 7 C 3-6 In some embodiments, C 3-6 Carbocyclyl is cyclopropyl or cyclohexyl. 7 is a 5- to 6-membered heteroaryl. In some embodiments, the 5- to 6-membered heteroaryl is selected from oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl and pyrazinyl. In some embodiments, the 5- to 6-membered heteroaryl is selected from Where X 1 NR 6 , S or O, and R 6 is H or alkyl. 7 is a 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl is selected from Where X 1 NR 6 , S or O. In some embodiments, the 5-membered heteroaryl is selected from In some embodiments, R 7is a 3- to 6-membered heterocyclic group. In some embodiments, the 3- to 6-membered heterocyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0389] In some embodiments, R 8 are independently halogen, alkyl, haloalkyl, alkenyl, -OH, -Oalkyl, -N(alkyl) 2 , -CO 2 H, -CO 2 In some embodiments, R 8 Each is independently halogen, alkyl, haloalkyl, -OH, -Oalkyl, -Ohaloalkyl or -CO 2 H. In some embodiments, R 8 Each is independently halogen, alkyl, -OH, -Oalkyl or -CO 2 H.

[0390] In some embodiments, the compound of formula (X) has a structure according to one of the following:

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398] or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

[0399] In some embodiments, the compound of formula (X) has a structure according to one of the following:

[0400]

[0401]

[0402] or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

[0403] In some embodiments, the compound of formula (X) has a structure according to one of the following:

[0404]

[0405] or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

[0406] In some embodiments, the compound of formula (X) has a structure according to:

[0407]

[0408] or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

[0409] 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 below. In some embodiments, the compound of formula (X) is a compound provided in Table 3 below.

[0410] In some embodiments of the present disclosure, the compound of formula (X) is not one or more of the following:

[0411]

[0412] in:

[0413] (a)R 2 is H, and R 4 yes or

[0414] (b)R 2 is Me, and R 4 yes or

[0415] (c)R 2 is Et, and R 4 yes or

[0416] (d) R 2 is nPr, C(O)Me or CO 2 nBu, and R 4 yes

[0417] In some embodiments of the present disclosure, the compound of formula (X) is not one or more of the following:

[0418]

[0419] In some embodiments of the present invention, the compound of formula (X) is not:

[0420]

[0421] In some embodiments of Formula (X), when -LR 4 When is -alkylene-aryl, the compound of formula (X) is not:

[0422]

[0423] in:

[0424] (a)R 2 is H, and R 4 yes or

[0425] (b)R 2 is Me, and R 4 yes or

[0426] (c)R 2 is Et, and R 4 yes or

[0427] (d) R 2 is nPr, C(O)Me or CO 2 nBu, and R 4 yes or

[0428]

[0429] In some embodiments of Formula (X), when -LR 4 When is -alkylene-aryl, the compound of formula (X) is not:

[0430]

[0431] In some embodiments of Formula (X), when -LR 4 When is -alkenylene-aryl, the compound of formula (X) is not:

[0432]

[0433] In some embodiments of Formula (X), when -LR 4 Yes-CH 2 When C(O)-aryl, the compound of formula (X) is not:

[0434]

[0435] In some embodiments of Formula (X), when -LR 4 Yes-CH 2 C(O)N(R 5 )-aryl, the compound of formula (X) is not:

[0436]

[0437] In some embodiments of Formula (X), when -LR 4 When is -alkylene-heteroaryl, the compound of formula (X) is not:

[0438]

[0439] In various embodiments of the present disclosure, the compound of formula (X) is not a compound disclosed in WO2019 / 051269 or WO2019 / 046778.

[0440] In some embodiments of the present disclosure, the compound of formula (X) is a compound of formula (XX):

[0441]

[0442] or a pharmaceutically acceptable salt, hydrate or tautomer thereof,

[0443] Among them, L, W, X, Y 1 , Y 2 , R 1 , R 2 , R 3 and R 4 As defined above in formula (X).

[0444] In some embodiments, the compound of formula (XX) is selected from Where R 1 , R 2 , R 3 and R 6 As defined above for formula (X). In some embodiments, the compound of formula (XX) is selected from In some embodiments, the compound of formula (XX) is selected from In some embodiments, the compound of formula (XX) is Where R 1 , R 2 , R 3 and R 6 As defined above for formula (X).

[0445] In some embodiments of the present disclosure, the compound of formula (X) is a compound of formula (XXa):

[0446]

[0447] or a pharmaceutically acceptable salt, hydrate or tautomer thereof,

[0448] Among them, L, W, X, Y 1 , Y 2 , R 1 , R 2 and R 3 As defined in formula (X) above, and Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each independently is CR 8 or N.

[0449] 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 yet 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 is N, and Z 2 To Z 4 CR 8 In some embodiments, Z 5 is N, and Z 1 To Z 4 CR 8 .

[0450] In some embodiments of Formula (XXa), R 8Each is independently halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 In some embodiments, R 8 are each independently H, halogen, -C 1-5 Alkyl, -CF 3 、-OH、-O(C 1-5 Alkyl), -OCF 3 、-OSO 2 Me, -COOH, -C(O)OMe, or -SO 2 Me.

[0451] In some embodiments of Formula (XXa), Selected from

[0452] In some embodiments of Formula (XXa), Selected from Where p is 0, 1 or 2.

[0453] In some embodiments of Formula (XXa), Selected from Where p is 0, 1 or 2.

[0454] In some embodiments of the present disclosure, the compound of formula (X) is a compound of formula (XXb):

[0455]

[0456] or a pharmaceutically acceptable salt, hydrate or tautomer thereof,

[0457] Among them, L, W, X, Y 1 , Y 2 , R 1 , R 2 , R3 , R 5 , m and n are as defined above in formula (X), and Z 1 , Z 2 , Z 3 , Z 4 and Z 5 Each independently is CR 8 or N.

[0458] 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. In yet 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 is N, and Z 2 To Z 4 CR 8 In some embodiments, Z 5 is N, and Z 1 To Z 4 CR 8 .

[0459] In some embodiments of Formula (XXb), R 8 Each is independently halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 In some embodiments, R 8 are independently H, halogen, -C 1-5 Alkyl, -CF 3 、-OH、-O(C 1-5 Alkyl), -OCF 3 、-OSO 2 Me, -COOH, -C(O)OMe, or -SO 2 Me.

[0460] In some embodiments of Formula (XXb), Selected from

[0461] In some embodiments of Formula (XXb), Selected from Where p is 0, 1 or 2.

[0462] In some embodiments of Formula (XXb), Selected from Where p is 0, 1 or 2.

[0463] In some embodiments of the present disclosure, the compound of formula (X), formula (XXa) or formula (XXb) is selected from:

[0464] Where R 1 , R 2 , R 3 , R 5 , R 6 , m and n are as defined above in formula (X), and Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently is CR 8 or N is as defined above in formula (XXa).

[0465] In some embodiments of the present disclosure, the compound of formula (X), formula (XXa) or formula (XXb) is selected from:

[0466] Where R 1 , R 2 , R 3 , R5 , R 5a , R 5b and R 6 As defined in the above formulae (A1), (A2) and (X), and Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently is CR 8 or N is as defined above in formula (XXa).

[0467] 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 , Z 4 and Z 5 One of is N. In yet 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 is N, and Z 2 To Z 4 CR 8 In some embodiments, Z 5 is N, and Z 1 To Z 4 CR 8 .

[0468] In some embodiments of Formula (XXc), Formula (XXd), Formula (XXe), and Formula (XXf), R 8 Each is independently halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 In some embodiments, R 8 are each independently H, halogen, -C 1-5 Alkyl, -CF 3 、-OH、-O(C 1-5 Alkyl), -OCF 3 、-OSO 2 Me, -COOH, -C(O)OMe, or -SO 2 Me.

[0469] In some embodiments of Formula (XXc), Formula (XXd), Formula (XXe) and Formula (XXf), Selected from

[0470]

[0471] In some embodiments of Formula (XXc), Formula (XXd), Formula (XXe), and Formula (XXf), Selected from Where p is 0, 1 or 2.

[0472] In some embodiments of Formula (XXc), Formula (XXd), Formula (XXe) and Formula (XXf), Selected from Where p is 0, 1 or 2.

[0473] In some embodiments, the present disclosure provides a compound of formula (Y) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0474]

[0475] in:

[0476] U is C or N;

[0477] in,

[0478] When U is C, Y is or

[0479] When U is N, Y is

[0480] V is N or CR10 ;

[0481] W is CH or N;

[0482] X is S, O, NLR 11 or NR 12 ;

[0483] L is selected from alkylene, alkenylene, optionally substituted -alkylene-(NR 12 )-, optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted

[0484] R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, alkylenecarbocyclic, -OLR 11 , -SLR 11 、-N(R 12 )-LR 11 , -LR 11 ;

[0485] R 11 is alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted; and

[0486] R 12 Each independently represents H, alkyl, alkylene carbocyclic group or carbocyclic group, wherein two R 12 The groups together with the carbon atoms to which they are attached are capable of forming a heterocyclic group;

[0487] R 14 is a carbocyclyl, heterocyclyl or heteroaryl;

[0488] R 15 is H, alkyl, carbocyclyl, alkylenecarbocyclyl or alkylenearyl;

[0489] Z 1 , Z 2 , Z 3 , and Z 4 Each independently is CR 13 or N;

[0490] R 13 is H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 Aryl or -CN, where both R 13 together with the atoms to which they are attached are capable of forming a carbocyclyl, heterocyclyl or heteroaryl group, each of which is optionally substituted;

[0491] m is 0, 1 or 2; and

[0492] n is 1, 2 or 3;

[0493] The condition is that X is NLR 11 or R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 .

[0494] In some embodiments, X is NLR 11 , and R 10 X is H, alkyl, -O-alkyl, -S-alkyl, carbocyclyl or alkylenecarbocyclyl. In other embodiments, X is S, O or NR 12 , and R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 .

[0495] In some embodiments, the present disclosure provides a compound of formula (Y) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0496]

[0497] in:

[0498] U is C or N;

[0499] in,

[0500] When U is C, Y is or

[0501] When U is N, Y is

[0502] V is N or CR 10 ;

[0503] W is CH or N;

[0504] X is S, O, NLR 11 or NR 12 ;

[0505] L is selected from alkylene, alkenylene, optionally substituted -alkylene-(NR 12 )-, optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted

[0506] R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, alkylenecarbocyclic, -OLR 11 , -SLR 11 、-N(R 12 )-LR 11 , -LR 11 ;

[0507] R 11 is alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted; and

[0508] R 12 Each independently represents H, alkyl, alkylene carbocyclic group or carbocyclic group, wherein two R 12 The groups together with the carbon atoms to which they are attached are capable of forming a heterocyclic group;

[0509] R 14 is a carbocyclyl, heterocyclyl or heteroaryl;

[0510] R 15 is H, alkyl, carbocyclyl, alkylenecarbocyclyl or alkylenearyl;

[0511] in:

[0512] When X is NLR 11 When V is N or CR 10 , where R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclyl or alkylenecarbocyclyl;

[0513] When X is S, O, or NR 12 When V is CR 10 , where R 10 for-OLR 11, -SLR 11 、-N(R 12 )-LR 11 or -LR 11 ;or

[0514] When U is N, V ​​is CR 10 , where R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 ;

[0515] Z 1 , Z 2 , Z 3 , and Z 4 Each independently is CR 13 or N;

[0516] R 13 is H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 Aryl or -CN, where both R 13 together with the atoms to which they are attached are capable of forming a carbocyclyl, heterocyclyl or heteroaryl group, each of which is optionally substituted;

[0517] m is 0, 1 or 2; and

[0518] n is 1, 2 or 3.

[0519] In some embodiments of Formula (Y), U is C. In other embodiments, U is N.

[0520] In some embodiments of Formula (Y), when U is C, Y is In other embodiments, when U is N, Y is

[0521] In some embodiments of Formula (Y), V is N. In other embodiments, V is CR 10 .

[0522] In some embodiments of Formula (Y), W is N. In other embodiments, W is CH.

[0523] In some embodiments of formula (Y), when X is S, O or NH, V is CR 10 , where R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 In some embodiments, when X is S or O, V is CR 10 , where R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 In some embodiments, when X is S, O or NH, V is CR 10 , where R 10 For-SLR 11 or -N(R 12 )-LR 11 In some embodiments, when X is S, O or NH, V is CR 10 , where R 10 For-SLR 11 In some embodiments, when X is S or O, V is CR 10 , where R 10 For-SLR 11 or -N(R 12 )-LR 11 In some embodiments, when X is S or O, V is CR 10 , where R 10 For-SLR 11 In some embodiments, when X is NH, V is CR 10 , where R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 In some embodiments, when X is NH, V is CR 10 , where R 10 For-SLR11 or -N(R 12 )-LR 11 In some embodiments, when X is NH, V is CR 10 , where R 10 For-SLR 11 .

[0524] In some embodiments of Formula (Y), X is NLR 11 , V is N. In some embodiments, X is NLR 11 and V is CR 10 , where R 10 is H, alkyl, -O-alkyl or -S-alkyl. In some embodiments, X is NLR 11 and V is CR 10 , where R 10 is H, -O-alkyl or -S-alkyl. In some embodiments, X is NLR 11 and V is CR 10 , where R 10 is H. In some embodiments of Formula (Y), X is NLR 11 and V is CR 10 , where R 10 is H, alkyl, -O-alkyl or -S-alkyl.

[0525] In some embodiments of Formula (Y), L is each optionally substituted alkylene-(NR 12 )-、 In some embodiments, L is optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted or optionally substituted In some embodiments, L is optionally substituted Optional Substituted Optional Substituted or optionally substituted In some embodiments, L is optionally substituted Optional Substituted or optionally substituted In some embodiments, L is optionally substituted or optionally substituted In some embodiments, L is optionally substituted In other embodiments, L is optionally substituted In yet other embodiments, L is optionally substituted In yet other embodiments, L is optionally substituted In another embodiment, L is optionally substituted In yet another embodiment, L is optionally substituted In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In other embodiments, L is In yet other embodiments, L is In yet other embodiments, L is In another embodiment, L is In yet another embodiment, L is

[0526] In some embodiments of Formula (Y), L is

[0527] in:

[0528] R 15 As defined above for formula (Y);

[0529] R 15a and R 15b are each independently selected from H, halogen, C 1-5 Alkyl, C 3-6 Carbocyclic group, alkylene-C 3-6 Carbocyclic, aryl, alkylene aryl or NH 2 ; Two of the C 1-5 The alkyl groups together with the carbon atom to which they are attached form a C 3-6 Carbocyclyl; and

[0530] m is 0 or 1.

[0531] In some embodiments of Formula (Y), L is selected from:

[0532]

[0533] In some embodiments of Formula (Y), L is selected from:

[0534] In some embodiments of formula (Y), when L comprises an alkylene group, the alkylene group is an optionally substituted C 1-4In some embodiments, the alkylene group is an optionally substituted C 1-3 In some embodiments, the alkylene group is an optionally substituted C 1-2 In some embodiments, the alkylene group is an optionally substituted C 2-4 In some embodiments, the alkylene group is an optionally substituted C 2-3 In some embodiments, the alkylene group is an optionally substituted C 3-4 In some embodiments, when L comprises an alkylene group, the alkylene group is C 1-4 In some embodiments, the alkylene group is C 1-3 In some embodiments, the alkylene group is C 1-2 In some embodiments, the alkylene group is C 2-4 In some embodiments, the alkylene group is C 2-3 In some embodiments, the alkylene group is C 3-4 Alkylene. In some embodiments, alkylene is methylene, ethylene, propylene or butylene, each of which is optionally substituted. In some embodiments, alkylene is ethylene, propylene or butylene, each of which is optionally substituted. In some embodiments, alkylene is an optionally substituted methylene. In some embodiments, alkylene is an optionally substituted ethylene. In some embodiments, alkylene is an optionally substituted propylene. In some embodiments, alkylene is an optionally substituted butylene. In some embodiments, alkylene is methylene, ethylene, propylene or butylene. In some embodiments, alkylene is methylene. In some embodiments, alkylene is ethylene. In some embodiments, alkylene is propylene. In some embodiments, alkylene is butylene.

[0535] In some embodiments of Formula (Y), when L comprises an alkenylene group, the alkenylene group is an optionally substituted C 2-4 In some embodiments, alkenylene is an optionally substituted C 2-3 In some embodiments, alkenylene is an optionally substituted C 3-4 In some embodiments, when L comprises an alkenylene group, the alkenylene group is C 2-4 In some embodiments, the alkenylene group is C 2-3 In some embodiments, the alkenylene group is C 3-4In some embodiments, the alkenylene is an optionally substituted vinylene, propenylene or butenylene. In some embodiments, the alkenylene is an optionally substituted vinylene. In some embodiments, the alkenylene is an optionally substituted propenylene. In some embodiments, the alkenylene is an optionally substituted butenylene. In some embodiments, the alkenylene is an optionally substituted vinylene, propenylene or butenylene. In some embodiments, the alkenylene is an vinylene. In some embodiments, the alkenylene is propenylene. In some embodiments, the alkenylene is butenylene.

[0536] In some embodiments of formula (Y), the optional substituents are selected from oxo, halogen, C 1-5 Alkyl, C 3-6 In some embodiments, the optional substituents are selected from oxo, C 1-5 Alkyl and C 3-6 In some embodiments, the optional substituents are selected from oxo and C 1-5 In some embodiments, the optional substituent is oxo. In other embodiments, the optional substituent is C 1-5 In some embodiments, C 1-5 Alkyl is methyl, ethyl, propyl or isopropyl. 1-5 Alkyl is methyl, ethyl or isopropyl. In other embodiments, C 1-5 In some embodiments, C 3-6 Cycloalkyl is cyclopropyl or cyclohexyl. In some embodiments, aryl is phenyl. In some embodiments, alkylene carbocyclyl is methylenecyclopropyl or methylenecyclohexyl. In some embodiments, alkylenearyl is methylenephenyl.

[0537] In some embodiments of Formula (Y), R 11 is each optionally substituted heterocyclyl, aryl or heteroaryl. 11 is each optionally substituted aryl or heteroaryl. 11 is an optionally substituted aryl. In some embodiments, the aryl group is an optionally substituted 6- to 12-membered aryl group. In some embodiments, the aryl group is an optionally substituted phenyl group. In some embodiments of formula (Y), the optionally substituted phenyl group is selected from

[0538] In some embodiments, R 11is an optionally substituted heteroaryl. In some embodiments, heteroaryl is a 5- to 12-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, 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 N, O, and S is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, the optionally substituted heteroaryl is selected from In some embodiments, heteroaryl is optionally substituted pyridinyl. In certain embodiments, optionally substituted pyridinyl is selected from where p is 0, 1, or 2.

[0539] In some embodiments, the aryl or heteroaryl groups are optionally substituted with one or more of the following groups: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 In some embodiments, the aryl or heteroaryl group is replaced by one or more H, halogen, -C 1-5 Alkyl, -CF 3 、-OH、-O(C 1-5 Alkyl), -OCF 3 、-OSO 2 Me, -COOH, -C(O)OMe, or -SO 2 Me is optionally substituted.

[0540] In some embodiments, R 11is an optionally substituted heterocyclic radical. In some embodiments, the heterocyclic radical is an optionally substituted 4- to 6-membered heterocyclic radical having 1 or 2 heteroatoms selected from S, O, and N. In some embodiments, the heterocyclic radical is an optionally substituted 3- to 6-membered heterocyclic radical having up to 2 nitrogen atoms. In some embodiments, the heterocyclic radical is an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl.

[0541] In some embodiments of Formula (Y), R 12 Each independently is H, C 1-5 Alkyl, CH 2 Aryl or CH 2 -(C 3-6 In some embodiments, R 12 Each independently is H, C 1-5 Alkyl or CH 2 Ph. In some embodiments of Formula (Y), R 12 Each independently is H or C 1-5 In some embodiments, C 1-5 The alkyl group is selected from methyl, ethyl and isopropyl. 12 Each is independently H.

[0542] In some embodiments of Formula (Y), R 14 is a heterocyclic group or a heteroaryl group. 14 is a heteroaryl. In some embodiments, the heteroaryl is an optionally substituted 5-membered or 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from S, O, and N. In some embodiments, the heteroaryl is selected from Where X 1 NR 16 , S or O; and R 16 is H or alkyl. In some embodiments of formula (Y), R 14 is a heterocyclyl. In some embodiments, the heterocyclyl is an optionally substituted 3- to 12-membered heterocyclyl having 1, 2, or 3 heteroatoms selected from S, O, and N. In some embodiments, the heterocyclyl is an optionally substituted 5- or 6-membered heterocyclyl having up to 2 nitrogen atoms. In some embodiments, the heterocyclyl is selected from

[0543] In some embodiments of Formula (Y), R 15 is H or alkyl. In some embodiments, alkyl is C 1-5 In certain embodiments, C 1-5 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopentyl and isobutyl. 1-5The alkyl group is selected from methyl, ethyl and isopropyl.

[0544] In some embodiments of Formula (Y), Z 1 , Z 2 , Z 3 and Z 4 Each is CR 13 In some embodiments, Z 1 , Z 2 , Z 3 and Z 4 At least one of is N. In some embodiments, Z 1 , Z 2 , Z 3 and Z 4 One of is N. In some embodiments, Z 1 , Z 2 , Z 3 and Z 4 In certain embodiments, two of Z are N. 1 is N and Z 2 , Z 3 and Z 4 Yes CR 13 In other embodiments, Z 2 is N and Z 1 , Z 3 and Z 4 Yes CR 13 In yet other embodiments, Z 3 is N and Z 1 , Z 2 and Z 4 Yes CR 13 In yet other embodiments, Z 4 is N and Z 1 , Z 2 and Z 3 Yes CR 13 In another embodiment, Z 1 and Z 4 Each is N, and Z 2 and Z 3 CR 13 In yet another embodiment, Z 1 and Z 3 Each is N, and Z 2 and Z 4 CR 13 In yet another embodiment, Z 2 and Z 4 Each is N, and Z 1 and Z 3 CR 13 .

[0545] In some embodiments of Formula (Y), R 13 Each is independently H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -Aryl, OSO 2 NH 2 , -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 In other embodiments, R 13 are each independently H, halogen, -C 1-5 Alkyl, -CF 3 、-OH、-O(C 1-5 Alkyl), -OCF 3 、-OSO 2 Me, -COOH, -C(O)OMe, or -SO 2 Me. In some embodiments, two R 13 Together with the atoms to which they are attached they can form a carbocyclyl, heterocyclyl or heteroaryl group which is optionally substituted.

[0546] 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.

[0547] 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.

[0548] In some embodiments of Formula (Y), m is 0 and n is 1. In other embodiments, m is 1 and n is 1. In yet other embodiments, m is 0 and n is 2. In yet another embodiment, m is 2 and n is 1.

[0549] In some embodiments, the compound of formula (Y) is selected from:

[0550] or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof,

[0551] in:

[0552] L, R 11 and R 13 As defined in formula (Y) above; and

[0553] o is an integer from 1 to 3.

[0554] In some embodiments, the compound of formula (Y) is selected from:

[0555]

[0556] or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof,

[0557] in:

[0558] L, R 10 , R 11 and R 13 As defined above in formula (Y); and

[0559] o is an integer from 1 to 3.

[0560] In some embodiments, the present disclosure provides a compound of formula (Y) having one of the following structures:

[0561]

[0562]

[0563]

[0564] or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof.

[0565] In other embodiments, the present disclosure provides a compound of formula (Y) having one of the following structures:

[0566]

[0567] or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof.

[0568] In other embodiments, the present disclosure provides a compound of formula (Y) having one of the following structures:

[0569]

[0570]

[0571] or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof.

[0572] In yet another embodiment, the present disclosure provides a compound of formula (Y) having one of the following structures:

[0573] or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof.

[0574] In various embodiments of the present disclosure, the compound of formula (Y) is not a compound disclosed in the following publications:

[0575] (a)Chang,L.,et al.J.Med.Chem.2014,57(23),10080-10100;

[0576] (b) Vankayalapati, H., et al. US20109 / 0031655.

[0577] 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:

[0578]

[0579] Among them, V, W, X, Z 1 , Z 2 , Z 3 and Z 4 As defined above in formula (Y).

[0580] 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:

[0581]

[0582] in:

[0583] R 10 is H, alkyl, alkylenecarbocyclyl, carbocyclyl, -O-alkyl, -S-alkyl; and

[0584] L, R 11 , Z 1 , Z 2 , Z 3 and Z 4As defined above in formula (Y).

[0585] In some embodiments of Formula (YYa), the alkyl group is C 1-5 In certain embodiments, C 1-5 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopentyl, butyl and isobutyl. 1-5 The alkyl group is selected from methyl, ethyl and isopropyl.

[0586] In some embodiments of Formula (YYa), the alkylene group is an optionally substituted C 1-4 In some embodiments, the alkylene group is an optionally substituted C 1-3 In some embodiments, the alkylene group is an optionally substituted C 1-2 In some embodiments, the alkylene group is an optionally substituted C 2-4 In some embodiments, the alkylene group is an optionally substituted C 2-3 In some embodiments, the alkylene group is an optionally substituted C 3-4 In some embodiments, when L comprises an alkylene group, the alkylene group is C 1-4 In some embodiments, the alkylene group is C 1-3 In some embodiments, the alkylene group is C 1-2 In some embodiments, the alkylene group is C 2-4 In some embodiments, the alkylene group is C 2-3 In some embodiments, the alkylene group is C 3-4 Alkylene. In some embodiments, alkylene is methylene, ethylene, propylene or butylene, each of which is optionally substituted. In some embodiments, alkylene is ethylene, propylene or butylene, each of which is optionally substituted. In some embodiments, alkylene is an optionally substituted methylene. In some embodiments, alkylene is an optionally substituted ethylene. In some embodiments, alkylene is an optionally substituted propylene. In some embodiments, alkylene is an optionally substituted butylene. In some embodiments, alkylene is methylene, ethylene, propylene or butylene. In some embodiments, alkylene is methylene. In some embodiments, alkylene is ethylene. In some embodiments, alkylene is propylene. In some embodiments, alkylene is butylene.

[0587] In some embodiments of Formula (YYa), the carbocyclyl group is C 3-6 In certain embodiments, C 3-6 Carbocyclyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0588] 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:

[0589]

[0590] in:

[0591] X is O, S or NR 12 ;

[0592] R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 , -LR 11 ;as well as

[0593] R 11 , R 12 , L, Z 1 , Z 2 , Z 3 and Z 4 As defined above in formula (Y).

[0594] In some embodiments, the present disclosure provides a compound of formula (Z) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0595]

[0596] in:

[0597] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 Each independently is N or CR 22 , the condition is:

[0598] (a) Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 One of them is –LR 18 -;

[0599] (b) Z 1 , Z 2 , Z 3 or Z 4 No more than two of them are N; and

[0600] (c)Z 6 or Z 7 One is N;

[0601] in:

[0602] L is a linker selected from the group consisting of: -N(R 19 )-、-alkylene-(NR 19 )-、

[0603] R 18 is alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted;

[0604] R 19 is H, alkyl, carbocyclyl, alkylenecarbocyclyl or alkylenearyl;

[0605] R 20 is H, alkyl, alkylene carbocyclyl, alkylene aryl;

[0606] R 21 is a carbocyclyl, heterocyclyl or heteroaryl;

[0607] R 22 Each is independently halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 Aryl or -CN;

[0608] m is 0, 1 or 2; and

[0609] n is 1, 2 or 3.

[0610] In some embodiments of Formula (Z), Z 1 , Z 2 , Z 3 and Z 4 Each independently is N or CR 22 In some embodiments, Z 1 , Z2 , Z 3 and Z 4 In some embodiments, two of Z are N. 1 , Z 2 , Z 3 or Z 4 One of Z is N. In some embodiments, Z 1 , Z 2 , Z 3 and Z 4 Each is CR 22 In certain embodiments, Z 1 is N and Z 2 , Z 3 and Z 4 Yes CR 22 In other embodiments, Z 2 is N and Z 1 , Z 3 and Z 4 Yes CR 22 In yet other embodiments, Z 3 is N and Z 1 , Z 2 and Z 4 Yes CR 13 In yet other embodiments, Z 4 is N and Z 1 , Z 2 and Z 3 Yes CR 22 In another embodiment, Z 1 and Z 4 Each is N, and Z 2 and Z 3 CR 22 In yet another embodiment, Z 1 and Z 3 Each is N, and Z 2 and Z 4 CR 22 In yet another embodiment, Z 2 and Z 4 Each is N, and Z 1 and Z 3 CR 22 .

[0611] In some embodiments of Formula (Z), Z 6 is N and Z 1 , Z 5 or Z 7 One of them is -LR 18 -. In some embodiments, Z 6 is N and Z 5or Z 7 One of them is -LR 18 -. In other embodiments, Z 6 Yes N, Z 7 Yes CR 22 , and Z 5 Yes -LR 18 -.

[0612] In some embodiments of Formula (Z), Z 7 is N and Z 1 , Z 5 or Z 6 One of them is -LR 18 -. In some embodiments, Z 7 is N and Z 5 or Z 6 One of them is -LR 18 -. In other embodiments, Z 7 Yes N, Z 6 Yes CR 22 , and Z 5 Yes -LR 18 -.

[0613] In some embodiments of Formula (Z), L is each optionally substituted In some embodiments, L is each optionally substituted In other embodiments, L is each optionally substituted In other embodiments, L is

[0614] In some embodiments of Formula (Z), L is selected from:

[0615] In some embodiments of formula (Z), when L comprises an alkylene group, the alkylene group is an optionally substituted C 1-4 In some embodiments, the alkylene group is an optionally substituted C 1-3 In some embodiments, the alkylene group is an optionally substituted C 1-2 In some embodiments, the alkylene group is an optionally substituted C 2-4 In some embodiments, the alkylene group is an optionally substituted C 2-3 In some embodiments, the alkylene group is an optionally substituted C 3-4 In some embodiments, when L comprises an alkylene group, the alkylene group is C 1-4In some embodiments, the alkylene group is C 1-3 In some embodiments, the alkylene group is C 1-2 In some embodiments, the alkylene group is C 2-4 In some embodiments, the alkylene group is C 2-3 In some embodiments, the alkylene group is C 3-4 Alkylene. In some embodiments, alkylene is methylene, ethylene, propylene or butylene, each of which is optionally substituted. In some embodiments, alkylene is ethylene, propylene or butylene, each of which is optionally substituted. In some embodiments, alkylene is an optionally substituted methylene. In some embodiments, alkylene is an optionally substituted ethylene. In some embodiments, alkylene is an optionally substituted propylene. In some embodiments, alkylene is an optionally substituted butylene. In some embodiments, alkylene is methylene, ethylene, propylene or butylene. In some embodiments, alkylene is methylene. In some embodiments, alkylene is ethylene. In some embodiments, alkylene is propylene. In some embodiments, alkylene is butylene.

[0616] In some embodiments of formula (Z), the optional substituents are selected from oxo, halogen, C 1-5 Alkyl, C 3-6 In some embodiments, the optional substituents are selected from oxo, C 1-5 Alkyl and C 3-6 In some embodiments, the optional substituents are selected from oxo and C 1-5 In some embodiments, the optional substituent is oxo. In other embodiments, the optional substituent is C 1-5 In some embodiments, C 1-5 Alkyl is methyl, ethyl, propyl or isopropyl. 1-5 Alkyl is methyl, ethyl or isopropyl. In other embodiments, C 1-5 In some embodiments, C 3-6 Cycloalkyl is cyclopropyl or cyclohexyl. In some embodiments, aryl is phenyl. In some embodiments, alkylene carbocyclyl is methylenecyclopropyl or methylenecyclohexyl. In some embodiments, alkylenearyl is methylenephenyl.

[0617] In some embodiments of Formula (Z), R 18 is an alkyl group, a heterocyclyl group, an aryl group or a heteroaryl group which is each optionally substituted.

[0618] In some embodiments of Formula (Z), R18 In some embodiments, the alkyl group is C 1-5 In certain embodiments, C 1-5 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopentyl, butyl and isobutyl. 1-5 The alkyl group is selected from methyl, ethyl and isopropyl.

[0619] In some embodiments, R 18 is each optionally substituted aryl or heteroaryl. 18 is an optionally substituted aryl. In some embodiments, the optionally substituted aryl is a 6- to 12-membered aryl. In some embodiments, the aryl is an optionally substituted 6- to 12-membered aryl. In some embodiments, the aryl is an optionally substituted phenyl. In some embodiments of formula (Z), the optionally substituted phenyl is selected from

[0620] In some embodiments, R 18 is an 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 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 N, O, and S is oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, the optionally substituted heteroaryl is selected from In some embodiments, heteroaryl is optionally substituted pyridinyl. In certain embodiments, optionally substituted pyridinyl is selected from where p is 0, 1, or 2.

[0621] In some embodiments, the aryl or heteroaryl groups are optionally substituted with one or more of the following groups: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 In some embodiments, the aryl or heteroaryl group is replaced by one or more H, halogen, -C 1-5 Alkyl, -CF 3 、-OH、-O(C 1-5 Alkyl), -OCF 3 、-OSO 2 Me, -COOH, -C(O)OMe, or -SO 2 Me is optionally substituted.

[0622] In some embodiments, heterocyclic radical is an optionally substituted 3- to 12-membered heterocyclic ring with 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, heterocyclic radical is an optionally substituted 3- to 6-membered heterocyclic radical with 1 or 2 nitrogen atoms. In some embodiments, 3- to 6-membered heterocyclic radical is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl. In some embodiments, 3- to 6-membered heterocyclic radical is an optionally substituted pyrrolidinyl, piperidinyl or piperazinyl. In other embodiments, 3- to 6-membered heterocyclic radical is an optionally substituted piperidinyl.

[0623] In some embodiments of Formula (Z), R 19 is H or alkyl. In some embodiments, alkyl is C 1-5 In certain embodiments, C 1-5 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isopentyl, butyl and isobutyl. 1-5 The alkyl group is selected from methyl, ethyl and isopropyl. 19 It's H.

[0624] In some embodiments of Formula (Z), R 20 It is H, -C 1-5 Alkyl, -C 3-6 Carbocyclic group, -CH 2 -Aryl or -CH 2 -(C 3-6 In some embodiments, R 20 is H, Me or -CH 2 Ph. In other embodiments, R 20 It's H.

[0625] In some embodiments of Formula (Z), R 21 is a heterocyclic group or a heteroaryl group.

[0626] In some embodiments of formula (Z), heteroaryl is an optionally substituted 5-membered or 6-membered heteroaryl having 1, 2 or 3 heteroatoms selected from S, O and N. In certain embodiments, the heterocyclyl is selected from Where: X 1 YesNR 16 , S or O; R 16 is H or alkyl.

[0627] In some embodiments of formula (Z), the heterocyclyl group is an optionally substituted 3- to 12-membered heterocyclyl group having 1, 2, or 3 heteroatoms selected from S, O, and N. In some embodiments, the heterocyclyl group is an optionally substituted 5- or 6-membered heterocyclyl group having up to 2 nitrogen atoms. In certain embodiments, the heterocyclyl group is selected from

[0628] 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.

[0629] 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.

[0630] In some embodiments of Formula (Z), m is 0 and n is 1. In other embodiments, m is 1 and n is 1. In yet other embodiments, m is 0 and n is 2. In yet another embodiment, m is 2 and n is 1.

[0631] In some embodiments, the present disclosure provides a compound of formula (Z) having one of the following structures:

[0632] or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

[0633] In some embodiments of the present disclosure, the compound of formula (Z) is a compound of formula (ZZ):

[0634]

[0635] in:

[0636] L, R 18 , Z 1 , Z 2 , Z 3 and Z 4As defined above in formula (Z).

[0637] In some embodiments of the present disclosure, the compound of formula (Z) is a compound of formula (ZZa):

[0638]

[0639] in:

[0640] L, R 18 and Z 1 As defined in formula (Z) above; and

[0641] p is 0, 1 or 2.

[0642] In various embodiments, compounds of Formula (Z), Formula (ZZ) and Formula (ZZa) do not include compounds disclosed in WO2019 / 051269.

[0643] The compounds of Formula (X), (XX), (XXa), (XXb), (XXc), (XXd), (XXe), (XXf), (XXd1), (XXf1), (XXf1), (Y), (YY), (YYa), (YYb), (Z), (ZZ) and (ZZa) described herein are meant to include all racemic mixtures, all individual enantiomers or combinations thereof, and all diastereomers or combinations thereof when two or more stereocenters are present, whether or not they are specifically described herein.

[0644] Treatment

[0645] The present disclosure provides compounds and compositions useful for treating cancer and other conditions associated with ENPP1 dysfunction. Thus, in some embodiments, the compounds disclosed herein are inhibitors of ENPP1. In some embodiments, the compounds of the present invention are cell permeable inhibitors of ENPP1.

[0646] In some embodiments, the method can be used to treat a disorder in which cell proliferation is uncontrolled in a subject in need thereof, the method comprising administering to the subject a therapeutic amount of a compound disclosed herein (e.g., a compound of Formula (A1)-(A2), (X), (XX), (XXa), (XXb), (XXc), (XXd), (XXe), (XXf), (XXd1), (XXf1), (Y), (YY), (YYa), (YYb), (Z), (ZZ), and (ZZa), a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, or a composition thereof. In some embodiments, the disorder in which cell proliferation is uncontrolled is cancer or a tumor. In some embodiments, the disorder or uncontrolled cell proliferation is associated with ENPP1 dysfunction, such as dysfunction caused by a mutation in ENPP1.

[0647] In some embodiments, the present disclosure also provides methods for reducing ENPP1 activity in a subject, the method comprising the step of 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.

[0648] 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.

[0649] In some embodiments, the present disclosure provides a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutic amount of a compound disclosed herein, a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, or a composition thereof. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from adrenal tumors, liver tumors, kidney tumors, bladder tumors, breast tumors, colon tumors, stomach tumors, ovarian tumors, cervical tumors, uterine tumors, esophageal tumors, colorectal tumors, prostate tumors, pancreatic tumors, lung tumors (small cells and non-small cells), thyroid tumors, carcinomas, sarcomas, glioblastomas, melanomas, and various head and neck tumors. In some embodiments, the solid tumor is breast cancer, lung cancer, or glioblastoma.

[0650] In some embodiments of the present disclosure, the cancer is a hematologic malignancy. In some embodiments, the hematologic malignancy is a leukemia, lymphoma, or myeloma. In some embodiments, the hematologic malignancy is a B-cell malignancy. In certain embodiments, the hematologic malignancy is multiple myeloma.

[0651] In some embodiments of the present disclosure, the cancer is a relapsed or refractory cancer. In some embodiments of the present disclosure, the cancer is a metastatic cancer.

[0652] In some embodiments, the present disclosure provides a method for treating a bacterial infection in a subject in need thereof, comprising administering to a subject a therapeutic amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, a solvate, a hydrate or a 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 (S.aureus) (e.g., methicillin-sensitive or methicillin-resistant) or Enterococcus faecalis (E.faecium). In other embodiments, the Gram-negative infection is an infection caused by Klebsiella pneumoniae (K.pneumoniae), Pseudomonas aeruginosa (P.aeruginosa), Enterobacter cloacae (E.cloacae) or Acinetobacter baumannii (A.baumannii). In some embodiments, the bacterial infection is multidrug-resistant. In some embodiments, the bacterial infection is caused by Mycobacterium tuberculosis (M.tuberculosis). Therefore, in various embodiments, the compounds and compositions of the present disclosure are effective for treating tuberculosis.

[0653] In some embodiments, the present disclosure provides a method for treating a viral infection in a subject in need thereof, comprising administering to a subject a therapeutic 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 caused by a herpes virus. In certain embodiments, the herpes virus is selected from herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), human herpes virus 6A (HHV-6A), human herpes virus 6B (HHV-6B), human herpes virus 7 (HHV-7) and Kaposi's sarcoma-associated herpes virus (KSHV). In a specific embodiment, the herpes virus is herpes simplex virus 1 (HSV-1). In some embodiments of the present disclosure, the viral infection is caused by a retrovirus. In some embodiments, the retrovirus is human immunodeficiency virus (HIV). In some embodiments, the viral infection is caused by a hepatitis virus. In certain embodiments, the hepatitis virus is hepatitis B virus (HBV) or hepatitis D virus (HDV). In certain other 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 caused by an RNA virus. In certain embodiments, the viral infection is caused by dengue virus, yellow fever virus, Ebola virus, Marburg virus, Venezuelan encephalitis virus or Zika virus.

[0654] Compound preparation

[0655] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an effective amount of a compound of Formula (A1), (A2), (X), (XX), (XXa), (XXb), (XXc), (XXd), (XXe), (XXf), (XXd1), (XXf1), (Y), (YYa), (YYb), (Z), (ZZ) or (ZZa), or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof. The pharmaceutical compositions provided herein comprise one or more pharmaceutically acceptable carriers or excipients.

[0656] In various embodiments, the pharmaceutical compositions of the present disclosure can be formulated with formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles for administration by various means, including oral, parenteral, by inhalation spray, topical or rectal administration. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular and intraarterial injections and various infusion techniques. Intraarterial and intravenous injections as used herein include administration by catheter.

[0657] The effective amount of the compound of the present disclosure (including pharmaceutically acceptable salts, esters, prodrugs, hydrates, solvates and isomers thereof, or pharmaceutical compositions thereof) can be determined by those skilled in the art based on known methods.

[0658] In one embodiment, the pharmaceutical composition or pharmaceutical preparation comprises 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, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0659] 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 0.01M to about 0.1M, for example, 0.05M 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 the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate).

[0660] Aqueous carriers suitable for the present application include, but are not limited to, water, ethanol, alcohol / water solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets, and the like.

[0661] Liquid carriers suitable for the present application can be used to prepare 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, a mixture thereof or a pharmaceutically acceptable oil or fat. The liquid carrier can include other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, pigments, viscosity modifiers, stabilizers or osmotic pressure regulators.

[0662] Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, such as cellulose derivatives, such as sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, such as glycols) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also include oily esters, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers may be used in sterile liquid forms containing compounds for parenteral administration. The liquid carrier for the pressurized compounds disclosed herein may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0663] Solid carriers suitable for the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol, and the like. The solid carrier may further include one or more substances used as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, or tablet disintegrants; the solid carrier may also be an encapsulating material. In powders, the carrier may 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 a suitable proportion and pressed into the desired shape and size. For example, powders and tablets contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinyl pyrrolidine, low melting point waxes, and ion exchange resins. Tablets may be made by compression or molding, optionally using one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient of a free-flowing form (e.g., powder or granules) in a suitable machine, optionally mixed with a binder (e.g., polyvidone, gelatin, hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate, cross-linked polyvidone, cross-linked sodium carboxymethylcellulose), a surfactant, or a dispersant. Molded tablets can be made by molding a mixture of a powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to provide a slow or controlled release of the active ingredient therein, for example, using different proportions of hydroxypropyl methylcellulose to provide a desired release profile. Tablets can optionally be provided with an enteric coating to provide release in the intestinal portion except the stomach.

[0664] Parenteral vehicles suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, and fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present, such as antimicrobial agents, antioxidants, chelating agents, inert gases, and the like.

[0665] Carriers suitable for use in the present application may be mixed as needed using conventional techniques known in the art with disintegrants, diluents, granulating agents, lubricants, binders, etc. The carrier may also be sterilized using a method that does not deleteriously react with the compound, as generally known in the art.

[0666] Diluent can be added in the preparation of the present invention.Diluent increases the volume of solid pharmaceutical composition and / or combination, and can make the pharmaceutical preparation comprising composition and / or combination easier for patient and nursing staff to handle.Diluent for solid composition and / or combination comprises, for example, microcrystalline cellulose (for example, AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, glucose, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (for example, EUDRAGIT (r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talcum.

[0667] The pharmaceutical composition of the present invention can be prepared into any type of preparation and drug delivery system by using any conventional method well known in the art. The pharmaceutical composition of the present invention can be formulated into an injectable preparation, which can be applied by including intrathecal, intraventricular, intravenous, intraperitoneal, intranasal, intraocular, intramuscular, subcutaneous or intraosseous approaches. In addition, it can also be applied orally or parenterally through the mucous membrane in the rectum, intestine or nasal cavity (see Gennaro, AR, ed. (1995) Remington's Pharmaceutical Sciences). In a specific embodiment, the composition is topically applied, rather than enteral administration. For example, compositions such as storage preparations or sustained release preparations can be injected or delivered via a targeted drug delivery system.

[0668] Pharmaceutical preparations of the present invention can be prepared by any method known in the art, such as mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing processes. As mentioned above, compositions of the present invention can include one or more physiologically acceptable carriers, such as excipients and adjuvants that promote the processing of active molecules into pharmaceutical preparations.

[0669] Suitable formulations depend on the chosen route of administration. For example, for injection, 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 invention, the compounds of the invention can be prepared as oral formulations. For oral administration, the compounds can be easily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the disclosed compounds to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a subject. The compound can also be formulated into a rectal composition, such as a suppository or retention enema, for example, containing a conventional suppository base such as cocoa butter or other glycerides.

[0670] Pharmaceutical preparations for oral administration can be obtained as solid excipients, optionally grinding the resulting mixture, and processing the granular mixture, if desired, after adding suitable adjuvants, 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, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; and / or polyvinylpyrrolidone (PVP) preparations. In addition, disintegrants, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts such as sodium alginate can be used. In addition, a wetting agent, such as sodium lauryl sulfate, can also be added.

[0671] The dragee cores have a suitable coating. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or characterization of different combinations of active compound dosages.

[0672] Although various inventive embodiments have been described and illustrated herein, a person of ordinary skill in the art will readily conceive of various other devices and / or structures for performing functions and / or obtaining results and / or one or more advantages described herein, and each such variation and / or modification is considered to be within the scope of the inventive embodiments described herein. More generally, a person skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are exemplary, and that actual parameters, dimensions, materials, and / or configurations will depend on the specific application or applications in which the invention is taught. Those skilled in the art will recognize or be able to determine many equivalents of the specific inventive embodiments described herein using only routine experiments. Therefore, it should be understood that the above embodiments are presented only as examples and within the scope of the appended claims and their equivalents; inventive embodiments may be implemented in a manner different from that specifically described and claimed. Inventive embodiments of the present disclosure relate to each individual feature, system, article, material, kit, and / or method described herein. In addition, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, any combination of two or more such features, systems, articles, materials, kits, and / or methods is also included within the scope of the invention disclosed herein.

[0673] The above embodiments may be implemented in any of a variety of ways. In addition, various inventive concepts may be embodied as one or more methods for which examples have been provided. The actions performed as part of the method may be ordered in any suitable manner. Thus, embodiments may be constructed that perform actions in a different order than that shown, and such embodiments may include performing some actions simultaneously, even though in illustrative embodiments they are shown as sequential actions.

[0674] All cited documents are incorporated herein by reference in their entirety for all purposes.

[0675] Example

[0676] 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 below.

[0677] Compound synthesis

[0678] Example 1: Compound 3

[0679]

[0680] 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 eluent system. Yield: 4 g (54%).

[0681] 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 performed by flash chromatography using dichloromethane:methanol as eluent system. Yield: 20 mg (9.15%).

[0682] Example 2: Compound 10

[0683]

[0684] Step 1: 2-Bromo-N-(3,4-dimethoxyphenyl)acetamide

[0685] Procedure: Potassium carbonate (1.35 g, 9.78 mmol) was added to a stirred solution of 3,4-dimethoxyaniline (1 g, 6.52 mmol) in dichloromethane (10 mL) 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 the reaction was completed, 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 performed by flash chromatography using hexane: ethyl acetate as the elution system. Yield: 1.7 g (98%).

[0686] Step 2: N-(3,4-dimethoxyphenyl)-2-(2-methyl-1H-benzo[d]imidazol-1-yl)acetamide

[0687] 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 obtain a crude residue. Purification was performed by flash chromatography using dichloromethane:methanol as the eluent system. Yield: 0.4 g (16.25%).

[0688] Example 3: Compound 37

[0689]

[0690] Step 1: Ethyl 2-((6,7-dimethoxyquinoxalin-2-yl)thio)acetate

[0691] 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 reflux temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, 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%).

[0692] Step 2: 2-((6,7-dimethoxyquinoxalin-2-yl)thio)acetic acid

[0693] Procedure: To a stirred solution of ethyl 2-((6,7-dimethoxyquinoxalin-2-yl)thio)acetate (0.34 g, 1.10 mmol) in THF:H 2 0 (1: 1, 5mL) solution was added with lithium hydroxide monohydrate (0.07 g, 1.65 mmol). The reaction process was monitored by TLC. After the reaction was completed, 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 obtain a pure compound.

[0694] Yield: 0.25 g (83%).

[0695] Step 3: N-(3,4-dimethoxyphenyl)-2-((6,7-dimethoxyquinoxalin-2-yl)thio)acetamide

[0696] 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) at 0°C were added 3,4-dimethoxyaniline (0.025 g, 0.16 mmol) and pyridine (0.043 mL, 0.53 mmol). 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 obtain a crude residue. Purification was performed by flash chromatography using dichloromethane:methanol as the eluent system. Yield: 0.20 g (27%).

[0697] Example 4: Compound 46

[0698]

[0699] Step 1: 2-Chloro-N-(3,4-dimethoxyphenyl)acetamide

[0700] 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 the reaction was completed, 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%).

[0701] Step 2: 2-((2-amino-7H-purin-6-yl)thio)-N-(3,4-dimethoxyphenyl)acetamide

[0702] 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 performed by flash chromatography using hexane:ethyl acetate as the eluent system. Yield: 0.6 g (27.9%).

[0703] Example 5: Compound 148

[0704]

[0705] Step 1: (3,4-Dimethoxybenzoyl)glycine ethyl ester

[0706] 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 thereto. The reaction mixture was 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 eluent system. Yield: 1.34 g (91%).

[0707] Step 2: N-(2-Hydroxyethyl)-3,4-dimethoxybenzamide

[0708] Procedure: To a stirred solution of (3,4-dimethoxybenzoyl)glycine ethyl ester (1.32 g, 4.93 mmol) in methanol (20 mL) was added sodium borohydride 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 performed by flash chromatography using hexane:ethyl acetate as the eluent system. Yield: 0.61 g (54.4%).

[0709] Step 3: N-(2-chloroethyl)-3,4-dimethoxybenzamide

[0710] Procedure: At 0°C, 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). 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 the reaction was completed, 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 performed by flash chromatography using hexane: ethyl acetate as the eluent system.

[0711] Yield: 0.27 g (40.6%).

[0712] Step 4: N-(2-((2-amino-7H-purin-6-yl)thio)ethyl)-3,4-dimethoxybenzamide

[0713] Procedure: To a stirred solution of 2-amino-1,7-dihydro-6H-purine-6-thione (0.1 g, 0.59 mmol) in dimethylformamide (3 mL) was added potassium carbonate (0.165 g, 1.19 mmol) at 0°C. After 30 minutes, N-(2-chloroethyl)-3,4-dimethoxybenzamide (0.159 g, 0.657 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 eluent system. Yield: 0.045 g (20.1%).

[0714] Table 1. Characterization data of synthesized compounds.

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728] Biological evaluation

[0729] Example 6: Colorimetric NPP Assay Using p-Nitrophenyl-5-TMP as Substrate

[0730] 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 form nucleotide-5'-monophosphates. ENPP1 inhibitors were synthesized and the ENPP1 inhibitory potency was evaluated by a colorimetric assay using thymidine 5'-monophosphate p-nitrophenyl ester (5'-TMP-pNP) as a substrate. ENPP1 hydrolyzes 5'-TMP-pNP to form a chromogenic product, p-nitrophenolate. The amount of p-nitrophenolate formed is proportional to the ENPP1 enzyme activity and is measured using its absorbance at 405 nm.

[0731] Enzyme inhibition assays were performed in clear 96-well microplates. The reaction mixture was in the presence of 1 mM CaCl 2 , 200 μM ZnCl 2 , 50mM Tris, pH9.0 containing different concentrations of ENPP1 inhibitors and 20ng of human ENPP1. The reaction mixture was pre-incubated at 37°C for 10 minutes, and the absorbance was measured at 405nm using a microplate reader as a pre-reading. The reaction was then initiated by adding 5'-TMP-pNP substrate at a final concentration of 400μM and kept incubated at 37°C for 20 minutes. Thereafter, the enzymatic reaction was terminated by adding 20μL of 1.0N NaOH. The amount of p-nitrophenolate released was measured at 405nm (after reading). Appropriate test sample controls and corresponding blank controls were taken to eliminate background absorbance. The incubation conditions and operating conditions were the same as above. The inhibition percentage of the test inhibitor at different concentrations was determined by comparing the absorbance of the inhibitor with the blank.

[0732] By using GraphPad The IC50 value was determined by plotting the percentage inhibition versus inhibitor concentration curve using a three-parameter nonlinear regression curve fit in the software. The Ki value was derived from the IC50 value using the Cheng-Prusoff equation:

[0733] Ki=IC50 / (1+[TMP-pNP] / Km),

[0734] Where [TMP-pNP] = 400 μM, the Michaelis-Menten constant (Km) value of 5'-TMP-pN is 222

[0735] μM.

[0736] Example 7: Capillary electrophoresis-based NPP assay using ATP as substrate

[0737] ENPP1 is a eukaryotic protein with broad substrate specificity that is able to hydrolyze nucleotides, such as ATP to AMP. Here, a capillary electrophoresis-based method was used to determine the IC50 values ​​of ENPP1 inhibitors for the ENNP1 protein.

[0738] The synthetic inhibitors were evaluated for their ENPP1 inhibitory potency against the natural substrate ATP. Enzyme inhibition assays were performed in 10 mM 2-(N-cyclohexylamino)-ethanesulfonic acid (CHES) buffer (pH 10.0) with varying inhibitor concentrations, including 1 mM MgCl 2 , 2 mM CaCl 2 and 400 μM ATP. The reaction mixture was incubated with 20 ng of human NPP1 at 37 ° C for 30 minutes in a final volume of 100 μL, and the reaction was stopped by heating at 90 ° C for 3 minutes. Finally, the reaction mixture was directly measured by capillary electrophoresis (CE). The CE instrument and operating conditions were as follows: P / ACE MDQ capillary electrophoresis system with DAD detection system (Beckman Instruments, Fullerton, CA, USA), polyacrylamide-coated capillaries with an effective length of 40 cm × 50 μm (id) from CS Chromatographie GmbH (Langerwehe, Germany), 50 mM phosphate buffer (pH 6.5) as running buffer, electrokinetic injection (-6 kV, 60 s), and a separation voltage of -15 kV. The amount of AMP produced was measured at 260 nm. Data collection and peak area analysis were performed by 32Karat software obtained from Beckman Coulter (Fullerton, CA, USA).

[0739] IC50 values ​​of the test compounds were calculated by plotting the data in the program Prism 5.0, and Ki values ​​were calculated from the IC50 values ​​using the Cheng-Prusoff equation (Tables 2 to 4).

[0740] Ki = IC50 / (1+[ATP] / Km),

[0741] Wherein [ATP] = 400 μM, and the Michaelis-Menten constant (Km) value of ATP is 8.17 μM.

[0742] Table 2. In vitro data for evaluated compounds.

[0743]

[0744]

[0745]

[0746]

[0747]

[0748] Table 3. In vitro data for evaluated compounds.

[0749]

[0750]

[0751]

[0752]

[0753] Table 4. In vitro data for evaluated compounds.

[0754]

[0755]

[0756] Example 8: In vivo efficacy evaluation of the combination of Compound 155, Compound 173 and Compound 174 with anti-PD-1 antibody CD279 in LLC1 syngeneic tumor model.

[0757]

[0758] Research Overview

[0759] In the syngeneic tumor model LLC1, compounds 155, 173 and 174 were combined with anti-PD-1 antibodies (checkpoint inhibitors) to evaluate anti-tumor efficacy. The compounds were administered orally at a dose of 100 mg / kg, once a day. The IV dose of the compound was administered at a dose of 10 mg / kg, twice a week or Q3D (compound 155, 2 mg / Kg IV). Anti-PD-1 antibodies were administered at a dose of 200 μg / animal via the IP route on days 1, 5 and 9 (Table 5).

[0760] Study Design

[0761] 0.2×10 6 LLC1 cells ( CRL-1642 TM ) were implanted subcutaneously into C57BL / 6 mice (female, 7-8 weeks old) to evaluate tumor growth in the murine Lewis lung cancer model. Based on approximately 50 mm 3 Up to 60mm 3 The tumor-bearing animals were randomly divided into different treatment groups of 8 animals based on the tumor size standard and were dosed according to the schedule in Table 5.

[0762] Table 5. Test groups and dosing regimens for the murine Lewis lung cancer model.

[0763]

[0764] Note: QD: once daily; Q4D: once every 4 days; TW: twice a week (Q3D)

[0765] Oral formulation: 0.4% Tween 80, 2% glycerol and 97.6% of 15% (w / v) HPβCD

[0766] IV formulation: 5% (v / v) DMA, 15% (v / v) Solutol, 30% (v / v) of 60% (v / v) HPβCD, and 50% (v / v) sodium carbonate buffer (pH 9.2)

[0767] Anti-PD-1: Dilution buffer (pH 7.0) (BioXcell, West Lebanon, NH)

[0768] Dosing regimen: Oral administration frequency is once daily, IV administration frequency is twice a week for two weeks; anti-PD-1 antibody is administered via IP route on days 1, 5, and 9.

[0769] Tumor measurement: Tumor growth was measured three times a week using a digital vernier caliper. Tumor volume was calculated as: Tumor volume (TV) = [length (L) × width (W)2] / 2 (where length is the maximum diameter of the tumor and width is the minimum diameter of the tumor)

[0770] Endpoints: Blood samples were taken from animals after 2 weeks of treatment to analyze cytokine levels in serum (IFN-β and IP-10). At the end of the study, tumor samples were collected from 4 / 8 animals in each treatment group for analysis of TILs by flow cytometry.

[0771] Efficacy evaluation: Tumor growth inhibition (TGI) was calculated as follows:

[0772]

[0773] Data analysis: Statistical analysis of the data was performed by one-way ANOVA followed by Dunnett's test using GraphPad Prism (version 5.03).

[0774] result

[0775] Antitumor efficacy of compound 155

[0776] PO administration: Once daily oral administration of compound 155 for 2 weeks resulted in a 33% TGI compared to the control group, which was statistically significant (p<0.0001). The combination of compound 155 (PO) with anti-PD-1 antibody resulted in a significant (p<0.0001) tumor growth inhibition (TGI) of 44% ( Figure 2 ).

[0777] IV dosing: Twice weekly IV administration of compound 155 resulted in a significant (p<0.0001) tumor growth inhibition (TGI) of 47%. The combination of compound 155 (IV) with anti-PD-1 antibody resulted in a significant (p<0.0001) tumor growth inhibition (TGI) of 57% ( Figure 3 ).

[0778] like Figure 4 As shown, PO and IV administration of compound 155 alone or in combination with anti-PD-1 antibody reduced tumor volume in the murine Lewis lung cancer model, with IV administration of compound 155 in combination with anti-PD-1 antibody providing the greatest reduction.

[0779] Antitumor efficacy of compound 173

[0780] PO dosing: Once daily oral administration of compound 173 for 2 weeks resulted in a 37% TGI compared to the control group, which was statistically significant (p<0.0001). The combination of compound 173 (PO) with anti-PD-1 antibody resulted in a significant (p<0.0001) tumor growth inhibition (TGI) of 47% ( Figure 5 ).

[0781] IV dosing: Twice weekly IV administration of compound 173 resulted in a significant (p<0.0001) tumor growth inhibition (TGI) of 48%. The combination of compound 173 (IV) with anti-PD-1 antibody resulted in a significant (p<0.0001) tumor growth inhibition (TGI) of 53% ( Figure 6 ).

[0782] like Figure 7 As shown, PO and IV administration of compound 173 alone or in combination with anti-PD-1 antibody reduced tumor volume in the murine Lewis lung cancer model, with IV administration of compound 173 in combination with anti-PD-1 antibody providing the greatest reduction.

[0783] Antitumor efficacy of compound 174

[0784] PO dosing: Once daily oral administration of compound 174 for 2 weeks resulted in a 52% TGI compared to the control group, which was statistically significant (p<0.0001). The combination of compound 174 (PO) with anti-PD-1 antibody resulted in a significant (p<0.0001) tumor growth inhibition (TGI) of 60% ( Figure 8 ).

[0785] IV dosing: Twice weekly IV administration of compound 174 resulted in a significant (p<0.0001) tumor growth inhibition (TGI) of 48%. The combination of compound 174 (IV) and anti-PD-1 antibody resulted in a significant (p<0.0001) tumor growth inhibition (TGI) of 57% ( Fig. 9 ).

[0786] like Fig.10 As shown, PO and IV administration of compound 173 alone or in combination with anti-PD-1 antibody reduced tumor volume in the murine Lewis lung cancer model, with IV administration of compound 174 in combination with anti-PD-1 antibody providing the greatest reduction.

[0787] Table 6. Efficacy of compounds 155, 173 and 174 in the murine Lewis lung cancer model.

[0788]

[0789] *** P < 0.0001, compared with vehicle control by one-way ANOVA followed by Dunnett's test

[0790] The present invention is further described by the following numbered embodiments:

[0791] 1. A compound of formula (X) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0792]

[0793] in:

[0794] L is a linker selected from the group consisting of alkylene, alkenylene, optionally substituted alkylene-S-, optionally substituted alkylene-O-, optionally substituted -alkylene-(NR 5 )-, optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted

[0795] U is S or NH;

[0796] 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 pyridyl ring;

[0797] W is CH or N;

[0798] X is O, S, NR 6 , -CH=CH- or -CH=N-;

[0799] Y 1 and Y 2 are each independently CH or N;

[0800] R 1 is H, OH, O-alkyl, alkyl or carbocyclyl;

[0801] R 2 and R 3 are each independently H, alkyl, alkylenearyl or -C(O)alkyl;

[0802] R 4 is carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted;

[0803] R 5 is H, alkyl, -C(O)alkyl, carbocyclyl, alkylenecarbocyclyl, or alkylenearyl;

[0804] R 6 is H, alkyl, carbocyclyl, alkylenecarbocyclyl, alkylenearyl, -C(O)alkyl, or -C(O)Oalkylenearyl;

[0805] R 7 is a carbocyclyl, heterocyclyl or heteroaryl;

[0806] m is 0, 1 or 2; and

[0807] n is 1, 2 or 3.

[0808] 2. The compound according to embodiment 1, wherein L is each optionally substituted

[0809] 2a. A compound according to embodiment 2, wherein the optionally substituted yes

[0810] in:

[0811] R5 is H, alkyl, -C(O)alkyl, carbocyclyl, alkylenecarbocyclyl, or alkylenearyl; and

[0812] R 5a and R 5b are each independently selected from H, halogen, C 1-5 Alkyl, C 3-6 Carbocyclic group, alkylene-C 3-6 Carbocyclic, aryl, alkylene aryl or NH 2 ; Two of the C 1-5 The alkyl groups together with the carbon atom to which they are attached form a C 3-6 Carbocyclic group.

[0813] 2b. A compound according to embodiment 2a, wherein Selected from:

[0814]

[0815]

[0816] in:

[0817] R 5 is H, Me or -C(O)alkyl; and

[0818] R 5c is halogen, alkyl, haloalkyl, hydroxy or alkoxy.

[0819] 2c. A compound according to embodiment 2a, wherein Selected from:

[0820]

[0821] Where R 5 is H, Me or -C(O)alkyl.

[0822] 3. A compound according to any one of embodiments 1 to 2c, wherein U is S.

[0823] 4. A compound according to any one of embodiments 1 to 3, wherein V is NR 2 R 3 .

[0824] 5. A compound according to any one of embodiments 1 to 4, wherein W is N.

[0825] 6. A compound according to any one of embodiments 1 to 5, wherein X is NR 6 .

[0826] 7. A compound according to any one of embodiments 1 to 6, wherein Y 1 and Y 2 All are N.

[0827] 8. A compound according to any one of embodiments 1 to 7, wherein R 1 is H, OH or C 1-5 alkyl.

[0828] 9. A compound according to any one of embodiments 1 to 8, wherein R 2 and R 3 are independently H, -C 1-5 Alkyl, -CH 2 Ph or –C(O)(C 1-5 alkyl).

[0829] 10. A compound according to any one of embodiments 1 to 9, wherein R 4 is each optionally substituted aryl or heteroaryl.

[0830] 10a. The compound according to any one of claims 1 to 10, wherein R 4 Selected from:

[0831]

[0832] in:

[0833] R 8 are independently halogen, C 1-5 Alkyl, -OH, -OC 1-5 Alkyl, -COOH or -CO 2 C 1-5 an alkyl group; and p is an integer from 0 to 3.

[0834] 10b. The compound according to any one of claims 1 to 10, wherein R 4 Selected from:

[0835]

[0836] in:

[0837] R 8 are independently halogen, C 1-5 Alkyl, -OH, -OC 1-5 Alkyl, -COOH or -CO 2 C 1-5 an alkyl group; and p is an integer from 0 to 3.

[0838] 11. A compound according to any one of embodiments 1 to 10, wherein R 5It is H, -C 1-5 Alkyl, -C 3-6 Carbocyclic group, -CH 2 -Aryl or -CH 2 -(C 3-6 carbocyclic group).

[0839] 12. A compound according to any one of embodiments 1 to 11, wherein R 6 It is H, -C 1-5 Alkyl, -CH 2 Aryl or -CH 2 -(C 3-6 carbocyclic group).

[0840] 13. A compound according to any one of embodiments 1 to 12, wherein R 7 It is C 3-6 carbocyclyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl.

[0841] 14. A compound according to any one of embodiments 1 to 13, wherein m is 0 or 1.

[0842] 15. A compound according to any one of embodiments 1 to 14, wherein n is 1 or 2.

[0843] 16. The compound according to embodiment 1 has one of the following structures:

[0844]

[0845]

[0846]

[0847]

[0848]

[0849] or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

[0850] 17. A compound of formula (Y) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0851]

[0852] in:

[0853] U is C or N;

[0854] in,

[0855] When U is C, Y is or

[0856] When U is N, Y is

[0857] V is N or CR 10 ;

[0858] W is CH or N;

[0859] X is S, O, NLR 11 or NR 12 ;

[0860] L is selected from alkylene, alkenylene, optionally substituted -alkylene-(NR 12 )-, optionally substituted Optional Substituted Optional Substituted Optional Substituted Optional Substituted

[0861] R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclic, alkylenecarbocyclic, -OLR 11 , -SLR 11 、-N(R 12 )-LR 11 , -LR 11 ;

[0862] R 11 is alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted; and

[0863] R 12 Each independently represents H, alkyl, alkylene carbocyclic group or carbocyclic group, wherein two R 12 The groups together with the carbon atoms to which they are attached are capable of forming a heterocyclic group;

[0864] R 14 is a carbocyclyl, heterocyclyl or heteroaryl;

[0865] R 15 is H, alkyl, carbocyclyl, alkylenecarbocyclyl or alkylenearyl;

[0866] in:

[0867] When X is NLR 11 When V is N or CR 10 , where R 10 is H, alkyl, -O-alkyl, -S-alkyl, carbocyclyl or alkylenecarbocyclyl;

[0868] When X is S, O, or NR 12 When V is CR10 , where R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 ;or

[0869] When U is N, V ​​is CR 10 , where R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 ;

[0870] Z 1 , Z 2 , Z 3 , and Z 4 Each independently is CR 13 or N;

[0871] R 13 is H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 Aryl or -CN, where both R 13 together with the atoms to which they are attached are capable of forming a carbocyclyl, heterocyclyl or heteroaryl group, each of which is optionally substituted;

[0872] m is 0, 1 or 2; and

[0873] n is 1, 2 or 3.

[0874] 18. The compound according to embodiment 17, wherein U is C.

[0875] 19. The compound according to embodiment 17 or 18, wherein W is N.

[0876] 20. The compound according to embodiments 17 to 19, wherein when X is S, O or NH, V is CR 10 , where R 10 for-OLR 11 , -SLR 11 、-N(R 12 )-LR 11 or -LR 11 .

[0877] 21. A compound according to any one of embodiments 17 to 20, wherein X is NLR 11 and V is CR 10 , where R 10 is H, alkyl, -O-alkyl or -S-alkyl.

[0878] 22. A compound according to any one of embodiments 17 to 21, wherein L is each optionally substituted -alkylene-(NR 12 )-、

[0879] 23. A compound according to any one of embodiments 17 to 22, wherein R 11 is a heterocyclyl, aryl or heteroaryl group which is each optionally substituted.

[0880] 24. A compound according to any one of embodiments 17 to 23, wherein R 12 Each independently is H or C 15 alkyl.

[0881] 25. A compound according to any one of embodiments 17 to 24, wherein R 14 is a heterocyclic group or a heteroaryl group.

[0882] 26. A compound according to any one of embodiments 17 to 25, wherein R 15 is H or alkyl.

[0883] 27. A compound according to any one of embodiments 17 to 26, wherein Z 1 , Z 2 , Z 3 and Z 4 Each is CR 13 .

[0884] 28. A compound according to any one of embodiments 17 to 26, wherein Z 1 , Z 2 , Z 3 and Z 4 At least one of them is N.

[0885] 29. A compound according to any one of embodiments 17 to 28, wherein m is 0 or 1.

[0886] 30. A compound according to any one of embodiments 17 to 29, wherein n is 1 or 2.

[0887] 31. The compound according to embodiment 17 has one of the following structures:

[0888]

[0889]

[0890]

[0891] or a pharmaceutically acceptable salt, tautomer, solvate or hydrate thereof.

[0892] 32. A compound of formula (Z) or a pharmaceutically acceptable salt, hydrate or tautomer thereof:

[0893]

[0894] in:

[0895] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 Each independently is N or CR 22 , the condition is:

[0896] (a) Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 or Z 7 One of them is –LR 18 -;

[0897] (b) Z 1 , Z 2 , Z 3 or Z 4 No more than two of them are N; and

[0898] (c)Z 6 or Z 7 One is N;

[0899] in:

[0900] L is a linker selected from the group consisting of: -N(R 19 )-、-alkylene-(NR 19 )-、

[0901] R 18 is alkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted;

[0902] R 19 is H, alkyl, carbocyclyl, alkylenecarbocyclyl or alkylenearyl;

[0903] R 20 is H, alkyl, alkylene carbocyclyl, alkylene aryl;

[0904] R 21 is a carbocyclyl, heterocyclyl or heteroaryl;

[0905] R 22 Each is independently halogen, alkyl, alkenyl, alkynyl, haloalkyl, carbocyclyl, OH, O-alkyl, O-haloalkyl, O-carbocyclyl, OSO 2 -Alkyl, OSO 2 -aryl, -C(O)alkyl, -C(O)Oalkyl, -C(O)Oalkylenearyl, -C(O)Oaryl, -SO 2 NH 2 、-SO 2 NH alkyl, -SO 2 NH(alkyl) 2 、-NH 2 、-NH alkyl、-N(alkyl) 2 、-N(H)SO 2 Alkyl, -N(H)SO 2 Aryl or -CN;

[0906] m is 0, 1 or 2; and

[0907] n is 1, 2 or 3.

[0908] 33. The compound according to embodiment 32, wherein Z 1 , Z 2 , Z 3 and Z 4 Each independently is N or CR 22 .

[0909] 34. The compound according to embodiment 32 or 33, wherein Z 6 is N and Z 1 , Z 5 or Z 7One of them is -LR 18 -.

[0910] 35. The compound according to embodiment 32 or 33, wherein Z 7 is N and Z 1 , Z 5 or Z 6 One of them is -LR 18 -.

[0911] 36. A compound according to any one of embodiments 32 to 35, wherein L is each optionally substituted

[0912] 37. A compound according to any one of embodiments 32 to 36, wherein R 18 is an alkyl group, a heterocyclyl group, an aryl group or a heteroaryl group which is each optionally substituted.

[0913] 38. A compound according to any one of embodiments 32 to 37, wherein R 19 is H or alkyl.

[0914] 39. A compound according to any one of embodiments 32 to 38, wherein R 20 It is H, -C 1-5 Alkyl, -C 3-6 Carbocyclic group, -CH 2 -Aryl or -CH 2 -(C 3-6 carbocyclic group).

[0915] 40. A compound according to any one of embodiments 32 to 39, wherein R 21 is a heterocyclic group or a heteroaryl group.

[0916] 41. A compound according to any one of embodiments 32 to 40, wherein m is 0 or 1.

[0917] 42. A compound according to any one of embodiments 32 to 41, wherein n is 1 or 2.

[0918] 43. The compound according to embodiment 32 has one of the following structures:

[0919]

[0920] or a pharmaceutically acceptable salt, tautomer, hydrate or solvate thereof.

[0921] 44. The compound according to embodiment 43 has one of the following structures:

[0922]

Claims

1. A compound of formula (X) or a pharmaceutically acceptable salt or tautomer thereof: in: L is a linker selected from the group consisting of: Optional Substituted and -alkylene-(NR 5 )-, wherein the alkylene group is ethylene, propylene or butylene, wherein the optionally substituted yes in: R 5 is H; and R 5a and R 5b Each independently selected from H, C 1-5 Alkyl, C 3-6 Carbocyclic, aryl, or alkylene aryl; wherein two C 1-5 The alkyl groups together with the carbon atom to which they are attached form a C 3-6 carbocyclyl, wherein the aryl is phenyl, and wherein the alkylene aryl is C 1-3 Alkylidene aryl; U is S; V is NR 2 R 3 ; W is N; X is NR 6 ; Y 1 and Y 2 Each independently is N; R 1 It is H; R 2 and R 3 Each independently is H; R 4 Selected from: in: R 8 are independently halogen, -OH, -OC 1-5 Alkyl, -COOH or -CO2C 1-5 Alkyl; and p is an integer from 0 to 3; R 5 It is H; R 6 It is H; m is 0, 1 or 2; and n is 1, 2 or 3.

2. The compound according to claim 1, wherein L is optionally substituted wherein the optionally substituted yes 3. The compound according to claim 1, wherein Selected from: in: R 5 It's H.

4. The compound according to claim 3, wherein Selected from: Where R 5 It's H.

5. The compound according to claim 3, wherein Selected from Where R 5 It's H.

6. The compound according to any one of claims 1 to 5, wherein m is 0 or 1.

7. The compound according to any one of claims 1 to 5, wherein n is 1 or 2.

8. The compound according to claim 1, having one of the following structures: or a pharmaceutically acceptable salt or tautomer thereof.

9. The compound according to claim 8, wherein The stereoisomers of compound (249) are:

10. The compound according to claim 1, wherein The compound has the following structure:

11. A pharmaceutical composition comprising (i) an effective amount of a compound according to claim 1 having ENPP1 inhibitory activity and (ii) one or more pharmaceutically acceptable excipients.

12. Use of the pharmaceutical composition according to claim 11 in preparing a drug for treating cancer, wherein: The cancer is a cancer associated with ENPP1 dysfunction.

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