ADAR1 inhibitors and methods of using same

Abstract

Compounds identified herein as inhibitors of ADAR1 activity, such as compounds represented by the following formula: [Formula 1] SUMMARY OF THE INVENTION Compounds having the formula: TIFF2025538892000229.tif22170 or a pharmaceutically acceptable salt or tautomer thereof are provided that are useful in the treatment of cancer and other disorders, such as those associated with aberrant ADAR1 expression.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to Indian Provisional Application No. 202241069761, dated December 2, 2022, which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Adenosine deaminase acting on RNA1 (ADAR1) is an RNA-binding protein that modifies double-stranded RNA (dsRNA) by catalyzing the post-transcriptional deamination of adenosine to inosine. Studies have shown that ADAR1 is frequently amplified in various types of cancer, including hepatocellular carcinoma, non-small cell lung cancer, thyroid cancer, pancreatic cancer, esophageal cancer, cervical cancer, and multiple myeloma, where its activity is elevated. Furthermore, depletion of ADAR1 in multiple cell lines results in decreased proliferation and increased apoptosis. Combined with evidence suggesting that ADAR1 promotes the progression and therapeutic resistance of a wide range of human malignancies, A-to-I editing of RNA catalyzed by ADAR1 has emerged as an important mechanism in cancer biology. Summary of the Invention

[0003] Accordingly, various embodiments are described herein that are directed to compounds, compositions, and methods useful for treating diseases and conditions associated with abnormal ADAR1 expression. Consequently, in some embodiments, the compounds disclosed herein are selective inhibitors of ADAR1, e.g., inhibitors that target the p150 isoform.

[0004] In some embodiments, the present disclosure provides a compound of formula (I):

[0005] [ka] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, L is a linker having the structure -A-L1-B-; where: A is -NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2-, S(O)2NR c - or -C(O)-, L1 is absent, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-,

[0006] [ka] -OC(CF3)-, -O-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)-, -S(O2)NR d - or heteroaryl, R c and R d are each independently H, alkyl, cycloalkyl, heterocyclyl, alkylene-aryl, acyl, or sulfonyl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, NR c NR d - or S-S bond is not present, X is C-R1 or N; Y is C-R4 or N; Z is O, S, or N-R5; Z3, Z4, Z5, Z6, and Z7 are each independently N or CH, and at most two of Z3, Z4, Z5, Z6, and Z7 are N; R1 is H, halogen, alkyl, -CN, -C(O)R a , -C(O)ORa , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -C(O)NR a R a , or -S(O)2R a , or -S(O)2OR a or R and R c together with the atom to which they are attached form a heterocyclyl or heteroaryl; R2 is H, halogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl; R3 independently represents halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, or -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or -CN, or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl; R4 is H, halogen, alkyl, -C(O)OR a , -C(O)NHR a or aryl, or R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R5 is H, alkyl, alkylenecycloalkyl, cycloalkyl, aryl, alkylenearyl, or heteroaryl, or R2 and R5 together with the adjacent carbon atoms to which they are attached form an aryl or heteroaryl; R a are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, aryl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl, or two R a groups together with the nitrogen atom to which they are attached form a heterocyclyl; R b is H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or aryl, or two R b The groups together with the nitrogen atom to which they are attached form a heterocyclyl, and further m is 0, 1, 2, or 3; wherein at least one of R1, R2, and R4, if present, is not H, and wherein the compound is

[0007] [ka] isn't it.

[0008] In another aspect, the present disclosure provides a compound of formula (II):

[0009] [ka] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, L is a linker having the structure -A-L1-B-; where: A is -NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2-, -S(O)2NR c - or -C(O)-, L1 is absent, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is a bond or -NR d-, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-,

[0010] [ka] -OC(CF3)-, -O-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)-, -S(O2)NR d - or heteroaryl, R c and R d are each independently H, alkyl, cycloalkyl, heterocyclyl, alkylene-aryl, acyl, or sulfonyl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, -NR c -NR d - or S-S bond is not present, X is C-R1; Y is C-R4 or N; Z1 is N or C-R5; Z2 is N or CH; Z3, Z4, Z5, Z6, and Z7 are each independently N or CH, where at most two of Y, Z1, and Z2 are N, and at most two of Z3, Z4, Z5, Z6, and Z7 are N; R1 is H, halogen, alkyl, -CN, -C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -C(O)NR a R a , -NR a R a , or -S(O)2R a , or -S(O)2OR a or R and R ctogether with the atom to which they are attached form a heterocyclyl or heteroaryl; R2 is H, halogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl; R3 independently represents halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, or -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or -CN, or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl; R4 is H, halogen, alkyl, -C(O)OR a , -C(O)NHR a or aryl, or R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R5 is H, halogen, alkyl, alkoxy, alkylenecycloalkyl, cycloalkyl, aryl, or heteroaryl, or R2 and R5 together with the adjacent carbon atoms to which they are attached form an aryl or heteroaryl; R a are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, aryl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl, or two R a groups together with the nitrogen atom to which they are attached form a heterocyclyl; R bis H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or aryl, or two R b The groups together with the nitrogen atom to which they are attached form a heterocyclyl, and further m is 0, 1, 2, or 3; wherein at least one of R1, R2, and R4 is not H.

[0011] In a further aspect, the present disclosure provides a compound of formula (A):

[0012] [ka] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony,

[0013] [ka] teeth,

[0014] [ka] and

[0015] [ka] is aryl, heteroaryl, cycloalkyl, or heterocyclyl; L is a linker having the structure -A-L1-B-; where: A is -NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2-, -S(O)2NR c - or -C(O)-, L1 is absent, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-,

[0016] [ka] -OC(CF3)-, -O-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)-, -S(O2)NR d - or heteroaryl, R c and R d are each independently H, alkyl, cycloalkyl, heterocyclyl, alkylene-aryl, acyl, or sulfonyl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, -NR c -NR d - or S-S bond is not present, R1 is H, halogen, alkyl, -CN, -C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)NR a R a , -NR a R a , or -S(O)2R a , or -S(O)2OR a or R and R c together with the atom to which they are attached form a heterocyclyl or heteroaryl; R2 is H, halogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl; R3 independently represents halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, or -S(O)2NHR b , -S(O)NR b R b, -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or -CN, or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl; R4 is H, halogen, alkyl, -C(O)OR a , -C(O)NHR a or aryl, or R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R a are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, aryl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl, or two R a groups together with the nitrogen atom to which they are attached form a heterocyclyl; R b is H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or aryl, or two R b The groups together with the nitrogen atom to which they are attached form a heterocyclyl, and m is 0, 1, 2, or 3; wherein at least one of R1, R2, and R4 is not H.

[0017] In some embodiments, the present disclosure provides a compound having the structure:

[0018] [ka] or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compounds of the present disclosure are adenosine deaminase (ADAR1) inhibitors acting on RNA1. In some embodiments, the compounds of the present disclosure are inhibitors of ADAR1p150. In some embodiments, the compounds of the present disclosure are selective inhibitors of ADAR1p150.

[0020] In some embodiments, the present disclosure provides pharmaceutical compositions comprising (i) a compound disclosed herein, and (ii) one or more pharmaceutically acceptable carriers or excipients.

[0021] In some embodiments, the present disclosure provides a method of treating cancer in a subject, wherein the subject is in need of treatment, the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition thereof.

[0022] In some embodiments, the cancer is a cancer characterized by overexpression of ADAR1. In some embodiments, the cancer is breast cancer, lung cancer, pancreatic cancer, melanoma, multiple myeloma, colon cancer, colorectal cancer, or glioblastoma.

[0023] In some embodiments, the present disclosure provides a method of treating an RNA virus infection in a subject, wherein the subject is in need of treatment, the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition thereof.

[0024] In some embodiments, the RNA viral infection is HIV-1, HTLV-1, or SARS-CoV-2. [Brief explanation of the drawings]

[0025] Those skilled in the art will understand that the drawings are primarily for illustrative purposes and are not intended to limit the scope of the inventive subject matter described herein. [Figure 1]

[0023] Figure 1A shows that treatment with Compound 1 induces IFN-β through inhibition of ADAR1. Figure 1A demonstrates dose-dependent IFN-β induction in A549p110KO cells, Figure 1B demonstrates that treatment of WT A549 cells with Compound 1 induces lower IFN-β compared to Figure 1A, and Figure 1C demonstrates that IFN-β induction in A549p110KO cells treated with Compound 1 is superior to that of the STING agonists cGAMP, ADU-S100, and MSA-002. [Figure 2] FIG. 1 provides a graph showing relative MDA5 levels in the human cancer cell line p110KO A549 treated with Compound 1. [Figure 3] Figure 3 provides graphs showing the relative levels of IFN-β (Figure 3A), CXCL-10 (Figure 3B), ISG15 (Figure 3C), and IFITM1 (Figure 3D) in the human cancer cell line p110KO A549 treated with compound 1. [Figure 4] FIG. 1 provides a graph showing relative MDA5 levels in the human cancer cell line HCT116 treated with Compound 1. [Figure 5] Figure 5 provides graphs showing the relative levels of IFN-β (Figure 5A), CXCL-10 (Figure 5B), ISG15 (Figure 5C), and IFITM1 (Figure 5D) in the human cancer cell line HCT116 treated with compound 1. [Figure 6] FIG. 1 provides a graph showing relative MDA5 levels in the mouse cancer cell line B16F10 treated with Compound 1. [Figure 7] 7A and 7B provide graphs showing the relative levels of IFN-β (FIG. 7A) and CXCL-10 (FIG. 7B) in the mouse cancer cell line B16F10 treated with Compound 1. [Figure 8]FIG. 1 provides a graph showing the results of an efficacy study in B16F10 melanoma mice treated with a vehicle control group, anti-PD-1 therapy, Compound 1, or a combination of anti-PD-1 therapy and Compound 1. Anti-PD-1 was administered on days 1, 4, and 7, and Compound 1 was administered on days 1, 5, and 9. [Figure 9] FIG. 1 provides a graph comparing tumor weight reduction in B16F10 melanoma mice treated with vehicle control, anti-PD-1 therapy, Compound 1, or a combination of anti-PD-1 therapy and Compound 1. [Figure 10] FIG. 1 provides a graph showing relative MDA5 levels in B16F10 tumor-bearing mice treated with Compound 1. [Figure 11] 11A and 11B provide graphs showing the relative levels of IFN-β (FIG. 11A) and CXCL-10 (FIG. 11B) in B16F10 tumor-bearing mice treated with Compound 1. DETAILED DESCRIPTION OF THE INVENTION

[0026] definition All definitions set forth and used herein should be understood to control by dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms. The use of flow diagrams is not meant to be limiting with respect to the order of operations performed for all embodiments. The indefinite articles "a" and "an," as used herein and in the claims, should be understood to mean "at least one," unless otherwise specified.

[0027] References throughout this specification to "one embodiment" or "an embodiment," etc., mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include their plural forms unless otherwise specified. It should also be noted that the term "or" is generally used in its sense, including "and / or," unless otherwise specified.

[0028] As used in this specification and claims, the phrase "at least one," in reference 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 element specifically listed in the list of elements, and not excluding any combinations of elements in the list of elements. This definition also allows for elements to be optionally present other than those specifically identified in the list of elements to which the phrase "at least one" refers, 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, in one embodiment, refer to at least one A, optionally including more than one, and no B (and, optionally, including elements other than B); in another embodiment, refer to at least one B, optionally including more than one, and no A (and, optionally, including elements other than A); and in yet another embodiment, refer to at least one A, optionally including more than one, and at least one B, optionally including more than one (and, optionally, including other elements).

[0029] In the claims and the foregoing specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," and "composed of" are to be understood to be open-ended, i.e., to mean including, but not limited to, something. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as defined in the U.S. Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0030] "Alkyl" or "alkyl group" refers to a fully saturated, straight or branched hydrocarbon chain radical 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 C1-C 12 Alkyl, alkyl containing up to 10 carbon atoms is C1-C 10 An alkyl is a C1-C6 alkyl, and an alkyl containing up to 6 carbon atoms is a C1-C6 alkyl, and an alkyl containing up to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties described above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10 Alkyl includes all of the moieties described above for C1-C5 alkyl and C1-C6 alkyl, but also includes C7, C8, C9, and C 10 Also includes alkyl. Similarly, C1-C 12 Alkyl includes all of the above moieties, but C 11 and C 12 Includes alkyl. C1-C 12Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0031] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched, divalent hydrocarbon chain radical. Included are alkylenes containing any number of carbon atoms from 1 to 12. C1-C 12 Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, and n-butynylene. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless specified otherwise in the specification, an alkylene chain can be optionally substituted.

[0032] "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 C2-C 12 Alkenyl containing up to 10 carbon atoms is C2-C 10 An alkenyl group containing up to 6 carbon atoms is a C2-C6 alkenyl, and an alkenyl containing up to 5 carbon atoms is a C2-C5 alkenyl. 2- C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all of the moieties listed above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C10 Alkenyl includes C2-C5 alkenyl and C 2- Includes all of the moieties described above for C6 alkenyl, but also includes C7, C8, C9, and C 10 Also includes alkenyl. 2- C 12 Alkenyl includes all of the above moieties, but C 11 and C 12 Includes alkenyl. C2-C 12 Non-limiting examples of alkenyl include ethenyl (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 Examples of undecenyl include 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Examples of C1-C3 alkyl include methyl, ethyl, n-propyl, and i-propyl. Examples of C1-C4 alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and sec-butyl. Unless otherwise specified in the specification, an alkyl group can be optionally substituted.

[0033] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain radical having from 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. 12 Non-limiting examples of alkenylene include ethene, propene, and butene. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless specified otherwise in the specification, an alkenylene chain can be optionally substituted.

[0034] "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 C2-C 12 Alkynyl containing up to 10 carbon atoms is C2-C 10 An alkynyl group containing up to 6 carbon atoms is C2-C6 alkynyl, and an alkynyl containing up to 5 carbon atoms is C2-C5 alkynyl. C2-C5 alkynyl includes C5 alkynyl, C4 alkynyl, C3 alkynyl, and C2 alkynyl. C2-C6 alkynyl includes all of the moieties listed above for C2-C5 alkynyl, but also includes C6 alkynyl. C2-C 10 Alkynyl includes all of the moieties listed above for C2-C5 alkynyl and C2-C6 alkynyl, but also includes C7, C8, C9, and C 10 Also includes alkynyl. Similarly, C2-C 12 Alkynyl includes all of the above moieties, but C 11 and C 12 Alkynyl is also included. C2-C 12 Non-limiting examples of alkenyl include ethynyl, propynyl, butynyl, pentynyl, etc. Unless stated otherwise in the specification, an alkyl group can be optionally substituted.

[0035] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain radical having from 2 to 12 carbon atoms and having one or more carbon-carbon triple bonds. 12 Non-limiting examples of alkynylene include ethynylene and propargylene. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless specified otherwise in the specification, an alkynylene chain can be optionally substituted.

[0036] "Alkoxy" means a group of the formula -OR a where R a is an alkyl, alkenyl, or alkynyl radical, as defined above, having from 1 to 12 carbon atoms. Unless stated otherwise in the specification, an alkoxy group can be optionally substituted.

[0037] "Alkylamino" refers to a group of the formula -NHR a or -NR a R a where each R a is independently an alkyl, alkenyl, or alkynyl radical, as defined above, having from 1 to 12 carbon atoms. Unless stated otherwise in the specification, an alkylamino group can be optionally substituted.

[0038] "Alkylcarbonyl" is -C(=O)R a refers to the part, where R a is an alkyl, alkenyl, or alkynyl radical as defined above. A non-limiting example of an alkylcarbonyl is a methylcarbonyl ("acetal") moiety. An alkylcarbonyl group may also be referred to as a "Cw-Cz acyl," where w and z are R as defined above. a It indicates the range of carbon numbers in the molecule. For example, "C1-C10 "Acyl" refers to an alkylcarbonyl group as defined above, where R a is the C1-C defined above. 10 Alkyl, C1-C 10 Alkenyl, or C1-C 10 Unless stated otherwise in the specification, an alkylcarbonyl group can be optionally substituted.

[0039] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 5 to 18 carbon atoms, and at least one aromatic ring. For purposes of this disclosure, an aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified in this specification, the term "aryl" is intended to include aryl radicals that are optionally substituted.

[0040] "Alkylenearyl" refers to a group of the formula -R b -R c where R b is alkylene as defined above, and R c is one or more aryl radicals, as defined above. Examples include benzyl, diphenylmethyl, and the like. Unless stated otherwise in the specification, an aralkyl group can be optionally substituted.

[0041] "Carbocyclyl," "carbocyclic ring," or "carbocycle" refers to a ring structure in which each atom forming the ring is carbon. A carbocyclic ring can contain from 3 to 20 carbon atoms in the ring. Carbocyclic rings include cycloalkyl. Cycloalkenyl and cycloalkynyl are defined herein. Unless otherwise specified herein, a carbocyclic group can be optionally substituted.

[0042] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from 3 to 20 carbon atoms, and optionally including fused or bridged ring systems, e.g., from 3 to 10 carbon atoms, and further attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified in the specification, cycloalkyl groups can be optionally substituted.

[0043] "Cycloalkenyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms having one or more carbon-carbon double bonds, which may include fused or bridged ring systems having 3 to 20 carbon atoms, e.g., 3 to 10 carbon atoms, and which is further attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkenyl radicals include, for example, and bicyclo[2.2.1]hept-2-enyl. Unless otherwise specified in the specification, cycloalkenyl groups can be optionally substituted.

[0044] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms having one or more carbon-carbon triple bonds, which may include fused or bridged ring systems having 3 to 20 carbon atoms, e.g., 3 to 10 carbon atoms, and which is further attached to the rest of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl and cyclooctynyl. Unless otherwise specified in the specification, cycloalkynyl groups can be optionally substituted.

[0045] An "alkylenecycloalkyl" is a group of the formula -R b -R d where R b is an alkylene group as defined above, and R d is a cycloalkyl or cycloalkenyl radical as defined above. Unless stated otherwise in the specification, an alkylenecycloalkyl group can be optionally substituted.

[0046] An "alkenylenecycloalkyl" is an alkyl group of the formula -R b -R d where R b is an alkenylene group as defined above, and R d is a cycloalkyl or cycloalkenyl radical as defined above. Unless stated otherwise in the specification, an alkenylenecycloalkyl group can be optionally substituted.

[0047] An "alkynylenecycloalkyl" is a group of the formula -R b -R d where R b is an alkynylene group as defined above, and R d is a cycloalkyl or cycloalkenyl radical, as defined above. Unless stated otherwise in the specification, an alkynylenecycloalkyl group can be optionally substituted.

[0048] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halo radicals, as defined above, such as, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. Unless stated otherwise in the specification, a haloalkyl group can be optionally substituted.

[0049] "Haloalkenyl" refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless stated otherwise in the specification, a haloalkenyl group can be optionally substituted.

[0050] "Haloalkynyl" refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless stated otherwise in the specification, a haloalkenyl group can be optionally substituted.

[0051] "Heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a stable 3- to 20-membered non-aromatic ring radical consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclic ring or heterocyclic ring includes heteroaryl, as defined below. Unless otherwise specified in the specification, a heterocyclic radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; further, the nitrogen, carbon, or sulfur atoms in the heterocyclic radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic radical can be partially or fully saturated. Examples of such heterocyclic radicals include, but are not limited to, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless otherwise specified in the specification, heterocyclic groups can be optionally substituted.

[0052] "N-heterocyclyl" refers to a heterocyclic radical as defined above having at least one nitrogen, and the point of attachment of the heterocyclic radical to the rest of the molecule is through a nitrogen atom within the heterocyclic radical. Unless otherwise specified in the specification, an N-heterocyclyl group can be optionally substituted.

[0053] "Alkyleneheterocyclyl" refers to a group of the formula -R b -R e where R bis alkylene as defined above, and R e is a heterocyclic radical as defined above, and if the heterocycle is a nitrogen-containing heterocycle, the heterocycle can be attached to the alkylene radical at a nitrogen atom. Unless specified otherwise in the specification, an alkyleneheterocyclyl group can be optionally substituted.

[0054] "Heteroaryl" refers to a 5- to 20-membered ring system radical containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; further, the nitrogen, carbon, or sulfur atoms within the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indophenyl, and indophenyl. Examples include, but are not limited to, dolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in this disclosure, a heteroaryl group can be optionally substituted.

[0055] "N-heteroaryl" refers to a heteroaryl radical, as defined above, having at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom within the heteroaryl radical. Unless otherwise specified in the specification, an N-heteroaryl group can be optionally substituted.

[0056] An "alkylene heteroaryl" is a heteroaryl group of the formula -R b -R f where R b is alkylene as defined above, and R f is a heteroaryl radical as defined above. Unless stated otherwise in the specification, an alkyleneheteroaryl group can be optionally substituted.

[0057] A "thioalkyl" is a group of the formula -SR a where R a is an alkyl, alkenyl, or alkynyl radical as defined above having 1 to 12 carbon atoms. Unless stated otherwise in the specification, a thioalkyl group can be optionally substituted.

[0058] The term "substituent" as used herein means any of the above groups (i.e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, 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 selected from the group consisting of, but not limited to, F, Cl, B and halogen atoms such as r and I; oxygen atoms in groups such as hydroxyl, alkoxy, and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups. "Substituent" also refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. For example, "substituent" refers to any of the above groups in which one or more hydrogen atoms have been replaced by a higher bond (e.g., a double or triple bond) to a heteroatom, such as -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h"Substituents" also include any of the above groups substituted with -C(=O)R. g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituents" further refers to any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl group. In addition, each of the above substituents may also be optionally substituted with one or more of the above substituents.

[0059] As used herein, the symbols

[0060] [ka] (which may hereinafter be referred to as a "point bond") denotes a bond that is a point of attachment between two chemical entities, one of which is shown as being attached to the point bond and the other of which is not shown as being attached to the point bond. For example,

[0061] [ka] indicates that a chemical entity "XY" is attached to another chemical entity via a point-of-attachment bond. Furthermore, specific points of attachment to chemical entities not shown can be identified by inference. For example, R 3 is H or

[0062] [ka] The compound CH3-R 3 is R 3 When "XY" is the bond at the attachment point, R 3 is the same bond shown as being attached to CH3.

[0063] "Fused" refers to any ring structure described herein that is fused to an existing ring structure in the compounds of the present invention. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring can be replaced with a nitrogen atom.

[0064] "Geminal" refers to any two substituents (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc., as described herein) attached to the same atom. In some embodiments, geminal substitution refers to substitution on the same carbon atom. The following structure:

[0065] [ka] illustrates geminal methyl substitution on cyclohexane. In some embodiments, the optional substitution is a geminal substitution.

[0066] "Optional" or "optionally" means that the subsequently described circumstance event can or cannot occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted aryl" means that the aryl radical can or cannot be substituted, and that the description includes both substituted and unsubstituted aryl radicals.

[0067] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may possess one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomers that can be defined as I- or (S)- in terms of their absolute stereochemistry relative to an amino acid, or as (D)- or (L)-. The present invention is intended to encompass all such possible isomers, as well as their racemic and optically pure forms, whether or not they are specifically depicted herein. Optically active (+) and (-), I- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or separated using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) 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 specified, the compounds are intended to include both the E and Z geometric isomers, as well as all tautomers.

[0068] "Stereoisomers" refer to compounds made up of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0069] "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 above compounds.

[0070] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, without limitation, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0071] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0072] "Pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effectiveness and properties of the free bases, which salts are not biologically or otherwise undesirable, and which include salts of inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as salts of 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, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gen It can be formed using organic acids such as thiazole, glucoheptonic, gluconic, glucuronic, glutamic, glutaric, 2-oxo-glutaric, glycerophosphoric, glycolic, hippuric, isobutyric, lactic, lactobionic, lauric, maleic, malic, malonic, mandelic, methanesulfonic, mucic, naphthalene-1,5-disulfonic, naphthalene-2-sulfonic, 1-hydroxy-2-naphthoic, nicotinic, oleic, orotic, oxalic, palmitic, pamoic, propionic, pyroglutamic, pyruvic, salicylic, 4-aminosalicylic, sebacic, stearic, succinic, tartaric, thiocyanic, p-toluenesulfonic, trifluoroacetic, and undecylenic acids.

[0073] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, and which salts are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts, and the like. In some embodiments, inorganic salts include ammonium, sodium, potassium, calcium, 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, dianol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benezamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. In certain embodiments, the organic base includes isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0074] Crystallization is a commonly used method for isolating a reaction product, such as one of the compounds disclosed herein, in a purified form. Crystallization often produces a solvate of the compound of the present invention. As used herein, the term "solvate" refers to an aggregate containing one or more molecules of a compound of the present invention with one or more molecules of a solvent, typically in a co-crystallized form. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compound of the present invention may exist as a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a pentacene hydrate, a trihydrate, a tetrahydrate, and the like, as well as the corresponding solvated forms. While the compound of the present invention may be a true solvate, in other cases, the compound of the present invention may simply retain adventitious water or may be a mixture of water and an adventitious solvent.

[0075] The chemical naming protocols and structural diagrams used herein are modified IUPAC nomenclature, using software naming programs such as the ACD / Name Version 9.07 software program, ChemDraw Ultra Version 11.0.1, and / or ChemDraw Ultra Version 14.0, and / or ChemDraw Professional 16.0.0.82 (CambridgeSoft). For complex chemical names used herein, substituents are named before the group to which they are attached. For example, cyclopropylethyl contains an ethyl skeleton with a cyclopropyl substituent. Except as noted below, in the chemical structural diagrams herein, all bonds are identified, except for some carbon atoms which are assumed to be attached to sufficient hydrogen atoms to complete valence.

[0076] The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, and the like, of the administered compound, primarily by enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to produce a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the invention to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0077] "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.

[0078] As used herein, a "subject" may be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, insect, etc. The subject may have or be suspected of being at risk of having cancer, such as a blood cancer, or another disease or condition. Diagnostic methods for various cancers and clinical delineations of cancer are known to those skilled in the art. The subject may also be suspected of having an infection or cardiovascular dysfunction.

[0079] "Mammal" includes humans and both domestic animals such as laboratory animals and pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits, etc.) and non-domestic animals such as wildlife.

[0080] A "pharmaceutical composition" refers to a formulation of a compound of the present invention and a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human. Such a vehicle includes any pharmaceutically acceptable carrier, diluent, or excipient therefor.

[0081] An "effective amount" refers to a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective at a dosage and for a period of time necessary to achieve a desired therapeutic result, such as a reduction in tumor size, an increase in lifespan, or an increase in life expectancy. A therapeutically effective amount of a compound can vary depending on factors such as the subject's disease state, age, sex, and weight, as well as the ability of the compound to elicit a desired response in a subject. Dosage regimens can be adjusted to provide an optimal therapeutic response. A therapeutically effective amount is also an amount in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective at a dosage and for a period of time necessary to achieve a desired prophylactic result, such as a reduction in tumor size, an increase in lifespan, an increase in lifespan, or an increase in life expectancy, or prevention of cancer progression to a resistant form. Typically, a prophylactic dose is used in subjects before or at an early stage of disease, so the prophylactically effective amount may be less than the therapeutically effective amount.

[0082] As used herein, "treatment" or "therapy" covers the treatment of a disease or condition of interest in a mammal, such as a human having the disease or condition of interest, and includes the following: 1. Preventing a disease or condition from occurring in a mammal, particularly when such mammal is susceptible to the disease or condition but has not yet been diagnosed as having it; 2. inhibiting a disease or condition, i.e., halting its development; 3. Alleviating the disease or condition, i.e., causing regression of the disease or condition (from reducing the severity of the disease or condition to curing the disease or condition), or 4. Relieving symptoms resulting from a disease or condition, i.e., relieving pain without addressing the underlying disease or condition As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular disease or condition may have a known causative agent (and thus the etiology has not yet been elucidated) and therefore is not yet recognized as a disease, but only as an undesirable state or syndrome, with a more or less specific set of symptoms identified by clinicians.

[0083] Throughout this specification, the terms "about" and / or "approximately" can be used in conjunction with numerical values ​​and / or ranges. The term "about" is understood to mean a value close to the stated value. For example, "about 40 units" can mean within ±25% of 40 (e.g., from 30 to 50), ±20%, ±15%, ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, ±1%, less than ±1%, or any other value or range of values ​​herein. Furthermore, the phrases "less than about [value]" or "greater than about [value]" should be understood in light of the definition of the term "about" provided herein. The terms "about" and "approximately" can be used interchangeably.

[0084] Numerical ranges can be provided for particular quantities. These ranges should be understood to include all subranges therein. Thus, a range "from 50 to 80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range can be endpoints for the range encompassed thereby (e.g., a range of 50-80 includes ranges with endpoints of 55-80, 50-75, etc.).

[0085] The following is a more detailed description of various concepts and embodiments related to the compounds and methods of the present invention for the treatment of liver disease and liver abnormalities.It should be appreciated that the various concepts introduced above and discussed in more detail below can be implemented in any of many ways, as the disclosed concepts are not limited to any specific implementation mode.The examples of specific implementation and application are provided mainly for illustrative purposes.

[0086] Adenosine deaminase acting on RNA (ADAR1) is an RNA-binding protein that modifies double-stranded RNA (dsRNA) through the deamination of adenosine (A) to inosine (I). ADAR1 is overexpressed in various cancers, including breast, lung, and pancreatic cancers. Therefore, identifying inhibitors of this enzyme could provide therapeutic benefits.

[0087] Provided herein are compounds and compositions useful for inhibiting ADAR1 activity and treating cancer.

[0088] Compounds and Compositions In some embodiments of the present disclosure, a compound of formula (I)

[0089] [ka] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, L is a linker having the structure -A-L1-B-; where: A is -NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2-, -S(O)2NR c - or -C(O)-, L1 is absent, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is a bond or -NR d-, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-,

[0090] [ka] -OC(CF3)-, -O-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)-, -S(O2)NR d - or heteroaryl, R c and R d are each independently H, alkyl, cycloalkyl, heterocyclyl, alkylene-aryl, acyl, or sulfonyl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, -NR c -NR d - or S-S bond is not present, X is C-R1 or N; Y is C-R4 or N; Z is O, S, N—R, or N(R)—CH—; Z3, Z4, Z5, Z6, and Z7 are each independently N or CH, and at most two of Z3, Z4, Z5, Z6, and Z7 are N; R1 is H, halogen, alkyl, -CN, -C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -C(O)NR a R a , or -S(O)2R a , or -S(O)2OR a or R and R c together with the atom to which they are attached form a heterocyclyl or heteroaryl; R2 is H, halogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl; R3 independently represents halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, or -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b , N.R. b R b , -CN, or P(O)(OR b )2, or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl; R4 is H, halogen, alkyl, -C(O)OR a , -C(O)NHR a or aryl, or R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R5 is H, alkyl, alkylenecycloalkyl, cycloalkyl, aryl, or heteroaryl, or R2 and R5 together with the adjacent carbon atoms to which they are attached form an aryl or heteroaryl; R a are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, aryl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl, or two R a groups together with the nitrogen atom to which they are attached form a heterocyclyl; R bis H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or aryl, or two R b groups together with the nitrogen atom to which they are attached form a heterocyclyl; m is 0, 1, 2, or 3; wherein the compound is

[0091] [ka] isn't it.

[0092] In some embodiments of the present disclosure, a compound of formula (I)

[0093] [ka] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, L is a linker having the structure -A-L1-B-; where: A is -NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2-, -S(O)2NR c - or -C(O)-, L1 is absent, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-,

[0094] [ka] -OC(CF3)-, -O-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)-, -S(O2)NR d - or heteroaryl, R c and R d are each independently H, alkyl, cycloalkyl, heterocyclyl, alkylene-aryl, acyl, or sulfonyl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, -NR c -NR d - or S-S bond is not present, X is C-R1 or N; Y is C-R4 or N; Z is O, S, N—R, or N(R)—CH—; Z3, Z4, Z5, Z6, and Z7 are each independently N or CH, and at most two of Z3, Z4, Z5, Z6, and Z7 are N; R1 is H, halogen, alkyl, -CN, -C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -C(O)NR a R a , or -S(O)2R a , or -S(O)2OR a or R and R c together with the atom to which they are attached form a heterocyclyl or heteroaryl; R2 is H, halogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl; R3 independently represents halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, or -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b, -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b , N.R. b R b , -CN, or -P(O)(OR b )2, or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl; R4 is H, halogen, alkyl, -C(O)OR a , -C(O)NHR a or aryl, or R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R5 is H, alkyl, alkylenecycloalkyl, cycloalkyl, aryl, or heteroaryl, or R2 and R5 together with the adjacent carbon atoms to which they are attached form an aryl or heteroaryl; R a are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, aryl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl, or two R a groups together with the nitrogen atom to which they are attached form a heterocyclyl; R b is H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or aryl, or two R b groups together with the nitrogen atom to which they are attached form a heterocyclyl; m is 0, 1, 2, or 3; where X is C-R1, Y is C-R5, and Z is S, then -A-L1-B- is

[0095] [ka] isn't it.

[0096] In some embodiments, X is C-R. In some embodiments, X is N.

[0097] In some embodiments, Y is C-R4. In some embodiments, Y is N.

[0098] In some embodiments, Z is O, S, or N-R5. In some embodiments, Z is O or S. In some embodiments, Z is S. In some embodiments, Z is O. In some embodiments, Z is N-R5.

[0099] X, Y, and Z can be combined in any manner that provides a stable heteroaryl ring. In some embodiments, X is C-R1 or N, Y is C-R4 or N, and Z is S. In some embodiments, X is C-R1, Y is C-R4, and Z is S. In some embodiments, X is C-R1, Y is N, and Z is S. In some embodiments, X and Y are N, and Z is S. In some embodiments, X is N, Y is C-R4, and Z is S.

[0100] In some embodiments, Z3, Z4, Z5, Z6, and Z7 are each H. In some embodiments, at most one of Z3, Z4, Z5, Z6, and Z7 is N. In some embodiments, one of Z3, Z4, Z5, Z6, and Z7 is N. In some embodiments, Z3 is N and Z4, Z5, Z6, and Z7 are each H. In some embodiments, Z4 is N and Z3, Z5, Z6, and Z7 are each H. In some embodiments, Z5 is N and Z3, Z4, Z6, and Z7 are each H. In some embodiments, Z6 is N and Z3, Z4, Z4, and Z7 are each H. In some embodiments, Z7 is N and Z3, Z4, Z5, and Z6 are each H. In some embodiments, at most two of Z3, Z4, Z5, Z6, and Z7 are each N. In some embodiments, two of Z3, Z4, Z5, Z6, and Z7 are each N. In some embodiments, Z3 and Z4 are each N. In some embodiments, Z3 and Z5 are each N. In some embodiments, Z3 and Z6 are each N. In some embodiments, Z4 and Z6 are each N. In some embodiments, Z4 and Z7 are each N. In some embodiments, Z5 and Z7 are each N. In some embodiments, Z3 and Z7 are each N. In some embodiments, Z6 and Z7 are each N. In some embodiments, Z5 and Z6 are each N. In some embodiments, Z4 and Z5 are each N.

[0101] In some embodiments, A is —NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2- or -S(O)2NR c In some embodiments, A is -NR c C(O)-, -C(O)NR c -, -NR c S(O)2- or S(O)2NR c In some embodiments, A is -NR cC(O)-, -C(O)NR c In some embodiments, A is -NR c C(O)- or -NR c In some embodiments, A is -NR c C(O)- or -S(O)NR c In some embodiments, A is -NR c In some embodiments, R c is H, C 1-5 Alkyl, C 3-6 cycloalkyl, or -CH-phenyl. In some embodiments, R c is H or C 1-5 In some embodiments, C is alkyl. 1-5 Alkyl is methyl, ethyl, or isopropyl. 1-5 Alkyl is methyl. In some embodiments, C 3-6 Cycloalkyl is cyclopropyl. In some embodiments, R c is H or methyl. In some embodiments, R c is H.

[0102] In some embodiments, L is absent, alkylene, cycloalkyl, heterocyclyl, or heteroaryl. In some embodiments, L is absent, alkylene, cycloalkyl, or heterocyclyl. In some embodiments, L is absent, alkylene, or heterocyclyl. In some embodiments, L is alkylene or heterocyclyl. In some embodiments, alkylene is C 1-5 In some embodiments, alkylene is C 1-3 In some embodiments, L is alkylene. In some embodiments, the alkylene is methylene. In some embodiments, the alkylene is geminally substituted. In some embodiments, L is alkylene, and the alkylene is C 1-3In some embodiments, the alkylene is an optionally substituted methylene. In some embodiments, the alkylene has the following structure:

[0103] [ka] where R e are independently H, F, and C 1-5 alkyl, -CHOH, -CHcycloalkyl, or -CHaryl, or two R e C along with the carbon atoms to which they are attached 3-6 In some embodiments, R e is H or C 1-5 It is alkyl.

[0104] In some embodiments, L comprises a heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl has the following structure:

[0105] [ka] where * represents the point of attachment to A and ** represents the point of attachment to B.

[0106] In some embodiments, B is a bond or —NR b C(O)-, -NR bIn some embodiments, B is S(O)2-, -C(O)-, -OC(O)-, -C(O)-O-, or heteroaryl. In some embodiments, B is a bond, -OC(O)-, or C(O)-. In some embodiments, B is -OC(O)-. In some embodiments, B is -C(O)-. In some embodiments, B is a bond. In some embodiments, B is heteroaryl. In some embodiments, heteroaryl is a 5- or 6-membered nitrogen-containing heteroaryl. In some embodiments, heteroaryl is triazole. In some embodiments, heteroaryl is 1,2,3-triazole or 1,2,4-triazole.

[0107] In some embodiments, L is a linker having the structure -A-L1-B-, where A is -NR c C(O)- or -C(O)NR c wherein L1 is absent, alkylene, cycloalkyl, or heterocyclyl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)- or -S(O2)NR d - and R c and R d are each independently H, alkyl, cycloalkyl, or alkylene-aryl, with the proviso that -A-L1-B- is -OO, -NR C -O, -O-NR d -, -NR C -NR d - or has no S-S bond. c and R d are each independently H, alkyl, cycloalkyl, alkylene-aryl, acyl, or sulfonyl. c and R d are each independently H or alkyl. In some embodiments, R c and R dare each independently H or C 1-5 In some embodiments, R c and R d are H, respectively.

[0108] In some embodiments, L is a linker having the structure -A-L1-B-, where A is -NR c In some embodiments, A is -C(O)-, L is alkylene or heterocyclyl, and B is -C(O)- or -OC(O)-. c C(O)- and L1 is C 1-3 In some embodiments, A is -NR c In some embodiments, A is -C(O)-, L is methylene or pyrrolidine, and B is -C(O)- or -OC(O)-. c C(O)-, and L1 is methylene or

[0109] [ka] and B is -C(O)- or -OC(O)-. In some embodiments, L is a linker having the structure -A-L1-B-, where A is -NR c C(O)-, L is absent, and B is heteroaryl. In some embodiments, heteroaryl is a 5-membered heteroaryl. In some embodiments, heteroaryl is oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, thiazolyl, or imidazolyl. In some embodiments, heteroaryl is

[0110] [ka] It has the following structure.

[0111] In some embodiments, -A-L1-B- has the structure:

[0112] [ka] and where R c and R d are each independently H, alkyl, cycloalkyl, alkylene-aryl, acyl, or sulfonyl; R e are independently H, F, and C 1-5 alkyl, -CH2 cycloalkyl, or -CH2 aryl, or two R e C along with the carbon atoms to which they are attached 3-6 cycloalkyl or 4- to 6-membered heterocyclyl, and t is 0, 1, or 2. In some embodiments, R c is H or alkyl. In some embodiments, R c is H or C 1-5 In some embodiments, R c is H. In some embodiments, R e are each independently H, F, or C 1-5 In some embodiments, R e are each independently H, F, Me, Et, or iPr. e is H. In some embodiments, s is 1. In some embodiments, t is 1.

[0113] In some embodiments, -A-L1-B- has the structure:

[0114] [ka] In some embodiments, R c is H or alkyl. In some embodiments, R c is H or C 1-5 In some embodiments, R c is H.

[0115] In some embodiments, R1 is alkyl, —CN, —C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -C(O)NR a R a , or -S(O)R a , or S(O)2OR a In some embodiments, R is alkyl, —C(O)OR a , -C(O)N(R a )(R a ), or -C(O)NHR a In some embodiments, R is —C(O)OR a In some embodiments, each R a are independently H or C 1-5 alkyl (e.g., methyl, ethyl, or n- or i-propyl, etc.), or two R a The groups together with the nitrogen atom to which they are attached form a heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered nitrogen-containing heterocyclyl. In some embodiments, the heterocyclyl has the following structure:

[0116] [ka] In some embodiments, R a is C 1-5 In some embodiments, R a is methyl, ethyl, or n-propyl or i-propyl. a is ethyl.

[0117] In some embodiments, X is C-R, and R and R ctogether with the atom to which they are attached form a heterocyclyl or heteroaryl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl.

[0118] In some embodiments, R4 is H, alkyl, —CN, —C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -C(O)NR a R a , or S(O)2R a , or S(O)2OR a In some embodiments, R4 is H, alkyl, aryl, -C(O)OR a , or -C(O)NHR a In some embodiments, R4 is H, alkyl, -C(O)OR a , -C(O)N(R a )(R a ), or -C(O)NHR a In some embodiments, R4 is H, halogen, or -C(O)OR a In some embodiments, R4 is H. In some embodiments, R4 is halogen. In some embodiments, halogen is F or Cl. In some embodiments, halogen is Cl. In some embodiments, R4 is H or -C(O)OR a In some embodiments, R4 is H. In some embodiments, R a is C 1-5 alkyl or -CHcycloalkyl. In some embodiments, R a is C 1-5 In some embodiments, R a is methyl, ethyl, or n-propyl or i-propyl. In some embodiments, each Ra is independently H or C 1-5alkyl (e.g., methyl, ethyl, or n- or i-propyl, etc.), or two R a The groups together with the nitrogen atom to which they are attached form a heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered nitrogen-containing heterocyclyl. In some embodiments, the heterocyclyl has the following structure:

[0119] [ka] In some embodiments, R a is C 1-5 In some embodiments, R a is methyl, ethyl, or n-propyl or i-propyl. a is ethyl.

[0120] In some embodiments, R2 is aryl or heteroaryl. In some embodiments, the aryl is phenyl and the heteroaryl is a 6-membered nitrogen-containing heteroaryl. In some embodiments, the aryl is phenyl and the heteroaryl is pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl, etc.). In some embodiments, R2 is phenyl or naphthyl. In some embodiments, R2 is phenyl. In some embodiments, R2 is

[0121] [ka] where R s are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, amino (e.g., —NH, —NHCH, —N(CH), etc.), or heterocyclyl, or two R s together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and p is 0, 1, 2, or 3. In some embodiments, R2 is

[0122] [ka] where R c are each independently halogen, alkyl, haloalkyl, -OH, alkoxy, haloalkoxy, or amino.

[0123] [ka] In some embodiments, R2 is a 6-membered nitrogen-containing heteroaryl.

[0124] [ka] where R s are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R s together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and p is 0, 1, or 2. In some embodiments, R2 is

[0125] [ka] where R s are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R s together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and p is 0, 1, or 2. In some embodiments, R s are independently H, F, and C 1-5 Alkyl, -OC 1-5 alkyl, CF, -OCF, or -CN. In some embodiments, R sare each independently H or F. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0126] In some embodiments, R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl. In some embodiments, a cycloalkyl is selected from the group consisting of C 5-7 In some embodiments, cycloalkyl is C 5-6 In some embodiments, cycloalkyl is C 4-6 It is cycloalkyl.

[0127] In some embodiments, when X is C-R1 and Y is C-R4, at least two of R1, R2, and R4 are not H. In some embodiments, R1 and R2 are not H and R4 is H. In some embodiments, when X is C-R1 and Y is C-R4, R1 is -C(O)OR a , -C(O)N(R a )(R a ), or -C(O)NHR a and R2 is optionally substituted phenyl and R4 is H, where R a is as defined herein. In some embodiments, R is —C(O)OR a and R2 is optionally substituted phenyl and R4 is H, where R a is as defined herein. In some embodiments, R is —C(O)OR a and R2 is

[0128] [ka] and R4 is H, where R a is as defined herein. In some embodiments, X and Y are N and R2 is

[0129] [ka] In some embodiments, Z is S. In some embodiments, Z is O. In some embodiments, Z is N-R5.

[0130] In some embodiments, R5 is H, alkyl, alkylenecycloalkyl, cycloalkyl, aryl, or alkylenearyl. In some embodiments, R5 is H, alkyl, or alkylenecycloalkyl. In some embodiments, R5 is H or alkyl. In some embodiments, alkyl is Me, Et, or iPr. In some embodiments, aryl is phenyl. In some embodiments, cycloalkyl is C 3-6 In some embodiments, alkylene is C 1-3 In some embodiments, the alkylene is methylene.

[0131] In some embodiments, each R3 is independently halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b , or -P(O)(OR bor two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl. In some embodiments, each R3 is independently halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , or -NHC(O)NR b R b or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl. In some embodiments, each R3 is independently halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or -CN, or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl. In some embodiments, each R3 is independently halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)ORb , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or -CN. In some embodiments, R3 is -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or -CN. In some embodiments, R3 is -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b In some embodiments, R3 is -N(H)S(O)2 alkyl, -N(H)S(O)2 cycloalkyl, -S(O)2 NH2, -C(O) alkyl, or -CN. In some embodiments, R3 is -N(H)S(O)2(C 1-5 alkyl), -S(O)N(C 1-5 alkyl) 2、 -S(O)N(H)(C 1-5 In some embodiments, R is —N(H)S(O)(C 1-5In some embodiments, R3 is -N(H)S(O)2CH3, -S(O)2NH2, -C(O)CH3, or -CN. In some embodiments, R3 is -N(H)S(O)2CH3, -S(O)2NH2, or -C(O)CH3. In some embodiments, R3 is -N(H)S(O)2CH3 or -S(O)2NH2. In some embodiments, R3 is -N(H)S(O)2CH3 or -S(O)2NH2.

[0132] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0133] In some embodiments, X is C-R1, Y is C-R4, R2 is aryl, heteroaryl, R3 is -N(H)S(O)2CH3, -S(O)2NH2, -C(O)CH3, or -CN, and L is a linker having the structure -A-L1-B-, where A is -NR c L is alkylene or heterocyclyl, and B is —C(O)— or —OC(O)—, where R 1、 R2 and R4 are as defined above for formula (I). In some embodiments, X is C-R1, Y is C-R4, and R2 is

[0134] [ka] wherein R3 is -N(H)S(O)2CH3, -S(O)2NH2, -C(O)CH3, or -CN; and L is a linker having the structure -A-L1-B-, where A is -NR c L1 is alkylene or heterocyclyl, and B is -C(O)- or -OC(O)-, where R1, R4, R s and p is as defined above for formula (I). In some embodiments, A is -NRc C(O)- and L1 is C 1-3 In some embodiments, A is -NR c In some embodiments, A is -C(O)-, L is methylene or pyrrolidine, and B is -C(O)- or -OC(O)-. c C(O)-, and L1 is methylene or

[0135] [ka] and B is -C(O)- or -OC(O)-. In some embodiments, X is C-R1, Y is C-R4, R2 is phenyl or 6-membered heteroaryl, R3 is -N(H)S(O)2CH3, -S(O)2NH2, -C(O)CH3, or -CN, and L is a linker having the structure -A-L1-B-, where -A-L1-B- is

[0136] [ka] and R1, R4, R s and p are as defined above for formula (I). In some embodiments, X is C-R1, Y is C-R4, and R2 is

[0137] [ka] wherein R3 is —N(H)S(O)2CH3, —S(O)2NH2, —C(O)CH3, or —CN; and L is a linker having the structure —A-L1-B-, where —A-L1-B- is

[0138] [ka] and R1, R4, R s , and p are as defined above for formula (I).

[0139] In some embodiments, the compound of formula (I) has the structure:

[0140] [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein L, X, Y, Z, Z3, Z4, Z5, Z6, Z 7、 R2, R3, and m are as defined above for formula (I).

[0141] In some embodiments, the compound of formula (I) has the structure:

[0142] [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein L, Y, Z3, Z4, Z5, Z6, Z7, R 1、 R2, R3, and m are as defined above for formula (I).

[0143] In some embodiments, the compound of formula (I) has the structure:

[0144] [ka] or a pharmaceutically acceptable salt thereof, wherein L, X, Y, R2, R3, and m are as defined above in formula (I).

[0145] In some embodiments, the compound of formula (I) has the structure:

[0146] [ka] or a pharmaceutically acceptable salt thereof, wherein L, Y, R1, R2, R3, and m are as defined above in formula (I).

[0147] In some embodiments, the compound of formula (I) has the structure:

[0148] [ka] or a pharmaceutically acceptable salt thereof, where: L, Y, R1, R2, and R3 are as defined above in formula (I); R 3a are each independently H, halogen, —OH, —CN, alkyl, haloalkyl, alkoxy, or haloalkoxy; q is 0, 1, or 2.

[0149] In some embodiments, R 3a are independently F, -OH, and C 1-5 Alkyl, C 1-5 alkoxy, CF, or -OCF. In some embodiments, R 3a are each independently F, —OH, Me, Et, iPr, —OMe, OEt, OiPr, CF, or OCF. 3a is H.

[0150] In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0151] In some embodiments, the compound of formula (I) has the structure:

[0152] [ka] or a pharmaceutically acceptable salt thereof, where: L, R, R, and m are as defined herein; R s are each independently halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, sulfonyl, or two R Ctogether with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; p is 0, 1, 2, or 3.

[0153] In some embodiments, the compound of formula (I) has the structure:

[0154] [ka] or a pharmaceutically acceptable salt thereof, where: A, B, L1, R1, R3, and m are as defined herein; R s are each independently halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, sulfonyl, or two R s together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; p is 0, 1, 2, or 3.

[0155] In some embodiments, R s are independently H, F, and C 1-5 Alkyl, -OC 1-5 alkyl, CF, -OCF, or -CN. In some embodiments, R s are each independently H or F. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 1 and R c In some embodiments, p is 1 and R c is in meta position.

[0156] In some embodiments, the compound of formula (I) has the structure:

[0157] [ka] or a pharmaceutically acceptable salt thereof, where: -L1-B- is -CH2-OC(O)-,

[0158] [ka] and R3 is

[0159] [ka] -S(O)2NH2, -C(O)CH3, or -N(H)S(O)2CH3; R s is H or F.

[0160] In some embodiments, -L1-B- is -CH2-OC(O)-. In some embodiments, -L1-B- is

[0161] [ka] In some embodiments, -L1-B- is

[0162] [ka] is.

[0163] In some embodiments, R3 is -S(O)2NH2 or -N(H)S(O)2CH3.

[0164] In some embodiments, R s is H. In some embodiments, R s is F.

[0165] In some embodiments, the compound of formula (I) has the structure:

[0166] [ka] TIFF2025538892000056.tif171170 TIFF2025538892000057.tif89170 or a pharmaceutically acceptable salt or tautomer thereof.

[0167] In some embodiments, the compound of formula (I) has the structure:

[0168] [ka] TIFF2025538892000059.tif121170 or a pharmaceutically acceptable salt or tautomer thereof.

[0169] In some embodiments, the compound of formula (I) has the structure:

[0170] [ka] TIFF2025538892000061.tif78170 or a pharmaceutically acceptable salt or tautomer thereof.

[0171] In some embodiments of the present disclosure, a compound of formula (II)

[0172] [ka] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, L is a linker having the structure -A-L1-B-; where: A is -NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2- or -S(O)2NRc - and L1 is absent, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-,

[0173] [ka] -OC(CF3)-, -O-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)-, -S(O2)NR d - or heteroaryl, R c and R d are each independently H, alkyl, cycloalkyl, heterocyclyl, alkylene-aryl, acyl, or sulfonyl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, NR c NR d - or S-S bond is not present, X is C-R1 or N; Y is C-R4 or N; Z1 is N or C-R5; Z2 is N or CH; Z3, Z4, Z5, Z6, and Z7 are each independently N or CH, and at most two of Y, Z1, and Z2 are N, and at most two of Z3, Z4, Z5, Z6, and Z7 are N; R1 is H, halogen, alkyl, -CN, -C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -NR a R a, or -S(O)2R a , or -S(O)2OR a or R and R c together with the atom to which they are attached form a heterocyclyl or heteroaryl; R2 is H, halogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl; R3 independently represents halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, or -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or -CN, or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl; R4 is H, halogen, alkyl, -C(O)OR a , -C(O)NHR a or aryl, or R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R5 is H, halogen, alkyl, alkoxy, aryl, or heteroaryl, or R2 and R5 together with the adjacent carbon atoms to which they are attached form an aryl or heteroaryl; R a are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, aryl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl, or two R a groups together with the nitrogen atom to which they are attached form a heterocyclyl; R b is H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or aryl, or two R b groups together with the nitrogen atom to which they are attached form a heterocyclyl; m is 0, 1, 2, or 3; wherein at least one of R1, R2, and R4 is not H.

[0174] In some embodiments, X is C-R. In some embodiments, X is N.

[0175] In some embodiments, Y is C-R4. In some embodiments, Y is N.

[0176] In some embodiments, Z1 is N. In some embodiments, Z1 is C-R5.

[0177] In some embodiments, Z2 is N. In some embodiments, Z2 is CH.

[0178] X, Y, Z1, and Z2 can be combined in any manner that provides a stable heteroaryl ring, such that at most two of Y, Z1, and Z2 are N. In some embodiments, X is C-R1, Y is C-R4, Z1 is N, and Z2 is CH. In some embodiments, X is C-R1, Y is N, Z1 is C-R5, and Z2 is CH. In some embodiments, X is N, Y is C-R4, Z1 is C-R5, and Z2 is CH. In some embodiments, X is C-R1, Y is C-R4, Z1 is C-R5, and Z2 is N. In some embodiments, X is C-R1, Y is N, Z1 is N, and Z2 is CH. In some embodiments, X is N, Y is C-R4, Z1 is N, and Z2 is CH. In some embodiments, X is N, Y is C-R4, Z1 is N, and Z2 is CH. In some embodiments, X is C-R1, Y is N, Z1 is C-R5, and Z2 is N.

[0179] In some embodiments, Z3, Z4, Z5, Z6, and Z7 are each H. In some embodiments, at most one of Z3, Z4, Z5, Z6, and Z7 is N. In some embodiments, one of Z3, Z4, Z5, Z6, and Z7 is N. In some embodiments, Z3 is N and Z4, Z5, Z6, and Z7 are each H. In some embodiments, Z4 is N and Z3, Z5, Z6, and Z7 are each H. In some embodiments, Z5 is N and Z3, Z4, Z6, and Z7 are each H. In some embodiments, Z6 is N and Z3, Z4, Z4, and Z7 are each H. In some embodiments, Z7 is N and Z3, Z4, Z5, and Z6 are each H. In some embodiments, at most two of Z3, Z4, Z5, Z6, and Z7 are each N. In some embodiments, two of Z3, Z4, Z5, Z6, and Z7 are each N. In some embodiments, Z3 and Z4 are each N. In some embodiments, Z3 and Z5 are each N. In some embodiments, Z3 and Z6 are each N. In some embodiments, Z4 and Z6 are each N. In some embodiments, Z4 and Z7 are each N. In some embodiments, Z5 and Z7 are each N. In some embodiments, Z3 and Z7 are each N. In some embodiments, Z6 and Z7 are each N. In some embodiments, Z5 and Z6 are each N. In some embodiments, Z4 and Z5 are each N.

[0180] In some embodiments, A is —NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2- or S(O)2NR c In some embodiments, A is -NR c C(O)-, -C(O)NR c -, -NR c S(O)2- or S(O)2NR c In some embodiments, A is -NR cC(O)-, -C(O)NR c In some embodiments, A is -NR c C(O)- or NR c In some embodiments, A is -NR c In some embodiments, R c is H, C 1-5 Alkyl, C 3-6 cycloalkyl, or -CH-phenyl. In some embodiments, R c is H or C 1-5 In some embodiments, C is alkyl. 1-5 Alkyl is methyl, ethyl, or isopropyl. 1-5 Alkyl is methyl. In some embodiments, C 3-6 Cycloalkyl is cyclopropyl. In some embodiments, R c is H or methyl. In some embodiments, R c is H.

[0181] In some embodiments, L is absent, alkylene, cycloalkyl, heterocyclyl, or heteroaryl. In some embodiments, L is absent, alkylene, cycloalkyl, or heterocyclyl. In some embodiments, L is absent, alkylene, or heterocyclyl. In some embodiments, L is alkylene or heterocyclyl. In some embodiments, alkylene is C 1-5 In some embodiments, alkylene is C 1-3 In some embodiments, L is alkylene. In some embodiments, the alkylene is methylene. In some embodiments, L is alkylene, and the alkylene is C 1-3 In some embodiments, the alkylene is an optionally substituted methylene. In some embodiments, the alkylene has the following structure:

[0182] [ka] where R e are independently H, F, and C 1-5 alkyl, -CHOH, -CHcycloalkyl, or -CHaryl, or two R e C along with the carbon atoms to which they are attached 3-6 In some embodiments, R e is H or C 1-5 It is alkyl.

[0183] In some embodiments, L comprises a heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl has the following structure:

[0184] [ka] where * represents the point of attachment to A and ** represents the point of attachment to B.

[0185] In some embodiments, B is a bond or —NR b C(O)-, -NR b In some embodiments, B is S(O)2-, -C(O)-, -OC(O)-, -C(O)-O-, or heteroaryl. In some embodiments, B is a bond, -OC(O)-, or -C(O)-. In some embodiments, B is -OC(O)-. In some embodiments, B is -C(O)-. In some embodiments, B is a bond. In some embodiments, B is heteroaryl. In some embodiments, heteroaryl is a 5- or 6-membered nitrogen-containing heteroaryl. In some embodiments, heteroaryl is triazole. In some embodiments, heteroaryl is 1,2,3-triazole or 1,2,4-triazole.

[0186] In some embodiments, L is a linker having the structure -A-L1-B-, where A is -NRc C(O)- or C(O)NR c wherein L1 is absent, alkylene, cycloalkyl, or heterocyclyl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)- or S(O2)NR d - and R c and R d are each independently H, alkyl, cycloalkyl, or alkylene-aryl, with the proviso that -A-L1-B- is -OO, -NR C -O, -O-NR d -, -NR C -NR d - or has no S-S bond. c and R d are each independently H, alkyl, cycloalkyl, alkylene-aryl, acyl, or sulfonyl. c and R d are each independently H or alkyl. In some embodiments, R c and R d are each independently H or C 1-5 In some embodiments, R c and R d are H respectively.

[0187] In some embodiments, L is a linker having the structure -A-L1-B-, where A is -NR c In some embodiments, A is -C(O)-, L is alkylene or heterocyclyl, and B is -C(O)- or -OC(O)-. c C(O)- and L1 is C 1-3 In some embodiments, A is -NR cIn some embodiments, A is -C(O)-, L is methylene or pyrrolidine, and B is -C(O)- or -OC(O)-. c C(O)-, and L1 is methylene or

[0188] [ka] and B is -C(O)- or -OC(O)-. In some embodiments, L is a linker having the structure -A-L1-B-, where A is -NR c C(O)-, L is absent, and B is heteroaryl. In some embodiments, heteroaryl is a 5-membered heteroaryl. In some embodiments, heteroaryl is oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, thiazolyl, or imidazolyl. In some embodiments, heteroaryl has the following structure:

[0189] [ka] It has.

[0190] In some embodiments, -A-L1-B- has the structure:

[0191] [ka] where R c and R d are each independently H, alkyl, cycloalkyl, alkylene-aryl, acyl, or sulfonyl; R e are independently H, F, and C 1-5 alkyl, -CH2 cycloalkyl, or -CH2 aryl, or two R e C along with the carbon atoms to which they are attached 3-6 cycloalkyl or 4- to 6-membered heterocyclyl, and t is 0, 1, or 2. In some embodiments, R cis H or alkyl. In some embodiments, R c is H or C 1-5 In some embodiments, R c is H. In some embodiments, R e are each independently H, F, or C 1-5 In some embodiments, R e are each independently H, F, Me, Et, or iPr. e is H. In some embodiments, t is 1.

[0192] In some embodiments, -A-L1-B- has the structure:

[0193] [ka] In some embodiments, R c is H or alkyl. In some embodiments, R c is H or C 1-5 In some embodiments, R c is H.

[0194] In some embodiments, R1 is alkyl, —CN, —C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -C(O)NR a R a , or -S(O)R a , or -S(O)2OR a In some embodiments, R is alkyl, —C(O)OR a , -C(O)N(R a )(R a ), or -C(O)NHR a In some embodiments, R is —C(O)OR a In some embodiments, each Ra are independently H or C 1-5 alkyl (e.g., methyl, ethyl, or n- or i-propyl, etc.), or two R a The groups together with the nitrogen atom to which they are attached form a heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered nitrogen-containing heterocyclyl. In some embodiments, the heterocyclyl has the following structure:

[0195] [ka] In some embodiments, R a is C 1-5 In some embodiments, R a is methyl, ethyl, or n-propyl or i-propyl. a is ethyl.

[0196] In some embodiments, X is C-R, and R and R c together with the atom to which they are attached form a heterocyclyl or heteroaryl.

[0197] In some embodiments, R4 is H, alkyl, —CN, —C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -C(O)NR a R a , or -S(O)R a , or -S(O)2OR a In some embodiments, R4 is H, alkyl, aryl, -C(O)OR a , or -C(O)NHR a In some embodiments, R4 is H, alkyl, -C(O)OR a , -C(O)N(R a )(R a), or -C(O)NHR a In some embodiments, R4 is H or -C(O)OR a In some embodiments, R4 is H. In some embodiments, R a is C 1-5 alkyl or -CHcycloalkyl. In some embodiments, R a is C 1-5 In some embodiments, R a is methyl, ethyl, or n-propyl or i-propyl. a are independently H or C 1-5 alkyl (e.g., methyl, ethyl, or n- or i-propyl, etc.), or two R a The groups together with the nitrogen atom to which they are attached form a heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered nitrogen-containing heterocyclyl. In some embodiments, the heterocyclyl has the following structure:

[0198] [ka] In some embodiments, R a is C 1-5 In some embodiments, R a is methyl, ethyl, or n-propyl or i-propyl. a is ethyl.

[0199] In some embodiments, R2 is aryl or heteroaryl. In some embodiments, the aryl is phenyl and the heteroaryl is a 6-membered nitrogen-containing heteroaryl. In some embodiments, the aryl is phenyl and the heteroaryl is pyridyl. In some embodiments, R2 is phenyl or naphthyl. In some embodiments, R2 is phenyl. In some embodiments, R2 is

[0200] [ka] where R c are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino (e.g., —NH, —NHCH, —N(CH), etc.), or two R c together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and p is 0, 1, 2, or 3. In some embodiments, R2 is

[0201] [ka] where R c are each independently halogen, alkyl, haloalkyl, -OH, alkoxy, haloalkoxy, or amino.

[0202] [ka] In some embodiments, R2 is a 6-membered nitrogen-containing heteroaryl.

[0203] [ka] where R c are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R c together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and p is 0, 1, or 2. In some embodiments, R2 is

[0204] [ka] where R care each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R c together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and p is 0, 1, or 2. In some embodiments, R c are independently H, F, and C 1-5 Alkyl, -OC 1-5 alkyl, CF, -OCF, or -CN. In some embodiments, R c are each independently H or F. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0205] In some embodiments, R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl. In some embodiments, a cycloalkyl is selected from the group consisting of C 5-7 In some embodiments, cycloalkyl is C 5-6 In some embodiments, cycloalkyl is C 4-6 It is cycloalkyl.

[0206] In some embodiments, when X is C-R1 and Y is C-R4, at least two of R1, R2, and R4 are not H. In some embodiments, R1 and R2 are not H and R4 is H. In some embodiments, when X is C-R1 and Y is C-R4, R1 is -C(O)OR a , -C(O)N(R a )(R a ), or -C(O)NHR a and R2 is optionally substituted phenyl and R4 is H, where R ais as defined herein. In some embodiments, R is —C(O)OR a and R2 is optionally substituted phenyl and R4 is H, where R a is as defined herein. In some embodiments, R is —C(O)OR a and R2 is

[0207] [ka] and R4 is H, where R a is as defined herein. In some embodiments, X and Y are N and R2 is

[0208] [ka] In some embodiments, Z is S. In some embodiments, Z is O. In some embodiments, Z is N-R5.

[0209] In some embodiments, R5 is H, halogen, alkyl, alkylenecycloalkyl, cycloalkyl, aryl, or alkylenearyl. In some embodiments, R5 is H, halogen, alkyl, or alkylenecycloalkyl. In some embodiments, R5 is H, halogen, or alkyl. In some embodiments, R5 is H or halogen. In some embodiments, R5 is H or alkyl. In some embodiments, alkyl is Me, Et, or iPr. In some embodiments, aryl is phenyl. In some embodiments, cycloalkyl is C 3-6 In some embodiments, alkylene is C 1-3 In some embodiments, the alkylene is methylene. In some embodiments, the halogen is F, Cl, or Br. In some embodiments, the halogen is F.

[0210] In some embodiments, R3 is -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or -CN. In some embodiments, R3 is -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b In some embodiments, R3 is -N(H)S(O)2 alkyl, -N(H)S(O)2 cycloalkyl, -S(O)2 NH2, -C(O) alkyl, or -CN. In some embodiments, R3 is -N(H)S(O)2(C 1-5 alkyl), -S(O)N(C 1-5 alkyl)2, -S(O)2N(H)(C 1-5 In some embodiments, R is —N(H)S(O)(C 1-5 In some embodiments, R3 is -N(H)S(O)2CH3, -S(O)2NH2, -C(O)CH3, or -CN. In some embodiments, R3 is -N(H)S(O)2CH3 or -S(O)2NH2.

[0211] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0212] In some embodiments, X is C-R1, Y is C-R4, Z1 is N, Z2 is CH, R2 is aryl, heteroaryl, R3 is -N(H)S(O)2CH3, -S(O)2NH2, -C(O)CH3, or -CN, and L is a linker having the structure -A-L1-B-, where A is -NR c L is alkylene or heterocyclyl, and B is —C(O)— or —OC(O)—, where R 1、 R2 and R4 are as defined above for formula (I). In some embodiments, X is C-R1, Y is C-R4, Z1 is N, Z2 is CH, and R2 is

[0213] [ka] and R3 is -N(H)S(O)2CH3, -S(O)2NH2, -C(O)CH3, or -CN; and L is a linker having the structure -A-L1-B-, where A is -NR c L1 is alkylene or heterocyclyl, and B is -C(O)- or -OC(O)-, where R1, R4, R s and p is as defined above for formula (I). In some embodiments, A is -NR c C(O)- and L1 is C 1-3 In some embodiments, A is -NR c In some embodiments, A is -C(O)-, L is methylene or pyrrolidine, and B is -C(O)- or -OC(O)-. cC(O)-, and L1 is methylene or

[0214] [ka] and B is -C(O)- or -OC(O)-. In some embodiments, X is C-R1, Y is C-R4, Z1 is N, Z2 is CH, R2 is phenyl or 6-membered heteroaryl, R3 is -N(H)S(O)2CH3, -S(O)2NH2, -C(O)CH3, or -CN, and L is a linker having the structure -A-L1-B-, where -A-L1-B- is

[0215] [ka] and R1, R4, R s and p are as defined above for formula (I). In some embodiments, X is C-R1, Y is C-R4, Z1 is N, Z2 is CH, R2 is

[0216] [ka] wherein R3 is —N(H)S(O)2CH3, —S(O)2NH2, —C(O)CH3, or —CN; and L is a linker having the structure —A-L1-B-, where —A-L1-B- is

[0217] [ka] and R1, R4, R s , and p are as defined above for formula (I).

[0218] In some embodiments, the compound of formula (II) has the following structure:

[0219] [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein L, Y, Z2, Z3, Z4, Z5, Z6, Z 7、 R1, R2, R3, and m are as defined above for formula (II).

[0220] In some embodiments, the compound of formula (II) has the following structure:

[0221] [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein L, Z3, Z4, Z5, Z6, Z 7、 R1, R2, R3, and m are as defined above for formula (II).

[0222] In some embodiments, the compound of formula (II) has the following structure:

[0223] [ka] or a pharmaceutically acceptable salt thereof, wherein L, Y, Z2, Z3, Z4, Z5, Z6, Z7, R1, R2, R3, and m are as defined above in formula (II).

[0224] In some embodiments, R 3a are independently F, -OH, and C 1-5 Alkyl, C 1-5 alkoxy, CF, or -OCF. In some embodiments, R 3a are each independently F, —OH, Me, Et, iPr, —OMe, OEt, OiPr, CF, or —OCF. 3a is H.

[0225] In some embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0226] In some embodiments, the compound of formula (II) has the following structure:

[0227] [ka] or a pharmaceutically acceptable salt thereof, where: L, X, Y, Z2, R3, and m are as defined herein; R c are each independently halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, sulfonyl, or two R c together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; p is 0, 1, 2, or 3.

[0228] In some embodiments, the compound of formula (II) has the following structure:

[0229] [ka] or a pharmaceutically acceptable salt thereof, where: L, Y, R, R, and m are as defined herein; R c are each independently halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, sulfonyl, or two R c together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; p is 0, 1, 2, or 3.

[0230] In some embodiments, R c are independently H, F, and C 1-5 Alkyl, -OC 1-5 alkyl, CF, -OCF, or -CN. In some embodiments, R care each independently H or F. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 1 and R c In some embodiments, p is 1 and R c is in meta position.

[0231] In some embodiments, the compound of formula (II) has the following structure:

[0232] [ka] or a pharmaceutically acceptable salt or tautomer thereof.

[0233] In some embodiments, the present disclosure provides a compound having the structure:

[0234] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, L, Y, R, R and p are as defined above in formula (I); M is O or —NH; R p are each independently alkylene-OC(O)-alkyl, -alkylene-OC(O)-Oalkyl, -alkylene-C(O)-Oalkyl, or aryl, or two R p together with the atoms to which they are attached form a heterocyclyl ring.

[0235] In some embodiments, R p are each independently alkylene-OC(O)-alkyl, -alkylene-OC(O)-Oalkyl, -alkylene-C(O)-Oalkyl, or aryl, where alkylene is C 1-3Alkylene, alkyl is C 1-5 In some embodiments, alkylene is -CH(Me)-. In some embodiments, C 1-5 Alkyl is methyl, ethyl, isopropyl, or tert-butyl. In some embodiments, R p are each independently CH2-OC(O)-alkyl, -CH2-OC(O)-Oalkyl, -CH2-C(O)-Oalkyl, or phenyl. p are each independently CH2-OC(O)-C 1-5 Alkyl, -CH(Me)-OC(O)-C 1-5 Alkyl, -CH2-OC(O)-O(C 1-5 alkyl), -CH(Me)OC(O)-O(C 1-5 alkyl), -CH2-C(O)-O(C 1-5 alkyl), -CH(Me)-C(O)-O(C 1-5 alkyl), or phenyl. In some embodiments, R p are each independently CH2-OC(O)-C 1-5 Alkyl, -CH2-OC(O)-O(C 1-5 alkyl), -CH2-C(O)-O(C 1-5 alkyl), or phenyl. In some embodiments, C 1-5 Alkyl is methyl, ethyl, isopropyl, or tert-butyl. 1-5 Alkyl is isopropyl or tert-butyl.

[0236] In some embodiments, two R p together with the atom to which they are attached form a 5- to 10-membered heterocyclyl ring. In some embodiments, the heterocyclyl ring contains a disulfide bond. In some embodiments, the heterocyclyl ring has the structure

[0237] [ka] It has.

[0238] In some embodiments, M is O. In some embodiments, M is —NH.

[0239] In some embodiments, the compound of formula (III) has the structure:

[0240] [ka] It has.

[0241] In some embodiments, the present disclosure provides a compound having the structure:

[0242] [ka] or a pharmaceutically acceptable salt thereof, where:

[0243] [ka] teeth

[0244] [ka] and

[0245] [ka] is aryl, heteroaryl, cycloalkyl, or heterocyclyl; L is a linker having the structure -A-L1-B-, where A, L1, B, R1, R2, R3, R4, and m are as defined above for Formula (I) and Formula (II); wherein at least one of R1, R2, and R4 is not H.

[0246] In some embodiments,

[0247] [ka] teeth

[0248] [ka] where * represents the point of attachment to L and ** represents the point of attachment to one or more R3.

[0249] [ka] teeth

[0250] [ka] In some embodiments,

[0251] [ka] teeth

[0252] [ka] is.

[0253] In some embodiments, the compounds disclosed herein have the following structure:

[0254] [ka] TIFF2025538892000104.tif236170TIFF2025538892000105.tif241170TIFF2025538892000106.tif238170TIFF2025538892000107.tif243170TIFF2025538892000108.tif233170TIFF2025538892000109.tif212170TIFF2025538892000110.tif220170TIFF2025538892000111.tif253170TIFF2025538892000112.tif230170TIFF2025538892000113.tif248170TIFF2025538892000114.tif217170TIFF2025538892000115.tif253170TIFF2025538892000116.tif253170TIFF2025538892000117.tif217170TIFF2025538892000118.tif253170TIFF2025538892000119.tif233170TIFF2025538892000120.tif233170TIFF2025538892000121.tif246170TIFF2025538892000122.tif209170TIFF2025538892000123.tif243170TIFF2025538892000124.tif251170TIFF2025538892000125.tif253170TIFF2025538892000126.tif220170TIFF2025538892000127.tif217170TIFF2025538892000128.tif251170TIFF2025538892000129.tif253170TIFF2025538892000130.tif253170TIFF2025538892000131.tif248170TIFF2025538892000132.tif248170TIFF2025538892000133.tif255170TIFF2025538892000134.tif217170TIFF2025538892000135.tif248170TIFF2025538892000136.tif248170TIFF2025538892000137.tif253170TIFF2025538892000138.tif217170TIFF2025538892000139.tif253170TIFF2025538892000140.tif217170TIFF2025538892000141.tif248170TIFF2025538892000142.tif217170TIFF2025538892000143.tif43170 and one of their pharmaceutically acceptable salts or tautomers.

[0255] In some embodiments, the compound of the present disclosure is a compound provided in Table 1, or a pharmaceutically acceptable salt or tautomer thereof.

[0256] In some embodiments, the compound of the present disclosure is a compound provided in Table 2, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound of the present disclosure is a compound provided in Table 2, or a pharmaceutically acceptable salt or tautomer thereof, that has "A" activity.

[0257] Compounds described herein of Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B1a), Formula (II), Formula (II-A), Formula (II-A1), Formula (II-A2), Formula (II-B), Formula (II-B1), and Formula (A) 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 shown herein.

[0258] Pharmaceutical Composition In some embodiments, the present disclosure provides pharmaceutical compositions comprising (i) an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof, and (ii) one or more pharmaceutically acceptable carriers or excipients.

[0259] In some embodiments, the present disclosure provides pharmaceutical compositions comprising (i) a compound disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof, (ii) an immune checkpoint inhibitor (ICI), and (iii) one or more pharmaceutically acceptable carriers or excipients.

[0260] In various embodiments, the pharmaceutical compositions of the present disclosure can be formulated for administration by various means, including oral, parenteral, by inhalation spray, topical, or rectal, in formulations containing pharmaceutically acceptable carriers, adjuvants, and solvents. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, and intraarterial injections with various infusion techniques. As used herein, intraarterial and intravenous injections include administration via a catheter.

[0261] An effective amount of a compound of the present disclosure, including its pharmaceutically acceptable salts, esters, prodrugs, hydrates, solvates, and isomers, or a pharmaceutical composition thereof, can be determined by one of skill in the art based on known methods.

[0262] In one embodiment, the pharmaceutical composition or formulation comprises a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, and / or excipient, including, but not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0263] In one embodiment, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, about 0.01 to about 0.1 M, for example, 0.05 M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents suitable for use herein include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.

[0264] Aqueous carriers suitable for use herein include, but are not limited to, water, ethanol, alcoholic / aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets, and the like.

[0265] Liquid carriers suitable for use herein 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 of both, or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavorings, suspending agents, thickeners, colorants, viscosity regulators, stabilizers, or osmotic pressure regulators.

[0266] Liquid carriers suitable for use herein include, but are not limited to, water (e.g., partially containing the above-mentioned additives, such as cellulose derivatives, e.g., sodium carboxymethylcellulose solution), alcohols and their derivatives (including monohydric and polyhydric alcohols, e.g., glycols), and oils (e.g., fractionated coconut oil and peanut oil). For parenteral administration, carriers may also include oily esters such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid forms containing compounds for parenteral administration. Liquid carriers for pressurized compounds disclosed herein may be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

[0267] Solid carriers suitable for use herein include, but are not limited to, inert substances such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, and mannitol. Solid carriers may further comprise one or more substances that act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, or tablet disintegrants, and may also be encapsulating materials. In powders, the carrier may be a finely divided solid mixed with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compressed into the desired shape and size. Powders and tablets contain, for example, up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone, low-melting waxes, and ion exchange resins. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropyl methylcellulose, etc.), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose, etc.), surfactant, or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets can optionally be coated or scored and can be formulated to provide slow or controlled release of the active ingredient therein, using, for example, hydroxypropyl methylcellulose in various proportions to provide the desired release profile. Tablets can optionally be provided with an enteric coating to provide release in parts of the intestine other than the stomach.

[0268] Parenteral carriers suitable for use herein include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, and fixed oils. Intravenous carriers 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, for example, antimicrobials, antioxidants, chelating agents, and inert gases.

[0269] Carriers suitable for use herein can be mixed, as needed, with disintegrants, diluents, granulating agents, lubricants, binders, etc., using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.

[0270] Diluents may be added to the formulations of the present invention. Diluents can increase the bulk of solid pharmaceutical compositions and / or combinations, making pharmaceutical dosage forms containing the compositions and / or combinations easier for patients and caregivers to handle. Diluents for solid compositions and / or combinations include, for example, microcrystalline cellulose (e.g., AVICEL, etc.), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGITI, etc.), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0271] The pharmaceutical compositions of the present invention can be prepared into any type of formulation and drug delivery system by using any conventional method well known in the art. The pharmaceutical compositions of the present invention can be formulated into injectable preparations, which can be administered by routes including intrathecal, intracerebroventricular, intravenous, intraperitoneal, intranasal, intraocular, intramuscular, subcutaneous, or intraosseous. They can also be administered orally or parenterally via the rectal, intestinal, or nasal mucosa (see Gennaro, AR, ed. (1995) Remington's Pharmaceutical Sciences). In certain embodiments, the compositions are administered topically rather than enterally. For example, the compositions can be injected or delivered via a targeted drug delivery system such as a depot or sustained-release formulation.

[0272] The pharmaceutical formulations of the present invention can be prepared by any method well known in the art, such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. As mentioned above, the compositions of the present invention may include one or more physiologically acceptable carriers, such as excipients and adjuvants, which facilitate processing of the active molecules into formulations for pharmaceutical use.

[0273] The appropriate formulation depends on the route of administration chosen. For injection, for example, the compositions can be formulated in aqueous solutions, such as Hank's solution, Ringer's solution, or physiologically compatible buffers such as physiological saline buffer. For transmucosal or nasal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. In one embodiment of the present invention, the compounds of the present invention can be prepared in oral formulations. For oral administration, the compounds can be readily formulated by combining the active compound with pharmaceutically acceptable carriers known in the art. Such carriers allow the disclosed compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject. The compounds can also be formulated in rectal compositions, such as suppositories or retention enemas, containing conventional suppository bases, such as cocoa butter or other glycerides.

[0274] Pharmaceutical preparations for oral use can be prepared as solid excipients, optionally with the addition of suitable adjuvants, followed by grinding the resulting mixture and processing the granulated mixture to obtain tablets or dragee cores, as desired. Suitable excipients can be, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or cellulose preparations, such as polyvinylpyrrolidone (PVP) preparations. Disintegrants, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can also be used. Wetting agents, such as sodium dodecyl sulfate, can also be added.

[0275] The dragee core is provided with a suitable coating.For this purpose, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and concentrated sugar solution, which may optionally contain suitable organic solvent or solvent mixture, can be used.For identification or to characterize different combinations of dosages of active compound, dyes or pigments can be added to the tablet or dragee coating.

[0276] Treatment method The present disclosure provides compounds and compositions useful for treating cancer and other conditions associated with abnormal ADAR1 expression levels. In some embodiments, cancer and other conditions are associated with increased ADAR1 expression. In some embodiments, the compounds disclosed herein are selective inhibitors of ADAR1. In some embodiments, the compounds disclosed herein are selective inhibitors of ADAR1p150.

[0277] In some embodiments, the method is useful for treating a disorder of uncontrolled cell proliferation in a subject in need of treatment, the method comprising administering to the subject a therapeutic amount of a compound disclosed herein, e.g., a compound of Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B1a), Formula (II), Formula (II-A), Formula (II-A1), Formula (II-A2), Formula (II-B), Formula (II-B1), or Formula (A), a pharmaceutically acceptable salt or tautomer thereof, or a composition thereof. In some embodiments, the disorder of uncontrolled cell proliferation is cancer or a tumor. In some embodiments, the disorder or uncontrolled cell proliferation is associated with elevated ADAR1 expression levels. In some embodiments, the disorder or uncontrolled cell proliferation is associated with elevated levels of the ADAR1 p150 isoform.

[0278] In some embodiments, the disclosure provides a method of treating cancer in a subject, the subject being in need of treatment, the method comprising administering to the subject an effective amount of a compound disclosed herein (e.g., a compound of Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B1a), Formula (II), Formula (II-A), Formula (II-A1), Formula (II-A2), Formula (II-B), Formula (II-B1), or Formula (A)), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition thereof).

[0279] In some embodiments, the disclosure provides a method of treating cancer in a subject, the subject being in need of treatment, the method comprising administering to the subject (i) a compound disclosed herein (e.g., a compound of Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B1a), Formula (II), Formula (II-A), Formula (II-A1), Formula (II-A2), Formula (II-B), Formula (II-B1), or Formula (A)), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition thereof, and (ii) an immune checkpoint inhibitor, in amounts effective to treat the subject.

[0280] In some embodiments, the method comprises administering to a subject a compound of Table 2. In some embodiments, the method comprises administering to a subject a compound of Table 2 that has "A" activity.

[0281] In some embodiments, the method further includes administering to the subject an immune checkpoint inhibitor in combination with a compound of the present disclosure (e.g., a compound of Formula (I), Formula (IA), Formula (I-A1), Formula (I-A2), Formula (I-A3), Formula (I-A4), Formula (IB), Formula (I-B1), Formula (I-B1a), Formula (II), Formula (II-A), Formula (II-A1), Formula (II-A2), Formula (II-B), Formula (II-B1), or Formula (A)). In some embodiments, the immune checkpoint inhibitor is an anti-programmed cell death protein-1 (anti-PD-1) or anti-programmed cell death protein-1 / ligand-1 (anti-PD-L1) antibody. In some embodiments, the anti-PD-1 antibody is pembrolizumab, nivolumab, cemiplimab, dostallimab, or retifanlimab. In some embodiments, the anti-PD-L1 antibody is durvalumab, atezolizumab, or avelumab.

[0282] In some embodiments of the method, administering a compound disclosed herein and an immune checkpoint inhibitor provides a synergistic effect in the treatment of cancer.

[0283] In some embodiments, the cancer is a cancer characterized by overexpression of ADAR1 relative to normal cells, hi some embodiments, the cancer is breast cancer, lung cancer, pancreatic cancer, melanoma, multiple myeloma, colon cancer, colorectal cancer, or glioblastoma.

[0284] The present disclosure further provides a method of treating an RNA virus infection in a subject, wherein the subject is in need of treatment, the method comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical composition thereof.

[0285] In some embodiments, the RNA viral infection is HIV-1, HTLV-1, or SARS-CoV-2.

[0286] Numbered Embodiments 1. The following structure

[0287] [ka] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, L is a linker having the structure -A-L1-B-; where: A is -NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2- or S(O)2NR c - and L1 is absent, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-,

[0288] [ka] -OC(CF3)-, -O-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)-, -S(O2)NR d - or heteroaryl, R c and R d are each independently H, alkyl, cycloalkyl, heterocyclyl, alkylene-aryl, acyl, or sulfonyl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, -NR c -NR d - or S-S bond is not present, X is C-R1 or N; Y is C-R4 or N; Z is O, S, N—R, or N(R)—CH—; Z3, Z4, Z5, Z6, and Z7 are each independently N or CH, where at most two of Z3, Z4, Z5, Z6, and Z7 are N; R1 is H, halogen, alkyl, -CN, -C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -C(O)NR a R a , or -S(O)2R a , or -S(O)2OR a or R and R c together with the atom to which they are attached form a heterocyclyl or heteroaryl; R2 is H, halogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl; R3 independently represents halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, or -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b , -CN, or -P(O)(OR b )2, or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl; R4 is H, halogen, alkyl, -C(O)OR a , -C(O)NHR aor aryl, or R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R5 is H, alkyl, alkylenecycloalkyl, cycloalkyl, aryl, alkylenearyl, or heteroaryl, or R2 and R5 together with the adjacent carbon atoms to which they are attached form an aryl or heteroaryl; R a are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, aryl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl, or two R a groups together with the nitrogen atom to which they are attached form a heterocyclyl; R b is H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or aryl, or two R b groups together with the nitrogen atom to which they are attached form a heterocyclyl; m is 0, 1, 2, or 3; wherein the compound is

[0289] [ka] Not a compound. 2. The compound of embodiment 1, wherein at least two of R1, R2, and R4 are not H. 3. The compound of embodiment 1 or 2, wherein at most one of Z3, Z4, Z5, Z6, and Z7 is N. 4. The compound of embodiment 1 or 2, wherein Z3, Z4, Z5, Z6, and Z7 are each H. 5. The following structure

[0290] [ka] or a pharmaceutically acceptable salt or tautomer thereof. 6. The compound has the following structure:

[0291] [ka] or a pharmaceutically acceptable salt thereof. 7. The compound has the following structure:

[0292] [ka] or a pharmaceutically acceptable salt thereof. 8. The compound has the following structure:

[0293] [ka] or a pharmaceutically acceptable salt thereof, where: R 3a are each independently halogen, —OH, alkyl, haloalkyl, alkoxy, or haloalkoxy; The compound of any of embodiments 1 to 7, wherein q is 0, 1, or 2. 9. L is a linker having the structure -A-L1-B-, where: A is -NR c C(O)- or -C(O)NR c and L1 is absent, alkylene, cycloalkyl, or heterocyclyl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)- or S(O2)NR d - and R c and R dare each independently H, alkyl, cycloalkyl, or alkylene-aryl; However, -A-L1-B- is -OO, -NR C -O, -O-NR d -, -NR C -NR d The compound of any of embodiments 1 to 8, wherein the compound has no - or S—S bonds. 10. A is -NR c C(O)-, -C(O)NR c 10. The compound of any one of embodiments 1 to 9, wherein: 11. A is -NR c The compound of any one of embodiments 1 to 10, wherein C(O)—. 12. R c is H, C 1-5 Alkyl, C 3-6 The compound of any one of embodiments 1 to 11, wherein the compound is cycloalkyl, or -CH2-phenyl. 13. The compound of any of embodiments 1 to 12, wherein L1 is absent, alkylene, or heterocyclyl. 14. L1 is alkylene, and the alkylene is C 1-3 The compound of any one of embodiments 1 to 13, wherein the compound is alkylene. 15. The compound of any one of embodiments 1 to 14, wherein the alkylene of L1 is optionally substituted methylene. 16. The alkylene of L1 has the following structure:

[0294] [ka] where R e are independently H, F, and C 1-5 alkyl, -CHOH, -CHcycloalkyl, or -CHaryl, or two R e C along with the carbon atoms to which they are attached 3-6 The compound of any one of embodiments 1 to 15, which forms a cycloalkyl or a 4- to 6-membered heterocyclyl. 17. R e is H or C 1-5 The compound of embodiment 16, wherein the aryl is alkyl. 18. The compound of any one of embodiments 1 to 13, wherein L1 is heterocyclyl. 19. The compound according to any one of embodiments 1 to 13 and 18, wherein the heterocyclyl of L1 is a 3- to 12-membered heterocyclyl. 20. The heterocyclyl of L1 has the following structure:

[0295] [ka] wherein * represents the point of attachment to A and ** represents the point of attachment to B. 21. B is a bond or -NR b C(O)-, -NR b The compound of any of embodiments 1 to 20, wherein the compound is —S(O)2—, —C(O)—, —OC(O)—, —C(O)—O—, or heteroaryl. 22. The compound of any of embodiments 1 to 21, wherein B is a bond, -OC(O)-, or -C(O)-. 23. The compound of embodiment 21, wherein the heteroaryl is a 5- or 6-membered nitrogen-containing heteroaryl. 24. -A-L1-B- has the following structure

[0296] [ka] and where: R c and R d are each independently H, alkyl, cycloalkyl, alkylene-aryl, acyl, or sulfonyl; R e are independently H, F, and C 1-5 alkyl, -CH2 cycloalkyl, or -CH2 aryl, or two R eC along with the carbon atoms to which they are attached 3-6 forming a cycloalkyl or a 4- to 6-membered heterocyclyl, 23. The compound of any of embodiments 1 to 22, wherein t is 0, 1, or 2. 25. A-L1-B has the following structure

[0297] [ka] 25. The compound of any of embodiments 1 to 24, having the following structure: 26. R c The compound of embodiment 24 or 25, wherein 27. A compound according to any one of embodiments 1 to 26, wherein X is C-R1. 28. R1 is halogen, alkyl, -C(O)OR a , or -C(O)NHR a 28. The compound of any of embodiments 1 to 27, wherein: 29. R1 is -C(O)OR a 29. The compound of any of embodiments 1 to 28, wherein: 30. The compound of any of embodiments 1-26, wherein X is N. 31. The compound of any one of embodiments 1 to 30, wherein Y is C-R4. 32. R4 is H, alkyl, aryl, or -C(O)OR a , or -C(O)NHR a 32. The compound of any of embodiments 1-31, wherein: 33. The compound of any of embodiments 1-32, wherein R4 is H. 34. R a is C 1-5 The compound of any of embodiments 1 to 33, wherein the aryl is alkyl or -CH2cycloalkyl. 35. R a is C 1-5 The compound of any one of embodiments 1 to 34, wherein is alkyl. 36. R aThe compound of any of embodiments 1-35, wherein is methyl, ethyl, or n-propyl or i-propyl. 37. The compound of any of embodiments 1-36, wherein R2 is aryl or heteroaryl. 38. A compound according to any one of embodiments 1 to 37, wherein R2 is phenyl or naphthyl. 39. R2 is

[0298] [ka] where R s are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R s The compound of any of embodiments 1 to 38, wherein together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and p is 0, 1, 2, or 3. 40. R2 is

[0299] [ka] 40. The compound of any of embodiments 1-39, wherein: 41. The compound of any of embodiments 1-37, wherein R2 is a 5- or 6-membered nitrogen-containing heteroaryl. 42. R2 is

[0300] [ka] where R s are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R s Compounds according to any of embodiments 1 to 37 and 41, wherein together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and p is 0, 1, or 2. 43. A compound according to any one of embodiments 1 to 31, wherein R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl. 44. The compound according to embodiment 43, wherein R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl. 45. Cycloalkyl is C 4-6 The compound of embodiment 43 or 44, which is cycloalkyl. 46. ​​The following structure

[0301] [ka] or a pharmaceutically acceptable salt thereof, where: R c are each independently halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, sulfonyl, or two R c together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; The compound of any of embodiments 1 to 40, wherein p is 0, 1, 2, or 3. 47. The following structure

[0302] [ka] or a pharmaceutically acceptable salt thereof, where: A is -NR a C(O)-, -C(O)NR a -, -NR a S(O)2- or -S(O)2NR a - and B is -NR d -, -NR d C(O)-, -OC(O)-, -C(O)-alkylene-, -C(O), -NR d S(O2)- or S(O2)NR d - and L1 is a bond or C 1-5 Alkylene, C 1-5 Alkenylene, C 1-5 47. The compound of any of embodiments 1 through 40 and 46, wherein alkynylene, or heterocyclyl, each of which is optionally substituted. 48. R3 is -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or —CN. 49. The compound of any of embodiments 1-48, wherein R3 is —N(H)S(O)2 alkyl, —N(H)S(O)2 cycloalkyl, —S(O)2 NH2, —C(O)alkyl, or —CN. 50. R3 is -N(H)S(O)2CH 3、 The compound of any of embodiments 1 to 49, wherein the compound is -S(O)2NH2, -C(O)CH3, or -CN. 51. The following structure

[0303] [ka] 51. The compound of any of embodiments 1 to 40 and 46 to 50, having TIFF2025538892000161.tif121170 or a pharmaceutically acceptable salt or tautomer thereof. 52. The following structure

[0304] [ka] or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, L is a linker having the structure -A-L1-B-; where: A is -NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2- or -S(O)2NR c - and L1 is absent, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-,

[0305] [ka] -OC(CF3)-, -O-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)-, -S(O2)NR d - or heteroaryl, R c and R d are each independently H, alkyl, cycloalkyl, heterocyclyl, alkylene-aryl, acyl, or sulfonyl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, -NR c -NR d - or S-S bond is not present, X is C-R1, Y is C-R4 or N; Z1 is N or C-R5; Z2 is N or CH; Z3, Z4, Z5, Z6, and Z7 are each independently N or CH, and at most two of Y, Z1, and Z2 are N, and at most two of Z3, Z4, Z5, Z6, and Z7 are N; R1 is H, halogen, alkyl, -CN, -C(O)R a, -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)N(R a )(R a ), -C(O)NR a R a , -NR a R a , or -S(O)2R a , or -S(O)2OR a or R and R c together with the atom to which they are attached form a heterocyclyl or heteroaryl; R2 is H, halogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl; R3 independently represents halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, or -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or -CN, or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl; R4 is H, halogen, alkyl, -C(O)OR a , -C(O)NHR a or aryl, or R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R5 is H, halogen, alkyl, alkoxy, alkylenecycloalkyl, cycloalkyl, aryl, or heteroaryl, or R2 and R5 together with the adjacent carbon atoms to which they are attached form an aryl or heteroaryl; R a are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, aryl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl, or two R a groups together with the nitrogen atom to which they are attached form a heterocyclyl; R b is H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or aryl, or two R b groups together with the nitrogen atom to which they are attached form a heterocyclyl; m is 0, 1, 2, or 3; wherein at least one of R1, R2, and R4 is not H. 53. The following structure

[0306] [ka] or a pharmaceutically acceptable salt or tautomer thereof. 54. The following structure

[0307] [ka] 54. The compound of embodiment 52 or 53, wherein: 55. The following structure

[0308] [ka] 54. The compound of embodiment 52 or 53, wherein: 56. L is a linker having the structure -A-L1-B-, where: A is -NR c C(O)- or -C(O)NR c and L1 is absent, alkylene, cycloalkyl, or heterocyclyl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)- or -S(O2)NR d - and R c and R d are each independently H, alkyl, cycloalkyl, or alkylene-aryl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, -NR c -NR d 56. The compound of any of embodiments 52 to 55, wherein the compound has no - or S—S bonds. 57. A is -NR c C(O)-, -C(O)NR c 57. The compound of any of embodiments 52-56, wherein: 58. A is -NR c The compound of any of embodiments 52 to 57, wherein C(O)—. 59. R c is H, C 1-5 Alkyl, C 3-6 The compound of any of embodiments 52 to 58, wherein the compound is cycloalkyl, or -CH2-phenyl. 60. A compound according to any of embodiments 52-59, wherein L1 is absent, alkylene, or heterocyclyl. 61. L1 is alkylene, and the alkylene is C 1-3 The compound of any of embodiments 52 to 60, wherein the compound is alkylene. 62. The compound of any one of embodiments 52 to 61, wherein the alkylene of L1 is optionally substituted methylene. 63. The alkylene in L1 has the following structure:

[0309] [ka] where R e are independently H, F, and C 1-5 alkyl, -CHOH, -CHcycloalkyl, or -CHaryl, or two R e C along with the carbon atoms to which they are attached 3-6 The compound of any of embodiments 52 to 62, wherein the compound forms a cycloalkyl or a 4- to 6-membered heterocyclyl. 64. R e is H or C 1-5 The compound of embodiment 63, wherein R is alkyl. 65. The compound of any of embodiments 52-60, wherein L1 is heterocyclyl. 66. The compound according to any one of embodiments 52 to 60 and 65, wherein the heterocyclyl of L1 is a 3- to 12-membered heterocyclyl. 67. The heterocyclyl of L1 has the following structure:

[0310] [ka] 67. The compound of any of embodiments 52 to 60, 65, and 66, having the formula: 68. B is a bond or -NR b C(O)-, -NR b The compound of any of embodiments 52 to 67, wherein the compound is —S(O)2—, —C(O)—, —OC(O)—, —C(O)—O—, or heteroaryl. 69. The compound of any of embodiments 52-68, wherein B is a bond, —OC(O)—, or —C(O)—. 70. The compound of embodiment 68, wherein heteroaryl is a 5- or 6-membered nitrogen-containing heteroaryl. 71. -A-L1-B- has the following structure:

[0311] [ka] and where: R c and R d are each independently H, alkyl, cycloalkyl, alkylene-aryl, acyl, or sulfonyl; R e are independently H, F, and C 1-5 alkyl, -CH2 cycloalkyl, or -CH2 aryl, or two R e C along with the carbon atoms to which they are attached 3-6 forming a cycloalkyl or a 4- to 6-membered heterocyclyl, The compound of any of embodiments 52-70, wherein t is 1 or 2. 72. A-L1-B has the following structure

[0312] [ka] 72. The compound of any of embodiments 52 to 71, having the following structure: 73. R c The compound of embodiment 71 or 72, wherein 74. The compound of any of embodiments 52-73, wherein X is C-R1. 75. R1 is H, halogen, alkyl, -C(O)OR a , or -C(O)NHR a 75. The compound of any of embodiments 52 to 74, wherein 76. R1 is halogen, alkyl, -C(O)OR a , or -C(O)NHR a 76. The compound of any of embodiments 52 to 75, wherein 77. R1 is -C(O)ORa 77. The compound of any of embodiments 52 to 76, wherein: 78. The compound of any of embodiments 52-77, wherein Y is C-R4. 79. R4 is H, alkyl, aryl, -C(O)OR a , or -C(O)NHR a The compound of any of embodiments 52 to 78, wherein 80. A compound according to any one of embodiments 52 to 79, wherein R4 is H. 81. R a is C 1-5 The compound of any of embodiments 52 to 80, wherein is alkyl or -CH2cycloalkyl. 82. R a is C 1-5 The compound of any of embodiments 52 to 81, wherein is alkyl. 83. R a The compound of any of embodiments 52-82, wherein is methyl, ethyl, or n-propyl or i-propyl. 84. The compound of any of embodiments 52-83, wherein R2 is aryl or heteroaryl. 85. A compound according to any of embodiments 52-84, wherein R2 is phenyl or naphthyl. 86. R2 is

[0313] [ka] where R s are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R s Compounds according to any of embodiments 52 to 85, wherein together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and p is 0, 1, 2, or 3. 87. R2 is

[0314] [ka] 87. The compound of any of embodiments 52-86, wherein 88. The compound according to any of embodiments 52-84, wherein R2 is a 5- or 6-membered nitrogen-containing heteroaryl. 89. R2 is

[0315] [ka] where R s are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R s Compounds according to any of embodiments 52 through 84 and 88, wherein together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and p is 0, 1, or 2. 90. A compound according to any of embodiments 52-78, wherein R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl. 91. The compound according to embodiment 90, wherein R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl. 92. Cycloalkyl is C 4-6 The compound of embodiment 90 or 91, which is cycloalkyl. 93. R3 is -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or —CN. 94. The compound of any of embodiments 52-93, wherein R3 is —N(H)S(O)2 alkyl, —N(H)S(O)2 cycloalkyl, —S(O)2NH2, —C(O)alkyl, or —CN. 95. R3 is -N(H)S(O)2CH 3、 The compound of any of embodiments 1 to 94, wherein the compound is -S(O)2NH2, -C(O)CH3, or -CN. 96. The compound has the following structure:

[0316] [ka] or a pharmaceutically acceptable salt thereof. 97. A pharmaceutical composition comprising one or more of: (i) a compound according to any one of embodiments 1 to 96; and (ii) a pharmaceutically acceptable carrier or excipient. 98. A method for treating cancer in a subject, wherein the subject is in need of treatment, the method comprising administering to the subject an effective amount of a compound described in any of embodiments 1 to 96 or a pharmaceutical composition described in embodiment 97. 99. The method of embodiment 98, wherein the cancer is breast cancer, lung cancer, pancreatic cancer, melanoma, multiple myeloma, colon cancer, colorectal cancer, or glioblastoma. 100. The method of embodiment 98 or 99, further comprising administering an anti-PD-1 antibody. 101. The method of embodiment 100, wherein administering the compound and the anti-PD-1 antibody to the subject results in a synergistic effect in the treatment of cancer. 102. The following structure

[0317] [ka] or a pharmaceutically acceptable salt thereof, During the ceremony,

[0318] [ka] teeth

[0319] [ka] and

[0320] [ka] is aryl, heteroaryl, cycloalkyl, or heterocyclyl; L is a linker having the structure -A-L1-B-; where: A is -NR c -, -NR c C(O)-, -C(O)NR c -, -NR c S(O)2- or S(O)2NR c - and L1 is absent, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-,

[0321] [ka] -OC(CF3)-, -O-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)-, -S(O2)NR d - or heteroaryl, R c and R d are each independently H, alkyl, cycloalkyl, heterocyclyl, alkylene-aryl, acyl, or sulfonyl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, -NR c -NR d - or S-S bond is not present, R1 is H, halogen, alkyl, -CN, -C(O)R a , -C(O)OR a , -C(O)NHR a , -C(O)N(alkyl)(R a ), -C(O)NR a R a , -NR a R a , or -S(O)2R a , or -S(O)2OR a or R and R c together with the atom to which they are attached form a heterocyclyl or heteroaryl; R2 is H, halogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl; R3 independently represents halogen, -OH, -CH2OH, alkyl, haloalkyl, alkoxy, haloalkoxy, or -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or -CN, or two R3 together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl; R4 is H, halogen, alkyl, -C(O)OR a , -C(O)NHR a or aryl, or R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R aare each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, aryl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl, or two R a groups together with the nitrogen atom to which they are attached form a heterocyclyl; R b is H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or aryl, or two R b groups together with the nitrogen atom to which they are attached form a heterocyclyl; m is 0, 1, 2, or 3; wherein at least one of R1, R2, and R4 is not H.

[0322] 103.

[0323] [ka] teeth

[0324] [ka] wherein * represents a point of attachment to L and ** represents a point of attachment to one or more R3. 104. The compound according to embodiments 102 and 103, wherein at least two of R1, R2, and R4 are not H. 105. L is a linker having the structure -A-L1-B-, where: A is -NR c C(O)- or -C(O)NR c and L1 is absent, alkylene, cycloalkyl, or heterocyclyl; B is a bond or -NR d -, -N(S(O)2-alkyl)-, -NR d C(O)-, -OC(O)-, -C(O)-alkylene-, -C(O)-, -NR d S(O2)- or -S(O2)NRd - and R c and R d are each independently H, alkyl, cycloalkyl, or alkylene-aryl; However, -A-L1-B- is -OO, -NR c -O, -O-NR d -, -NR c -NR d The compound of any of embodiments 102 to 104, wherein the compound has no - or S—S bonds. 106. A is -NR c C(O)-, -C(O)NR c 106. The compound of any of embodiments 102 to 105, wherein: 107. A is -NR c The compound of any of embodiments 102 to 106, wherein C(O)—. 108. R c is H, C 102-5 Alkyl, C 3-6 The compound of any of embodiments 102 to 107, wherein the compound is cycloalkyl, or -CH2-phenyl. 109. A compound according to any one of embodiments 102 to 108, wherein L1 is absent, alkylene, or heterocyclyl. 110. L1 is alkylene, and the alkylene is C 102-3 110. The compound of any one of embodiments 102 to 109, wherein the compound is alkylene. 111. The compound of any of embodiments 102 to 110, wherein the alkylene of L1 is optionally substituted methylene. 112. The alkylene in L1 has the following structure:

[0325] [ka] where R e are independently H, F, and C 102-5 alkyl, -CHOH, -CHcycloalkyl, or -CHaryl, or two R eC along with the carbon atoms to which they are attached 3-6 The compound according to any of embodiments 102 to 111, wherein the compound forms a cycloalkyl or a 4- to 6-membered heterocyclyl. 113. R e is H or C 102-5 The compound of embodiment 16, wherein the aryl is alkyl. 114. The compound according to any of embodiments 102-109, wherein L1 is 3- to 12-membered heterocyclyl. 115. The heterocyclyl of L1 has the following structure:

[0326] [ka] 115. The compound according to any of embodiments 102 to 109 and 114, having the formula: 116. B is a bond or -NR b C(O)-, -NR b The compound of any of embodiments 102 to 115, wherein the compound is —S(O)2—, —C(O)—, —OC(O)—, —C(O)—O—, or heteroaryl. 117. The compound according to any of embodiments 102-116, wherein B is a bond, —OC(O)—, or —C(O)—. 118. The compound according to embodiment 116, wherein heteroaryl is a 5- or 6-membered nitrogen-containing heteroaryl. 119. -A-L1-B- has the following structure:

[0327] [ka] and where: R c and R d are each independently H, alkyl, cycloalkyl, alkylene-aryl, acyl, or sulfonyl; R e are independently H, F, and C 102-5alkyl, -CH2 cycloalkyl, or -CH2 aryl, or two R e C along with the carbon atoms to which they are attached 3-6 forming a cycloalkyl or a 4- to 6-membered heterocyclyl, The compound of any of embodiments 102-117, wherein t is 1 or 2. 120. A-L1-B has the following structure

[0328] [ka] 120. The compound of any of embodiments 102 to 119, having the following structure: 121. R c The compound of embodiment 119 or 120, wherein 122. R1 is halogen, alkyl, -C(O)OR a , or -C(O)NHR a 122. The compound of any of embodiments 102 to 121, wherein 123. R1 is -C(O)OR a 123. The compound of any of embodiments 102 to 122, wherein 124. R4 is H, alkyl, aryl, -C(O)OR a , or -C(O)NHR a 124. The compound of any of embodiments 102 to 123, wherein 125. A compound according to any one of embodiments 102 to 124, wherein R4 is H. 126. R a is C 1-5 The compound of any of embodiments 102 to 125, wherein is alkyl or -CH2cycloalkyl. 127. R a is C 1-5 The compound of any of embodiments 102 to 126, wherein is alkyl. 128. R a 128. A compound according to any of embodiments 102 to 127, wherein is methyl, ethyl, or n-propyl or i-propyl. 129. A compound according to any one of embodiments 102-128, wherein R2 is aryl or heteroaryl. 130. A compound according to any of embodiments 102-129, wherein R2 is phenyl or naphthyl. 131. R2 is

[0329] [ka] where R s are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R s Compounds according to any of embodiments 102 to 130, wherein together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and p is 0, 1, 2, or 3. 132. R2 is

[0330] [ka] 132. The compound of any of embodiments 102 to 131, wherein 133. A compound according to any one of embodiments 102-129, wherein R2 is a 5- or 6-membered nitrogen-containing heteroaryl. 134. R2 is

[0331] [ka] where R s are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R s Compounds according to any of embodiments 102 to 129 and 133, wherein together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and p is 0, 1, or 2. 135. A compound according to any of embodiments 102-123, wherein R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl. 136. Compounds according to embodiment 135, wherein R2 and R4 together with the carbon atom to which they are attached form a cycloalkyl. 137. Cycloalkyl is C 4-6 137. The compound of embodiment 135 or 136, which is cycloalkyl. 138. R3 is -S(O)2NHR b , -S(O)NR b R b , -NHS(O)2R b , -C(O)R b , -C(O)NHR b , -C(O)NR b R b , -NHC(O)R b , -NHC(O)NR b R b or —CN. 139. The compound of any of embodiments 102-138, wherein R3 is —N(H)S(O)2 alkyl, —N(H)S(O)2 cycloalkyl, —S(O)2NH2, —C(O)alkyl, or —CN. 140. R3 is -N(H)S(O)2CH 3、 The compound of any of embodiments 102 to 139, which is -S(O)2NH2, -C(O)CH3, or -CN. 141. A pharmaceutical composition comprising one or more of: (i) a compound according to any of embodiments 102 to 140; and (ii) a pharmaceutically acceptable carrier or excipient. 142. A method for treating cancer in a subject, wherein the subject is in need of treatment, the method comprising administering to the subject an effective amount of a compound described in any of embodiments 102 to 140 or a pharmaceutical composition described in embodiment 141. 143. The method of embodiment 142, wherein the cancer is breast cancer, lung cancer, pancreatic cancer, melanoma, multiple myeloma, colon cancer, colorectal cancer, or glioblastoma. 144. The method of embodiment 142 or 143, further comprising administering an anti-PD-1 antibody. 145. The method of embodiment 144, wherein administering the compound and an anti-PD-1 antibody to a subject results in a synergistic effect in the treatment of cancer. 146. The compound has the following structure:

[0332] [ka] The method of any of embodiments 98-101 and 142-145, comprising administering to a patient a compound of formula (I) or (II) of formula (II) or a pharmaceutically acceptable salt or tautomer thereof.

[0333] While various inventive embodiments have been described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions described herein and / or obtaining the results and / or one or more advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be illustrative, and that the actual parameters, dimensions, materials, and / or configurations will depend on the specific application or applications for which the teachings of the present invention are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific inventive embodiments described herein. Accordingly, it should be understood that the above-described embodiments are presented by way of example only, and that, within the scope of the appended claims and their equivalents, inventive embodiments may be practiced otherwise than as specifically described and claimed. The inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods is included within the inventive scope of the present disclosure, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0334] The above-described embodiments can be implemented in any of numerous ways. Also, various inventive concepts can be embodied as one or more methods, examples of which have been provided. The acts performed as part of a method can be ordered in any suitable manner. Thus, embodiments can be constructed in which acts are performed in an order different from that illustrated, which may include performing some acts simultaneously even if shown as sequential acts in the exemplary embodiments.

[0335] All cited documents are incorporated herein by reference in their entirety for all purposes. [Example]

[0336] Representative Synthesis of Compounds Disclosed herein Synthesis of Compound 1

[0337] [ka] Step 1: Ethyl 2-(2-chloroacetamido)-5-phenylthiophene-3-carboxylate Procedure: To a solution of ethyl 2-amino-5-phenylthiophene-3-carboxylate (1.0 g, 4.40 mmol) in anhydrous dichloromethane (30 mL) was added triethylamine (0.84 mL, 6.06 mmol). The resulting reaction mixture was cooled to 0° C., and chloroacetyl chloride (0.38 mL, 4.80 mmol) was added dropwise. The reaction mixture was then stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, water (50 mL) was added, and the organic layer was separated. The aqueous layer was further extracted with dichloromethane. The organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash chromatography using ethyl acetate:hexane as the eluent. Yield: 0.9 g (85%).

[0338] Step 2: Ethyl 5-phenyl-2-(2-((3-sulfamoylbenzoyl)oxy)acetamido)thiophene-3-carboxylate Procedure: To a solution of ethyl 2-(2-chloroacetamido)-5-phenylthiophene-3-carboxylate (529 mg, 1.64 mmol) and 3-sulfamoylbenzoic acid (300 mg, 1.49 mmol) in anhydrous dimethylformamide (15 mL), potassium carbonate (412.1 mg, 2.98 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 10 minutes. Next, TBAI (55.07 mg, 0.149 mmol) was added, and the reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, water (50 mL) was added to the reaction mixture, and it was extracted with ethyl acetate. The organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude residue. The crude compound was triturated with pentane and dichloromethane, and the solvent was decanted. The resulting compound was dissolved in 10% methanol:dichloromethane, filtered, and dried. White solid; Yield: 237 mg (30%).

[0339] Synthesis of compound 66

[0340] [ka] Step 1: Ethyl 3-(methylsulfonamido)benzoate Procedure: To a stirred solution of ethyl 3-aminobenzoate (10.0 g, 60.53 mmol) in dichloromethane (100.0 mL), pyridine (10.0 mL, 121.06 mmol) was added, followed by methanesulfonyl chloride (10 mL, 127.12 mmol) at 0° C. The reaction mixture was allowed to stir at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness. The crude residue was dissolved in water and extracted with ethyl acetate. The organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to give compound. Yield: 14.0 g (95%).

[0341] Step 2: 3-(Methylsulfonamido)benzoic acid Procedure: To a stirred solution of ethyl 3-(methylsulfonamido)benzoate (14.0 g, 57.58 mmol) in a mixture of THF:HO (1:1, 140.0 mL) was added LiOH.HO (7.2 g, 172.7 mmol) and the reaction mixture was allowed to stir at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated to dryness and quenched with 1N HCl to give a precipitate. The precipitate was filtered and dried under vacuum to give an off-white solid. Yield: 11.7 g, (95%).

[0342] Step 3: Ethyl 2-(2-((3-(methylsulfonamido)benzoyl)oxy)acetamido)-5-phenylthiophene-3-carboxylate Procedure: To a stirred solution of ethyl 2-(2-chloroacetamido)-5-phenylthiophene-3-carboxylate (200 mg, 0.62 mmol) and 3-(methylsulfonamido)benzoic acid (137 mg, 0.68 mmol) in DMF (2.0 mL) was added K2CO3 (188 mg, 1.38 mmol), and the resulting reaction mixture was stirred at room temperature for 10 minutes. TBAI (23 mg, 0.062 mmol) was then added to the reaction mixture, which was then allowed to stir at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate. The organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude residue. The crude compound was purified by flash chromatography using methanol:dichloromethane as the eluent. Off-white solid; yield: 100 mg (32%).

[0343] Synthesis of compound 138

[0344] [ka] Step 1: tert-butyl 3-((3-(ethoxycarbonyl)-5-phenylthiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate Procedure: To a stirred solution of ethyl 2-amino-5-phenylthiophene-3-carboxylate (200 mg, 0.81 mmol) and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (174.0 mg, 0.81 mmol) in DCM (10 mL), EDC.HCl (309 mg, 1.61 mmol) was added, followed by DMAP (98.8 mg, 0.81 mmol), and the reaction mixture was stirred at room temperature. The reaction progress was monitored by TLC. After completion of the reaction, water (10 mL) was added to the reaction mixture and extracted with ethyl acetate. The organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude residue. The crude compound was purified by flash chromatography using ethyl acetate:hexane as the eluent. Yield: 150 mg (42%).

[0345] Step 2: Ethyl 5-phenyl-2-(pyrrolidine-3-carboxamido)thiophene-3-carboxylate hydrochloride Procedure: To a stirred solution of tert-butyl 3-((3-(ethoxycarbonyl)-5-phenylthiophen-2-yl)carbamoyl)pyrrolidine-1-carboxylate (150 mg, 0.34 mmol) in DCM (5 mL) was added 4 M HCl in dioxane (5 mL) and 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 removed to give the crude compound, which was washed with diethyl ether to give the compound as a white solid. Yield: 120 mg (94%).

[0346] Step 3: Ethyl 2-(1-(3-(methylsulfonamido)benzoyl)pyrrolidine-3-carboxamido)-5-phenylthiophene-3-carboxylate Procedure: To a solution of ethyl 5-phenyl-2-(pyrrolidine-3-carboxamido)thiophene-3-carboxylate hydrochloride (100 mg, 0.29 mmol) and 3-(methylsulfonamido)benzoic acid (62.5 mg, 0.29 mmol) in DMF:DCM (3:3 ml), HATU (220.4 mg, 0.58 mmol) and N-methylmorpholine (58.58 mg, 0.58 mmol) were added. The resulting reaction mixture was stirred at room temperature. The reaction progress was monitored by TLC. After completion of the reaction, water (10 mL) was added to the reaction mixture and extracted with ethyl acetate. The organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to give the crude residue. The crude compound was purified by flash chromatography using ethyl acetate:hexane as the eluent. Yield: 10 mg (7%).

[0347] [Table 1] TIFF2025538892000195.tif255170 TIFF2025538892000196.tif255170 TIFF2025538892000197.tif255170 TIFF2025538892000198.tif255170 TIFF2025538892000199.tif255170 TIFF2025538892000200.tif40170 [Example]

[0348] Compounds as inhibitors of ADAR1 Treatment of A549 cells with compound 1 induced IFN-β via inhibition of ADAR1 (Figures 1A-1C). Notably, treatment of A549p110KP cells demonstrated dose-dependent IFN-β induction in A549p110KO cells. Due to the presence of ADAR1p110 activity, lower IFN-β induction was observed in WT A549 cells treated with compound 1. Compound 1 demonstrated superior IFN-β induction in A549p110KO cells compared to the STING agonists cGAMP, ADU-S100, and MSA-002. [Example]

[0349] Evaluation of ADAR1 inhibition and binding affinity The 6xHis-tagged Zα domain of ADAR1 p150 was purified using a bacterial purification system. The protein was isolated from the supernatant of the cell lysate using Ni-NTA resin. For SPR binding assays, 10 μg / ml of the Zα domain of ADAR1 was immobilized on a CM5 chip using an anti-HIS antibody. Binding was quantified using the following conditions: Analytes: 25, 12.5, 6.25, 3.125, 1.56, 0.78, 0μM Contact time - 60 seconds Dissociation time - 320 seconds Flow rate - 30 μL / min Running buffer - PBSP + 5% DMSO After curve fitting, the instrument software was used to quantify the Kd values ​​for the synthesized compounds.

[0350] The biological activity (EC50) of the compounds disclosed herein was determined using an ADAR1 inhibition assay. 100 μL of p110KO A549 double cell suspension (20,000 cells per well) in supplemented DMEM was added to a flat-bottom 96-well plate. The next day, after medium change, 180 μL of supplemented DMEM was added. 20 μL of test compound or positive control was added to each well (final DMSO concentration was 1%). The plate was incubated at 37°C in a 5% CO2 incubator for 24 and 48 hours. After 24 and 48 hours, 20 μL of cell suspension was transferred to a black-well plate, 50 μL of Quanti-Luc was added to each well, and luminescence was measured using a microplate reader (Spectra Max). DMSO was used as a control, and relative light unit (RLU) values ​​were used to plot IFN induction folds (fold induction: sample RLU / average DMSO RLU).

[0351] [Table 2] TIFF2025538892000202.tif248170 TIFF2025538892000203.tif248170 TIFF2025538892000204.tif248170 TIFF2025538892000205.tif248170 TIFF2025538892000206.tif248170 TIFF2025538892000207.tif248170 TIFF2025538892000208.tif248170 TIFF2025538892000209.tif248170 TIFF2025538892000210.tif99170 [Example]

[0352] Treatment with compound 1 induces IFN-β via ADAR1 inhibition Compound 1 demonstrated dose-dependent induction of IFN-β (via ADAR1 inhibition) in A549p110KO cells (FIG. 1A).

[0353] Treatment of WT A549 cells with Compound 1 had lower IFN-β induction due to the presence of ADAR1p110 activity (FIG. 1B).

[0354] Compound 1 demonstrated superior IFN-β induction in A549p110KO cells compared with the STING agonists cGAMP, ADU-S100, and MSA-002 ( Figure 1C ).

[0355] Treatment with Compound 1 in the human cancer cell lines A549 (p110KO) and HCT116 induced dose-dependent expression of several interferon-activated genes (ISGs) (see Figures 2, 3A-3D, 4, and 5A-5D).

[0356] Treatment with Compound 1 in the mouse cancer cell line B16F10 induced dose-dependent upregulation of MDA5, IFN-β, and CXCL10 (see Figures 6 and 7A-7B). [Example]

[0357] Evaluation of the antitumor efficacy of the disclosed compounds in the B16F10 mouse melanoma model STUDY: The B16F10 mouse melanoma model was used to evaluate the antitumor efficacy of Compound 1 alone or in combination with anti-PD-1 therapy.

[0358] Results: As shown in Figure 8, compound 1 demonstrated monotherapy efficacy in the B16F10 mouse melanoma model by producing a 45% tumor growth inhibition (TGI) compared to approximately 30% TGI with anti-PD-1 treatment alone.

[0359] Combining Compound 1 with anti-PD-1 therapy resulted in a synergistic effect of 55% TGI, which was approximately 2-fold greater than anti-PD-1 treatment alone.

[0360] Tumor weight reduction was also assessed in B16F10 melanoma mice (Figure 9). As shown in Figure 9, mice treated with anti-PD-1 therapy experienced a 40% reduction in tumor weight compared to the vehicle control group, and treatment of mice with 100 μg of Compound 1 reduced tumor weight by approximately 60%. Combining Compound 1 with anti-PD-1 produced a synergistic effect by reducing tumor weight by approximately 70% compared to the control.

[0361] In a melanoma model, treatment with Compound 1 demonstrated a significant increase in tumor MDA5 mRNA levels, confirming that induction of downstream cytokines occurs via the ADAR1-MDA5 pathway (Figure 10).

[0362] Treatment with Compound 1 also demonstrated increased induction of IFN-β and CXCL10 in mice in B16F10 tumors, both as monotherapy and in combination with anti-PD-1 (Figures 11A and 11B).

[0363] Conclusions: Treatment of B16F10 melanoma mice with compound 1 demonstrated superior efficacy over anti-PD-1 monotherapy and synergistic effects with anti-PD-1.

Claims

1. The following structure 【Chemistry 1】 or a pharmaceutically acceptable salt or tautomer thereof, During the ceremony, L is the structure -A-L １ is a linker having -B-, where: A is -NR ｃ -, -NR ｃ C(O)-, -C(O)NR ｃ -, -NR ｃ S (O) ２ - or S(O) ２ NR ｃ - and L １ is absent, alkylene, alkenylene, alkynylene, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is a bond or —NR ｄ -, -N(S(O) ２ -alkyl)-, -NR ｄ C(O)-, -OC(O)-, 【Chemistry 2】 -OC(CF ３ )-, —O—, —C(O)-alkylene-, —C(O)—, —NR ｄ S (O ２ ) -, -S(O ２ ) NR ｄ - or heteroaryl, R ｃ and R ｄ are each independently H, alkyl, cycloalkyl, heterocyclyl, alkylene-aryl, acyl, or sulfonyl; However, -A-L １ -B- is -O-O, -NR ｃ —O, —O—NR ｄ -, -NR ｃ -NR ｄ - or does not have an S—S bond, X is C-R １ or N, Y is C-R ４ or N, Z is O, S, N-R ５ , or N(R ５ )-CH ２ - and Z ３ , Z ４ , Z ５ , Z ６ , and Z ７ are each independently N or CH, Z ３ , Z ４ , Z ５ , Z ６ , and Z ７ At most two of them are N, R １ is H, halogen, alkyl, —CN, —C(O)R ａ , -C(O)OR ａ , —C(O)NHR ａ , —C(O)N(alkyl)(R ａ ), -C(O)N(R ａ ) (R ａ ), —C(O)NR ａ R ａ , or -S(O) ２ R ａ , or -S(O) ２ OR ａ or R １ and R ｃ together with the atom to which they are attached form a heterocyclyl or heteroaryl; R ２ is H, halogen, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl; R ３ are each independently a halogen, —OH, or —CH ２ OH, alkyl, haloalkyl, alkoxy, haloalkoxy, —S(O) ２ NHR ｂ , -S(O) ２ NR ｂ R ｂ , -NHS(O) ２ R ｂ , -C(O)R ｂ , -C(O)OR ｂ , —C(O)NHR ｂ , —C(O)NR ｂ R ｂ , -NHC(O)R ｂ , -NHC(O)NR ｂ R ｂ , -CN, or P(O)(OR ｂ ) ２ or two R ３ together with the adjacent carbon atoms to which they are attached form an aryl, cycloalkyl, or heterocyclyl; R ４ is H, halogen, alkyl, —C(O)OR ａ , —C(O)NHR ａ , or aryl, or R ２ and R ４ together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ５ is H, alkyl, alkylenecycloalkyl, cycloalkyl, aryl, alkylenearyl, or heteroaryl, or R ２ and R ５ together with the adjacent carbon atoms to which they are attached form an aryl or heteroaryl; R ａ are each independently H, alkyl, cycloalkyl, alkylene-cycloalkyl, aryl, heteroaryl, alkylene-aryl, or alkylene-heteroaryl, or two R ａ groups together with the nitrogen atom to which they are attached form a heterocyclyl; R ｂ is H, alkyl, cycloalkyl, alkylene-cycloalkyl, heterocyclyl, or aryl, or two R ｂ groups together with the nitrogen atom to which they are attached form a heterocyclyl; m is 0, 1, 2, or 3; wherein the compound is 【Transformation 3】 Not a compound.

2. R １ , R ２ , and R ４ 2. The compound of claim 1, wherein at least two of

3. Z ３ , Z ４ , Z ５ , Z ６ , and Z ７ 3. The compound of claim 1 or 2, wherein at most one of

4. Z ３ , Z ４ , Z ５ , Z ６ , and Z ７ 3. The compound of claim 1 or 2, wherein each is H.

5. The following structure 【Chemistry 4】 5. The compound of claim 1, wherein R is an integer from 1 to 4; or a pharmaceutically acceptable salt or tautomer thereof.

6. The following structure 【Transformation 5】 or a pharmaceutically acceptable salt thereof.

7. The following structure 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

8. The following structure 【Transformation 7】 or a pharmaceutically acceptable salt thereof, where: R ３ａ are each independently halogen, —OH, alkyl, haloalkyl, alkoxy, or haloalkoxy; 8. The compound of claim 1, wherein q is 0, 1, or 2.

9. L is the structure -A-L １ is a linker having -B-, where: A is -NR ｃ C(O)- or -C(O)NR ｃ and L １ is absent, alkylene, cycloalkyl, or heterocyclyl; B is a bond or —NR ｄ -, -N(S(O) ２ -alkyl)-, -NR ｄ C(O)-, —OC(O)-, —C(O)-alkylene-, —C(O)-, —NR ｄ S (O ２ ) - or S(O ２ ) NR ｄ - and R ｃ and R ｄ are each independently H, alkyl, cycloalkyl, or alkylene-aryl; However, -A-L １ -B- is -O-O, -NR Ｃ —O, —O—NR ｄ -, -NR Ｃ -NR ｄ The compound according to any one of claims 1 to 8, which has no - or S-S bond.

10. A is -NR ｃ C(O)-, -C(O)NR ｃ The compound according to any one of claims 1 to 9, wherein the aryl group is - or -C(O)-.

11. A is -NR ｃ The compound according to any one of claims 1 to 10, which is C(O)-.

12. R ｃ is H, C １－５ Alkyl, C ３－６ cycloalkyl, or —CH ２ 12. The compound according to any one of claims 1 to 11, wherein R is -phenyl.

13. L １ 13. The compound of any one of claims 1 to 12, wherein is absent, alkylene or heterocyclyl.

14. L １ is alkylene, and the alkylene is C １－３ 14. The compound of any one of claims 1 to 13, which is alkylene.

15. L １ 15. The compound of any one of claims 1 to 14, wherein the alkylene is optionally substituted methylene.

16. L １ The alkylene has the following structure: 【Transformation 8】 where R ｅ are each independently H, F, C １－５ Alkyl, —CH ２ OH, -CH ２ Cycloalkyl or —CH ２ aryl or two R ｅ are C together with the carbon atoms to which they are attached. ３－６ 16. A compound according to any one of claims 1 to 15, which forms a cycloalkyl or a 4 to 6 membered heterocyclyl.

17. R ｅ is H or C １－５ 17. The compound of claim 16, wherein the compound is alkyl.

18. L １ 14. The compound of any one of claims 1 to 13, wherein is heterocyclyl.

19. L １ 19. The compound of any one of claims 1 to 13 and 18, wherein the heterocyclyl is a 3- to 12-membered heterocyclyl.

20. L １ The heterocyclyl has the following structure: 【Chemistry 9】 20. The compound of any one of claims 1 to 13, 18, and 19, having the formula: wherein * represents the point of attachment to A and ** represents the point of attachment to B.

21. B is a bond or —NR ｂ C(O)-, -NR ｂ S (O) ２ 21. The compound of any one of claims 1 to 20, which is -, -C(O)-, -OC(O)-, -C(O)-O-, or heteroaryl.

22. The compound according to any one of claims 1 to 21, wherein B is a bond, -OC(O)- or -C(O)-.

23. 22. The compound of claim 21, wherein the heteroaryl is a 5- or 6-membered nitrogen-containing heteroaryl.

24. -A-L １ -B- has the following structure: 【Chemistry 10】 and where: R ｃ and R ｄ are each independently H, alkyl, cycloalkyl, alkylene-aryl, acyl, or sulfonyl; R ｅ are each independently H, F, C １－５ Alkyl, —CH ２ Cycloalkyl or —CH ２ aryl or two R ｅ are C together with the carbon atoms to which they are attached. ３－６ forming a cycloalkyl or a 4- to 6-membered heterocyclyl, 23. The compound of any one of claims 1 to 22, wherein t is 0, 1, or 2.

25. A-L １ -B has the following structure: 【Chemistry 11】 25. The compound of any one of claims 1 to 24, having the formula:

26. R ｃ 26. The compound of claim 24 or 25, wherein is H.

27. X is C-R １ 27. The compound of any one of claims 1 to 26, wherein

28. R １ is a halogen, alkyl, or —C(O)OR ａ , or —C(O)NHR ａ 28. The compound of any one of claims 1 to 27, wherein:

29. R １ is -C(O)OR ａ 29. The compound of any one of claims 1 to 28, wherein

30. 27. The compound of any one of claims 1 to 26, wherein X is N.

31. Y is C-R ４ 31. The compound of any one of claims 1 to 30, wherein

32. R ４ is H, alkyl, aryl, -C(O)OR ａ , or —C(O)NHR ａ 32. The compound of any one of claims 1 to 31, wherein

33. R ４ 33. The compound of any one of claims 1 to 32, wherein is H.

34. R ａ is C １－５ Alkyl or -CH ２ 34. The compound of any one of claims 1 to 33, which is cycloalkyl.

35. R ａ is C １－５ 35. The compound of any one of claims 1 to 34, which is alkyl.

36. R ａ is methyl, ethyl, or n-propyl or i-propyl.

37. R ２ 37. The compound of any one of claims 1 to 36, wherein is aryl or heteroaryl.

38. R ２ 38. The compound of any one of claims 1 to 37, wherein is phenyl or naphthyl.

39. R ２ teeth, 【Chemistry 12】 where R ｓ are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R ｓ 39. The compound of any one of claims 1 to 38, wherein: together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and p is 0, 1, 2, or 3.

40. R ２ teeth 【Chemistry 13】 40. The compound of any one of claims 1 to 39, wherein

41. R ２ 38. The compound of any one of claims 1 to 37, wherein is a 5- or 6-membered nitrogen-containing heteroaryl.

42. R ２ teeth 【Chemistry 14】 where R ｓ are each independently halogen, alkyl, haloalkyl, —OH, alkoxy, haloalkoxy, or amino, or two R ｓ 42. The compound of any one of claims 1 to 37 and 41, wherein: together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; and p is 0, 1, or 2.

43. R ２ and R ４ 32. The compound of any one of claims 1 to 31, wherein together with the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl, or heteroaryl.

44. R ２ and R ４ 44. The compound of claim 43, wherein together with the carbon atom to which they are attached form a cycloalkyl.

45. The cycloalkyl is C ４－６ 45. The compound of claim 43 or 44, which is cycloalkyl.

46. The following structure 【Chemistry 15】 or a pharmaceutically acceptable salt thereof, where: R ｃ are each independently halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, sulfonyl, or two R ｃ together with the atom to which they are attached form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; 41. The compound of any one of claims 1 to 40, wherein p is 0, 1, 2, or 3.

47. The following structure 【Chemistry 16】 or a pharmaceutically acceptable salt thereof, where: A is -NR ａ C(O)-, -C(O)NR ａ -, -NR ａ S (O) ２ - or -S(O) ２ NR ａ - and B is -NR ｄ -, -NR ｄ C(O)-, —OC(O)-, —C(O)-alkylene-, —C(O), —NR ｄ S (O ２ ) - or -S(O ２ ) NR ｄ - and L １ is a bond or C １－５ Alkylene, C １－５ Alkenylene, C １－５ 47. The compound of any one of claims 1 to 40 and 46, which is alkynylene, or heterocyclyl, each of which is optionally substituted.

48. R ３ is -S(O) ２ NHR ｂ , -S(O) ２ NR ｂ R ｂ , -NHS(O) ２ R ｂ , -C(O)R ｂ , —C(O)NHR ｂ , —C(O)NR ｂ R ｂ , -NHC(O)R ｂ , -NHC(O)NR ｂ R ｂ 48. The compound of any one of claims 1 to 47, wherein the aryl group is -C, or -CN.

49. R ３ is -N(H)S(O) ２ Alkyl, —N(H)S(O) ２ Cycloalkyl, —S(O) ２ NH ２ , —C(O)alkyl, or —CN.

50. R ３ is -N(H)S(O) ２ CH ３ , -S(O) ２ NH ２ , —C(O)CH ３ 50. The compound of any one of claims 1 to 49, wherein the compound is -CN.

51. The following structure 【Chemistry 17】 【change】 51. The compound of any one of claims 1 to 40 and 46 to 50, wherein R is H or a pharmaceutically acceptable salt or tautomer thereof.

52. 52. A pharmaceutical composition comprising a compound according to any one of claims 1 to 51 and one or more pharmaceutically acceptable excipients.

53. A method for treating cancer in a subject, wherein the subject is in need of cancer treatment, the method comprising administering to the subject an effective amount of a compound described in any one of claims 1 to 51.

54. 54. The method of claim 53, wherein the cancer is breast cancer, lung cancer, pancreatic cancer, melanoma, multiple myeloma, colon cancer, colorectal cancer, or glioblastoma.

55. 55. The method of claim 53 or 54, further comprising administering an anti-PD-1 antibody.

56. 56. The method of claim 55, wherein administering the compound and the anti-PD-1 antibody to the subject results in a synergistic effect in the treatment of cancer.

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