Modulators of BCL6 protein degradation and related methods of use

Abstract

The present application relates to compounds, such as Compound A: TIFF2026500955000270.tif7797 or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] Related Applications This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 437,994, filed January 9, 2023, and U.S. Provisional Application No. 63 / 618,208, filed January 5, 2024, which applications are incorporated by reference in their entireties for all purposes.

[0002] Provided herein are compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and related methods of using the compounds, which are useful as regulators of target ubiquitination, such as B-cell lymphoma 6 protein (BCL6), which is degraded by a bifunctional compound according to the present disclosure. [Background technology]

[0003] Most small molecule drugs bind closely to enzymes or receptors in well-defined pockets. However, targeting protein-protein interactions using small molecules is notoriously challenging due to the large protein contact surfaces and shallow, groove-like, or flat interfaces involved. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination and are therefore more attractive therapeutic targets than general proteasome inhibitors due to their specificity for specific protein substrates. Developing ligands for E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small molecule E3 ligase inhibitor, nutrin, additional compounds targeting E3 ligases have been reported, but the field remains largely unexplored.

[0004] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, underscoring its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), cullin-4A (CUL4A), and regulator of cullin 1 (ROC1). This complex ubiquitinates numerous other proteins. Through a mechanism that is not fully understood, cereblon ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then regulates numerous developmental processes, such as limb and otic vesicle formation. It has been conclusively concluded that this ubiquitin ligase complex is important for limb development in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2 and functions as a DNA damage-binding protein.

[0005] Bifunctional compounds, such as those described in U.S. Patent Application Publication Nos. 2015-0291562 and 2014-0356322 (incorporated herein by reference), function to recruit endogenous proteins to E3 ubiquitin ligases for degradation. In particular, these patent publications describe bifunctional or proteolysis targeting chimeric (PROTAC) compounds that find utility as modulators of targeted ubiquitination of various polypeptides and other proteins, which are degraded and / or otherwise inhibited by the bifunctional compounds.

[0006] There is a continuing need in the art for effective treatments for diseases associated with (i) aberrant BCL6 expression and / or activity, and / or (ii) overexpression or aggregation of the B-cell lymphoma 6 protein (BCL6). However, nonspecific effects and the inability to target and regulate BCL6 remain obstacles to the development of effective therapies. Therefore, small molecule therapeutics that target BCL6 and exploit or enhance the substrate specificity of E3 ubiquitin ligases (e.g., cereblon) would be highly useful. Summary of the Invention

[0007] In one aspect, the application relates to a method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, the compound comprising: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0008] In one aspect, the application relates to a method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, wherein the compound is: [ka] [ka]

[0009] In one aspect, the present application relates to a method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, or a solid tumor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound comprising: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0010] In one aspect, the application relates to a method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, or a solid tumor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, wherein the compound is: [ka] [ka]

[0011] In one aspect, the present application relates to a method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor, the method comprising administering to a subject an effective amount of Compound A: [ka] or a pharmaceutically acceptable salt thereof.

[0012] In one aspect, the present application relates to a method for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor, the method comprising administering to a subject an effective amount of Compound A: [ka]

[0013] In one aspect, the present application relates to a method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL), the method comprising administering to a subject an effective amount of Compound A: [ka] or a pharmaceutically acceptable salt thereof.

[0014] In one aspect, the present application relates to a method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL), the method comprising administering to a subject an effective amount of Compound A: [ka]

[0015] In one aspect, the present application relates to a method of treating or ameliorating angioimmunoblastic T-cell lymphoma in a subject in need thereof, the method comprising administering to the subject an effective amount of Compound A: [ka] or a pharmaceutically acceptable salt thereof.

[0016] In one aspect, the present application relates to a method of treating or ameliorating angioimmunoblastic T-cell lymphoma in a subject in need thereof, the method comprising administering to the subject an effective amount of Compound A: [ka]

[0017] In one aspect, the present application relates to a method of treating a solid tumor in a subject in need thereof, the method comprising administering to the subject an effective amount of Compound A: [ka] or a pharmaceutically acceptable salt thereof.

[0018] In one aspect, the present application relates to a method of treating a solid tumor in a subject in need thereof, the method comprising administering to the subject an effective amount of Compound A: [ka] [Brief explanation of the drawings]

[0019] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several embodiments of the present disclosure and, together with the description herein, serve to explain the principles of the present disclosure. The drawings are solely for the purpose of illustrating embodiments of the present disclosure and are not to be construed as limiting the present disclosure. Further objects, features, and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings, which show exemplary embodiments of the present disclosure.

[0020] [Figure 1]1A-1B are diagrams of the general principle of the heterobifunctional degradation compound A of the present disclosure. In FIG. 1A, an exemplary heterobifunctional degradation compound A includes a protein targeting moiety (PTM; rectangle), a ubiquitin ligase binding moiety (ULM; triangle), and, optionally, a linker moiety (L; thick black line) that connects or joins the PTM and ULM. FIG. 1B illustrates the functional uses of the heterobifunctional degradation compound A described herein. Briefly, the ULM recognizes and binds a specific E3 ubiquitin ligase, and the PTM binds and recruits the target protein, bringing it into close proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-binding protein and, alone or through the E2 protein, catalyzes the attachment of ubiquitin to a lysine on the target protein via an isopeptide bond (small black oval). Polyubiquitinated proteins (far right) are then targeted for degradation by the cellular proteasome machinery. [Figure 2] Figures 2A-2C show the degradation of BCL6 protein by Compound A in germinal center B cell (GCB) and activated B cell (ABC) DLBCL cell lines. Figure 2A shows OCI-Ly1 treated with Compound A and its E3-binding-deficient analog for 24 hours. Figure 2B shows GCB DLBCL cell lines Farage, SU-DHL-4, SU-DHL-6, and OCI-Ly7 treated with Compound A for 24 hours. Figure 2C shows ABC DLBCL lines SU-DHL-2 and OCI-Ly10 treated with Compound A for 24 hours. [Figure 3] Figures 3A-3B show the antiproliferative effects of Compound A on DLBCL-derived cell lines in a 9-day cell growth inhibition assay. In Figure 3A, GCB lines OCI-Ly1, OCI-Ly7, SU-DHL-4, and SU-DHL-6 were administered seven three-fold serial dilutions of Compound A at a top dose of 30 nM. In Figure 3B, ABC lines SU-DHL-2 and OCI-Ly10 were administered seven three-fold serial dilutions of Compound A at a top dose of 30 nM. [Figure 4]Figure 4A shows the mean tumor growth of the xenograft model OCI-Ly1 derived from a DLBCL cell line with treatment with Compound A. Figure 4B shows the mean body weight of treated mice. [Figure 5] FIG. 5 shows BCL6 protein levels in tumor lysates in OCI-Ly1 cell line xenograft tumor tissues after a time course of treatment with Compound A. [Figure 6] FIG. 6 shows total Compound A plasma levels and tumor levels (FIG. 5). [Figure 7] Figure 7A shows the mean tumor growth of the OCI-Ly1 xenograft model derived from a DLBCL cell line using Compound A treatment. Figure 7B shows the mean body weight of treated mice. Figure 7C shows the BCL6 protein level in tumor lysates 16 hours after the final dose, analyzed by Western blotting. [Figure 8] Figure 8A shows the mean tumor growth of the OCI-Ly7 xenograft model derived from a DLBCL cell line using Compound A treatment. Figure 8B shows the mean body weight of treated mice. Figure 8C shows the BCL6 protein level in tumor lysates 16 hours after the final administration, analyzed by Western blotting. [Figure 9] Figure 9A shows the average tumor growth of the SU-DHL-2 xenograft model derived from a DLBCL cell line using Compound A treatment. Figure 9B shows the average body weight of treated mice. Figure 9C shows the protein level of BCL6 in tumor lysates 16 hours after the final dose, analyzed by Western blotting. [Figure 10] Figure 10A shows the average tumor growth of the OCI-Ly10 xenograft model derived from a DLBCL cell line using Compound A treatment. Figure 10B shows the average body weight of treated mice. Figure 10C shows the protein level of BCL6 in tumor lysates 16 hours after the final administration, analyzed by Western blotting. [Figure 11]11A-11D show the change in mean tumor volume in patient-derived xenograft (PDX) mouse models of diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, and non-Hodgkin's lymphoma (NHL)-not otherwise specified (NOS) treated with Compound A or vehicle, as described in Example 10. Data points represent the mean per group, and error bars represent the standard error of the mean. DETAILED DESCRIPTION OF THE INVENTION

[0021] The following is a detailed description provided to assist those skilled in the art in practicing the present disclosure. Those skilled in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, drawings and other references mentioned herein are expressly incorporated by reference in their entirety.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure.

[0023] Where a range of values ​​is provided, unless the context clearly dictates otherwise (e.g., in the case of a group containing a certain number of carbon atoms, each number of carbon atoms falling within the range is provided), it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range and any other stated range, or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the disclosure, as are any specifically excluded limits in the stated range. When a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0024] The following terms are used to describe this disclosure. If a term is not specifically defined herein, the term is given its art-recognized meaning by those of ordinary skill in the art who apply the term in the context of its use in describing this disclosure.

[0025] As used herein, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element.

[0026] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of the elements so conjoined. That is, in some instances, the elements are present conjunctively and in other instances, they are present disjointly. Multiple elements listed with "and / or" should be construed in the same manner, that is, "one or more" of the elements are so conjoined. Other elements other than the elements specifically identified by the "and / or" clause can optionally be present, whether related or not to those specifically identified elements. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements), etc.

[0027] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as inclusive, i.e., the inclusion of at least one, but also two or more, of a number or list of elements, and optionally additional unlisted items. Only terms clearly implied to the contrary, such as "only one of," or "exactly one of," or, when used in the claims, "consisting of," shall refer to the inclusion of exactly one element of a number or list of elements. Generally, as used herein, the term "or" should be interpreted to indicate exclusive alternatives (i.e., "one or the other, but not both") only when preceded by exclusive terms, such as "either," "one of," "only one of," or "exactly one of."

[0028] In the claims, as well as in the foregoing specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in Section 2111.03 of the United States Patent Examining Guidelines.

[0029] In certain methods described herein that include more than one step or action, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited, unless the context indicates otherwise.

[0030] The term "ubiquitin ligase" refers to a family of proteins that promote the transfer of ubiquitin to specific substrate proteins, targeting the substrate proteins for degradation. For example, cereblon is an E3 ubiquitin ligase protein, which, alone or in combination with an E2 ubiquitin conjugating enzyme, attaches ubiquitin to lysine on target proteins, subsequently targeting the specific protein substrate for proteasomal degradation. Thus, E3 ubiquitin ligases, either alone or in complex with an E2 ubiquitin conjugating enzyme, are involved in the transfer of ubiquitin to target proteins. Generally, ubiquitin ligases are involved in polyubiquitination, whereby a second ubiquitin is attached to the first ubiquitin, a third ubiquitin is attached to the second ubiquitin, and so on. Polyubiquitination marks proteins for proteasomal degradation. However, some ubiquitination events are limited to monoubiquitination, in which only one ubiquitin is added to a substrate molecule by a ubiquitin ligase. Monoubiquitinated proteins are not targeted for proteasomal degradation but may instead change their cellular location or function, for example, through binding to other proteins that contain domains capable of ubiquitin binding. Further complicating the issue, additional lysines on ubiquitin can be targeted by E3s to form chains. The most common lysine is Lys48 on the ubiquitin chain, which is used to generate polyubiquitin that is recognized by the proteasome.

[0031] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. With respect to treatment of an infection, condition, or pathology specific to a particular animal, e.g., a human patient, the term patient refers to the particular animal, including domestic animals, e.g., dogs or cats, or agricultural animals, e.g., horses, cows, sheep, etc. Generally, in this disclosure, the term patient refers to a human patient, unless otherwise indicated or implied by the context in which the term is used.

[0032] The term "effective," when used within the context of its intended use, is used to describe an amount of a compound, composition, or component that produces an intended result. The term effective includes all other effective amount or effective concentration terms that are otherwise described or used in this application.

[0033] Compounds of the Disclosure In some embodiments, the compounds of the present disclosure have the following chemical structure: CLM-L-PTM or a pharmaceutically acceptable salt thereof; During the ceremony, (a) CLM is a cereblon E3 ubiquitin ligase binding moiety represented by: [ka] During the ceremony, W is CH2, O, CHR (e.g., CH(CH3)), C=O, NH, or N; each X is independently selected from absent, O, S, and CH; Z is O, S or CH2; G is H, methyl or OH; Each of Q1, Q2, Q3 and Q4 independently represents N or C substituted with H or R; A is H, unsubstituted or substituted straight or branched chain alkyl, Cl, or F; n is an integer from 1 to 4 (e.g., 1 or 2, 1 to 3, 1, 2, 3, or 4); each R independently comprises a bond, H, -OR', -NR'R", -CR'R"-, unsubstituted or substituted linear or branched C1-C6 straight or branched alkyl (e.g., C1-C3 alkyl, and / or optionally substituted with one or more halogens), an unsubstituted or substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy, wherein the alkoxyl is optionally substituted with one or more halogens, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl), an optionally substituted 4-6 membered cycloalkyl, an optionally substituted 4-6 membered heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, or NO2, and one R is covalently bonded to L; R' and R" are each independently selected from a bond, H, and substituted or unsubstituted C1-C4 alkyl (e.g., methyl or ethyl); and [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; (b) the PTM is a small molecule comprising a B-cell lymphoma 6 protein (BCL6) targeting moiety selected from: [ka] During the ceremony, R PTM5 is H, an optionally substituted straight or branched chain C-C alkyl (e.g., methyl, ethyl, or isopropyl), C-C alkyl-O(C-C alkyl), C-C alkyl-O—, C-C alkyl-NH(C-C alkyl), C-C alkyl-N(C-C alkyl), optionally substituted C-C aryl, optionally substituted C-C heteroaryl, optionally substituted C-C cycloalkyl, or optionally substituted C-C heterocyclyl; Q6 and Q16 are each independently N or CH; Q7 and Q 14 are each independently N or CH; X PTM1 is H, Cl, or F; X PTM2 is H, Cl, F, or CN; Q8 and Q9 [ka] is a single or double bond, When Q8 and Q9 are connected by a single bond, Q8 is CH2; and Q9 is CH(R PTM3 ) or N(R PTM3 ) and; When Q8 and Q9 are connected by a double bond, Q8 is CH; and Q9 is C(R PTM3 ) and; R PTM3 -OH; -Cl; -F; -CN; optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted C1-C6 alkoxy (e.g., -OCH3 or -OCH2CH3); optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl, C1-C4 alkoxy, -Cl; -F, -CN, or -OH); or optionally substituted [ka] (e.g., optionally substituted with straight or branched chain C1-C4 alkyl, C1-C4 alkoxy, -Cl, -F, -CN, or -OH); R PTM1a and R PTM2aare each independently H, optionally substituted C1-C4 alkyl (e.g., CH3 or CH2CH3), optionally substituted C1-C4 alkoxy (e.g., -OCH3 or -OCH2CH3), or CH2OCH3; each t1 is independently 1, 2, 3, 4, or 5; and each t2 is independently 0, 1, 2, 3, 4, or 5; R PTM2 is H, OH, CN, -F, -Cl, optionally substituted straight or branched chain C1-C4 alkyl, optionally substituted -NH2 (e.g., -N(C1-C3 alkyl)2 or -NH(C1-C3 alkyl)), optionally substituted straight or branched chain -O-C1-C4 alkyl, optionally substituted monocyclic or bicyclic C3-C12 heterocycloalkyl (e.g., azetidin 1-yl, azetidin 1-yl-3-ol, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, homopiperazin-1-yl, [ka] each optionally substituted with one or more of OH, straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), optionally substituted -OC 3-12monocyclic or bicyclic heterocycloalkyl (e.g., optionally substituted with one or more OH, straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted C3-C12 cycloalkyl (e.g., optionally substituted with one or more OH, straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), optionally substituted C5-C6 heteroaryl (e.g., optionally substituted with one or more straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2), or optionally substituted C5-C6 aryl (e.g., optionally substituted with one or more straight or branched chain C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2); and PTM [ka] indicates the point of attachment to L; and (c) L is a chemical linker group that covalently connects the CLM and the PTM, represented by the formula: -(A L ) q -, During the ceremony, -(A L ) q - is a group attached to a CLM or PTM; q is an integer greater than or equal to 1; Each A is independently L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, 1 to 6 R L1 Groups and / or R L2 C optionally substituted with a group3-11 monocyclic or bicyclic cycloalkyl, 1 to 9 R L1 Groups and / or R L2 C optionally substituted with a group 5-13 spirocycloalkyl, 1 to 6 R L1 Groups and / or R L2 C optionally substituted with a group 3-11 monocyclic or bicyclic heterocyclyl, 1 to 8 R L1 Groups and / or R L2 C optionally substituted with a group 5-13 spiroheterocyclyl, 1 to 6 R L1 Groups and / or R L2 aryl optionally substituted with a group, and 1 to 6 R L1 Groups and / or R L2 heteroaryl optionally substituted with a group; and R L1 , R L2 , R L3 , R L4 and R L5 each independently represents H, a halogen, or C 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, C 3-11 cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, C 3-11 Heterocyclyl, OC 3-8 Cycloalkyl, SC 3-8 Cycloalkyl, NHC 3-8 Cycloalkyl, N(C 3-8 cycloalkyl)2, N(C 3-8 Cycloalkyl)(C 1-8 alkyl), OH, NH2, SH, SO2C 1-8 Alkyl, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C1-8 Alkyl)2, COC 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl)SO2N(C 1-8 alkyl)2, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 alkyl)2, or NH SO NH .

[0034] In some embodiments, compounds of the present disclosure have a PTM selected from: [ka] In the formula, PTM [ka] indicates the point of attachment to L.

[0035] In some embodiments, compounds of the present disclosure have a PTM selected from: [ka] In the formula, PTM [ka] indicates the point of attachment to L.

[0036] In some embodiments, compounds of the present disclosure have a PTM selected from: [ka] In the formula, PTM [ka] indicates the point of attachment to L.

[0037] In some embodiments, compounds of the present disclosure have at least one of the following: (a) R of PTMIIa1, PTMIIa2, PTMIIa4, PTMIIb1, PTMIIb2, PTMIIb4, PTMIIc1, PTMIIc2, and PTMIIc4 PTM2 is selected from the following: H, OH, NH2, -N(CH3)2, methyl, ethyl, [ka] During the ceremony, [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific; [ka] indicates the point of attachment of the PTM to the aryl or heteroaryl; (c) R of PTMIIa1, PTMIIa2, PTMIIa4, PTMIIb1, PTMIIb2, PTMIIb4, PTMIIc1, PTMIIc2, and PTMIIc4 PTM3 is selected from the following: [ka] During the ceremony, [ka] is the biheteroaryl or biheterocycle of the PTM and RPTM3 indicates the point of attachment of; or (d) R of PTMIIa1, PTMIIa2, PTMIIa4, PTMIIb1, PTMIIb2, PTMIIb4, PTMIIc1, PTMIIc2, and PTMIIc4 PTM5 is selected from the following: H, methyl, CFH2, CF2H, ethyl, propyl, isopropyl, cyclopropyl, butyl, pentyl, hexyl, [ka] During the ceremony, [ka] is the nitrogen of the biheteroaryl or biheterocycle of the PTM and R PTM5 indicates the point of attachment of; or (e) Any combination of (a), (b), (c), and (d).

[0038] In some embodiments, compounds of the present disclosure have a PTM that is: [ka] [ka]

[0039] In some embodiments, compounds of the present disclosure have a PTM that is: [ka] [ka]

[0040] In some embodiments, compounds of the present disclosure have a PTM that is: [ka]

[0041] In some embodiments, compounds of the present disclosure have a PTM that is: [ka]

[0042] In some embodiments, compounds of the present disclosure have a PTM that is: [ka]

[0043] In some embodiments, compounds of the present disclosure have a CLM that is: [ka] During the ceremony, W is CH2, O, CH(C 1-3 alkyl) (e.g., CH(CH3)), or C=O; G is H, methyl or OH; Each of Q1, Q2, Q3, and Q4 independently represents N, CH, or CR; A is H, unsubstituted or substituted straight or branched chain alkyl, Cl, or F; n is an integer from 1 to 4; R comprises a bond, H, -OR', -NR'R", -CR'R"-, unsubstituted or substituted linear or branched C1-C6 straight or branched alkyl (e.g., C1-C3 alkyl, and / or optionally substituted with one or more halogens), an unsubstituted or substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy, wherein the alkoxyl is optionally substituted with one or more halogens, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl), an optionally substituted 4-6 membered cycloalkyl, an optionally substituted 4-6 membered heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, or NO2, and one R is covalently bonded to L; R' and R" are each independently selected from a bond H, and substituted or unsubstituted C1-C4 alkyl (e.g., methyl or ethyl); [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0044] In some embodiments, compounds of the present disclosure have a CLM that is: [ka] During the ceremony, W is CH2, O, CH(C 1-3 alkyl) (e.g., CH(CH3)), or C=O; A is H, methyl, or optionally substituted straight or branched chain alkyl; n is an integer from 1 to 4; R is independently selected from H, O, OH, N, NH, NH, methyl, optionally substituted straight or branched chain alkyl (e.g., optionally substituted straight or branched chain C-C alkyl), C-C alkoxy, and -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C-C alkyl, C-C aryl, or a combination thereof), aryl (e.g., C-C aryl), amine, amide, or carboxy, wherein one R or W is optionally modified to be covalently attached to a chemical linker group (L); and In equation (g), [ka] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0045] In some embodiments, A is H.

[0046] In some embodiments, W is CH2 or C=O.

[0047] In some embodiments, W is CH2.

[0048] In some embodiments, W is C=O.

[0049] In some embodiments, compounds of the present disclosure have L selected from: [ka] During the ceremony, [ka] are each independently a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl (e.g., a 4- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl), and overlapping rings represent a spirocyclic ring; each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, or 6; R L H and C 1-3 alkyl; The linker optionally comprises (i) =O and (ii) C 1-3 substituted with at least one of 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); and [ka] indicates the point of attachment to the PTM or CLM.

[0050] In some embodiments, compounds of the present disclosure have L selected from: [ka] [ka] During the ceremony, [ka] are each independently a 3- to 7-membered cycloalkyl or a 3- to 7-membered heterocycloalkyl (e.g., a 4- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl), and overlapping rings represent a spirocyclic ring; [ka] is an 8- to 10-membered bridged cycloalkyl, an 8- to 10-membered bridged heterocycloalkyl, a 3- to 7-membered heterocyclyl having one or two double bonds (e.g., a 3- to 7-membered heterocyclyl having one or two double bonds), or a 7- to 10-membered fused bicyclic heterocycloalkyl (e.g., a 7- to 9-membered fused bicyclic heterocycloalkyl); each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, or 6; R L H and C 1-3 alkyl; The linker optionally comprises (i) =O and (ii) C 1-3 substituted with at least one of 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from alkyl (e.g., methyl), OH, and halogen (e.g., F, Cl, or Br); and [ka] indicates the point of attachment to the PTM or CLM.

[0051] In some embodiments, compounds of the present disclosure have L selected from: [ka] During the ceremony, The above chemical linker groups without substituents may optionally be selected from (i) ═O and (ii) C 1-3 substituted with at least one of 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * indicates an atom (e.g., nitrogen, carbon, or oxygen) that is covalently bonded to or shared with the CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and m, n, o, and p are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3).

[0052] In some embodiments, compounds of the present disclosure have L selected from: [ka] [ka] During the ceremony, The above chemical linker groups without substituents may optionally be selected from (i) ═O and (ii) C 1-3 substituted with at least one of 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * indicates an atom (e.g., nitrogen or carbon) covalently bonded to or shared with the CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and Each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3).

[0053] In some embodiments, compounds of the present disclosure have L selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] During the ceremony, The above chemical linker groups without substituents may optionally be selected from (i) ═O and (ii) C 1-3 substituted with at least one of 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * indicates an atom (e.g., nitrogen or carbon) covalently bonded to or shared with the CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and Each of m, n, and o is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3).

[0054] In some embodiments, compounds of the present disclosure have L selected from: [ka] [ka] [ka] During the ceremony, The above chemical linker groups without substituents may optionally be selected from (i) ═O and (ii) C 1-3 substituted with at least one of 1 to 4 (e.g., 1, 2, 3, or 4) substituents independently selected from alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); * indicates an atom (e.g., nitrogen or carbon) that is shared with or covalently bonded to a CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and Each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3).

[0055] In some embodiments, compounds of the present disclosure have L selected from: [ka] During the ceremony, X L is an N group or a CH group; each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (preferably 0, 1, 2, or 3); * indicates an atom (e.g., nitrogen or carbon) that is shared with or covalently bonded to a CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and The chemical linker comprises 0 to 4 substituents (preferably 0, 1, or 2 substituents), each substituent independently selected from the group consisting of C 1~3 It is alkyl (preferably methyl).

[0056] In some embodiments, compounds of the present disclosure have L selected from: [ka] During the ceremony, X L is an N or CH group; [ka] represents a stereospecific bond, one having the (R) configuration and the other having the (S) configuration; * indicates an atom (e.g., nitrogen or carbon) that is shared with or covalently bonded to a CLM or PTM; [ka] indicates the point of attachment to the PTM or CLM; and The chemical linker comprises 0 to 4 substituents (preferably 0, 1, or 2 substituents), each substituent independently selected from the group consisting of C 1~3 It is alkyl (preferably methyl).

[0057] In some embodiments, the compounds of the present disclosure are (a) A CLM that is: [ka] During the ceremony, CLM's [ka] indicates the point of attachment to L; and N * is a nitrogen atom shared with the chemical linker group; (b) [ka] wherein: [ka] indicates the point of attachment to L; and / or (c) L is [ka] is selected from: * indicates an atom (e.g., carbon or nitrogen) covalently bonded to or shared with the CLM or PTM; [ka] Each of the has a which indicates a point of attachment to a CLM or PTM.

[0058] In some embodiments, the compounds of the present disclosure are (a) A CLM that is: [ka] [ka] [ka] During the ceremony, CLM's [ka] indicates the point of attachment to L; and N * is a nitrogen atom shared with the chemical linker group; (b) a PTM that is: [ka] [ka] [ka] In the formula, PTM [ka] indicates the point of attachment to L; (c) L is selected from: [ka] During the ceremony, * represents an atom (e.g., carbon, nitrogen, or oxygen) covalently bonded to or shared with the CLM or PTM; [ka] each of which indicates a point of attachment to a CLM or PTM; or (d) any combination of (a), (b), and (c).

[0059] In some embodiments, the compounds of the present disclosure are (a) A CLM that is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] During the ceremony, CLM's [ka] indicates the point of attachment to L; and N * is a nitrogen atom shared with the chemical linker group; (b) a PTM that is: [ka] [ka] [ka] [ka] [ka] In the formula, PTM [ka] indicates the point of attachment to L; (c) L is selected from: [ka] [ka] [ka] During the ceremony, * represents an atom (e.g., carbon, nitrogen, or oxygen) covalently bonded to or shared with the CLM or PTM; [ka] each of which indicates a point of attachment to a CLM or PTM; or (d) any combination of (a), (b), or (c).

[0060] In some embodiments, the compound of the present disclosure is selected from the list of compounds in Table 1 or a pharmaceutically acceptable salt thereof. Table 1. Compounds of the present disclosure Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 Table 1-66 Table 1-67 Table 1-68

Table 1-69

Table 1-90

Table 1-100

[0061] In some embodiments, the compound of the present disclosure is Compound 81 (Compound A), Compound 163, Compound 208, Compound 209, Compound 211, or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the compounds of the present disclosure are [ka] or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the compounds of the present disclosure are [ka] is.

[0064] In some embodiments, the compound of the present disclosure is compound 163, or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the compound of the present disclosure is compound 163.

[0066] In some embodiments, the compound of the present disclosure is compound 208, or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the compound of the present disclosure is compound 208.

[0068] In some embodiments, the compound of the present disclosure is compound 209, or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the compound of the present disclosure is compound 209.

[0070] In some embodiments, the compound of the present disclosure is compound 211, or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the compound of the present disclosure is compound 211.

[0072] The compounds of the present disclosure can be synthesized using standard synthetic methods and procedures for the preparation of organic molecules, functional group transformations and manipulations, including the use of protecting groups, in the field of the present disclosure, as can be obtained from the relevant scientific literature or from standard reference textbooks in the field. Recognized reference textbooks on organic synthesis, without limitation to any one or several sources, include Smith, MB; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th ed.; John Wiley & Sons: New York, 2001, and Greene, T.W. Buts, P.G.M. Protective Groups in Organic Synthesis, 3 rdJohn Wiley & Sons: New York, 1999. The synthetic methods described in U.S. Patent Application Publication No. 2022 / 0395576 and WO 2022 / 221673 are incorporated herein by reference in their entirety.

[0073] As used herein, the term "independently" is used to indicate that the variables that are independently applied vary independently from application to application.

[0074] The term "alkyl" shall mean, within its context, a straight-chain, branched-chain, or cyclic, fully saturated hydrocarbon radical or group of alkyl, preferably C-C 10 , more preferably C1-C6 or C1-C3 alkyl groups, which may be optionally substituted. Examples of alkyl groups include methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methyl-propyl, cyclopropyl, cyclo-propyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl, among others. In certain embodiments, the alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I). In certain preferred embodiments, compounds according to the present disclosure may be used to covalently bind to dehalogenase enzymes. These compounds generally contain a side chain (often attached via a polyethylene glycol group) that terminates in an alkyl group bearing a halogen substituent (often chlorine or bromine) at its distal end, thereby forming a covalent bond between the compound containing the moiety and the protein.

[0075] The term "alkenyl" refers to a straight, branched or cyclic C-C alkyl group containing at least one C=C bond. 10 (Preferably C2-C6) hydrocarbon radicals.

[0076] The term "alkynyl" refers to a C-C alkyl group that is linear, branched, or cyclic and contains at least one C≡C bond. 10(Preferably C2-C6) hydrocarbon radicals.

[0077] The term "alkylene," when used, refers to an optionally substituted -(CH) n -group (n is generally an integer from 0 to 6). When substituted, alkylene groups are preferably substituted at one or more of the methylene groups with a C1-C6 alkyl group (including a cyclopropyl group or a t-butyl group), but may also be substituted with one or more halo groups, preferably 1 to 3 halo groups, or one or two hydroxyl groups, an O-(C1-C6 alkyl) group, or an amino acid side chain as otherwise disclosed herein. In certain embodiments, alkylene groups may be substituted with a urethane or alkoxy group (or other group), which in turn is substituted with a polyethylene glycol chain (a chain of 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to which an alkyl group (preferably, but not exclusively, on the distal end of the polyethylene glycol chain) is substituted, and the alkyl chain is substituted with a single halogen group, preferably a chlorine group. In still other embodiments, the alkylene (often methylene) group may be substituted with an amino acid side chain group, such as the side chain group of a natural or unnatural amino acid, e.g., alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan, or tyrosine.

[0078] The term "unsubstituted" is intended to mean substituted only with hydrogen atoms. A range of carbon atoms that includes C0 means that the carbon is absent and replaced with an H. Thus, a range of carbon atoms from C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, with an H replacing the carbon for C0.

[0079] The terms "substituted" or "optionally substituted" refer independently to one or more substituents (independently up to five substituents, preferably up to three substituents, often one or two substituents, on a moiety in a compound according to the present disclosure, which may include substituents that may themselves be further substituted) at any carbon (or nitrogen) position on the molecule in context (i.e., when there are multiple substituents, each substituent is independent of the other substituents), and include as substituents hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (preferably one, two, or three halogens, especially on alkyl, especially methyl groups such as, for example, trifluoromethyl), alkyl groups (preferably C1-C2), and the like. 10, more preferably C1-6), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy groups (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioethers (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), esters or thioesters (preferably C1-C6 alkyl or aryl), including alkylene esters (where the attachment is on the alkylene group rather than the ester functionality, and is preferably substituted with a C1-C6 alkyl or aryl group), preferably C1-C6 alkyl or aryl, halogens (preferably F or Cl), amines (including 5- or 6-membered cyclic alkylene amines, including C1- Further examples include C alkylamines or C1-C6 dialkylamines, where the alkyl groups may be substituted with one or two hydroxyl groups, or optionally substituted —N(C0-C6 alkyl)C(O)(O—C1-C6 alkyl) groups (which may be optionally substituted with a polyethylene glycol chain to which is further attached an alkyl group containing one halogen, preferably chlorine, substituent); hydrazines; amides, preferably substituted with one or two C1-C6 alkyl groups (including carboxamides optionally substituted with one or two C1-C6 alkyl groups); alkanols (preferably C1-C6 alkyl or aryl); or alkanoic acids (preferably C1-C6 alkyl or aryl). Substituents according to the present disclosure may include, for example, -SiR1R2R3 groups, where each of R1 and R2 is as otherwise described herein, and R3 is H or a C1-C6 alkyl group, preferably in this context R1, R2, R3 are C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the above groups may be directly bonded to the substituted moiety, or the substituent may be an optionally substituted -(CH2) m - or optionally substituted -(OCH2) m -, -(OCH2CH2) m -or-(CH2CH2O) mThe alkylene group -(CH) may be linked via a - group to a substituted moiety (preferably in an aryl or heteroaryl moiety), which may be substituted with any one or more of the above-mentioned substituents. m -or-(CH2) n -groups or other chains, such as the ethylene glycol chains identified above, may be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl groups, which may optionally be substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or an amino acid side chain as otherwise described herein, and optionally substituted amide (preferably carboxamide substituted as described above) or urethane groups (often with one or two C0-C6 alkyl substituents, which may also be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or an amino acid side chain as otherwise described herein. Moieties in the molecules of the present disclosure may optionally be substituted with up to five substituents, preferably up to three substituents. In most cases, moieties that are substituted in this disclosure will be substituted with one or two substituents.

[0080] The term "substituted" (each substituent independent of any other substituent) is intended to mean, within the context of its use, C-C alkyl, C-C alkoxy, halogen, amide, carboxamide, sulfone, including sulfonamide, keto, carboxy, C-C ester (oxyester or carbonylester), C-C keto, urethane-OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (particularly C-C alkylene-NR1R2, mono- or di-C-C alkyl-substituted amines, which may be optionally substituted with one or two hydroxyl groups). Each of these groups contains 1 to 6 carbon atoms, unless otherwise indicated within the context. In certain embodiments, preferred substituents, depending on the context of the use of the substituent, include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m - (where m and n are 1, 2, 3, 4, 5 or 6, in the context), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CHO) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CHO) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CHO) n C(O)-NR1R2, -S(O)2-R S , -S(O)-R S (R Sis C1-C6 alkyl or -(CH2) m The term "substituted" is intended to include an optionally substituted aryl or heteroaryl group, or an optionally substituted heterocyclic group as otherwise described herein, within the chemical context of the compound specified and the substituents used. Alkylene groups may also be substituted as otherwise disclosed herein, preferably with an optionally substituted C-C alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl being preferred, thereby providing a chiral center), the side chain of an amino acid group as otherwise described herein, an amide group as described above, or a urethane group, an O-C(O)-NRR group, where R and R are as otherwise described herein, although many other groups may also be used as substituents. Various optionally substituted moieties may be substituted with three or more substituents, preferably three or fewer, and preferably one or two substituents. Note that in compounds where substitution is required at a particular position in the molecule (primarily for valence reasons) but no substitution is indicated, the substituent is assumed or understood to be H unless the context of the substitution suggests otherwise.

[0081] The terms "aryl" or "aromatic," in context, refer to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenylphenyl, phenanthrenyl, etc.), which may be attached to a compound in accordance with the present disclosure at any available stable position on the ring or as otherwise specified in the provided chemical structure. Other examples of aryl groups, in context, include "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in a single ring such as heteroaromatic ring systems, e.g., imidazole, furyl, pyrrole, furanyl, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, etc., or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., among others, which may be optionally substituted as described above.Heteroaryl groups which may be mentioned in particular are nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenanacene, oxadiazole, benzyl Examples include imidazole, pyrrolopyridine, pyrrolopyrimidine, and pyridopyrimidine, sulfur-containing aromatic heterocycles such as thiophene and benzothiophene, oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran, and isobenzofuran, and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur, and oxygen such as thiazole, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoleoxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, and oxazole, all of which may be optionally substituted.

[0082] The term "substituted aryl" refers to an aromatic carbocyclic ring composed of at least one aromatic ring or composed of multiple fused rings, at least one of which is aromatic, in which the ring is substituted with one or more substituents. For example, an aryl group can be -(CH) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n-C(O)O(C0-C6) alkyl, -(CH2) n and -OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine, where the alkyl groups on the amine are optionally substituted with one or two hydroxyl groups, or up to three halo (preferably F, Cl), OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups, each of which may be substituted at the ortho, meta, and / or para positions of the phenyl ring, preferably the para position. and / or at least one of a phenyl group (which itself is preferably attached via a linker group to a PTM group, including a ULM group) and / or a F, Cl, OH, COOH, CH, CF, OMe, OCF, NO, or CN group (at the ortho, meta, and / or para positions of the phenyl ring, preferably at the para position), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, or any methyl-substituted oxazole, including methyl-substituted oxazole. optionally substituted oxazole, optionally substituted thiazole including methyl substituted thiazole, optionally substituted isothiazole including methyl substituted isothiazole, optionally substituted pyrrole including methyl substituted pyrrole, optionally substituted imidazole including methyl imidazole, optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oximidazole or methyloximidazole, optionally substituted diazole group including methyl diazole group, optionally substituted triazole group including methyl substituted triazole group, optionally substituted pyridine group including halo (preferably F) or methyl substituted pyridine group or oxapyridine group (wherein the pyridine group is attached to the phenyl group by an oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2, 3, or 4-azaindolizine), optionally substituted quinoline, and combinations thereof.

[0083] "Carboxyl" refers to the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, where these generic substituents have the same meaning as the corresponding groups defined herein.

[0084] The term "heteroaryl" or "hetaryl" includes, but is not limited to, optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3, or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzoxofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl, triisopropylsilyl, optionally substituted -(CH) m -O-C1-C6 alkyl group or optionally substituted -(CH2) m It may refer to a 1,2,3-triazole substituted with a —C(O)—O—C1-C6 alkyl group), an optionally substituted pyridine (2, 3, or 4-pyridine), or a group according to the following chemical structure: [ka] During the ceremony, S c is CHR SS , N.R. URE , or O; R HETis H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group, -C≡CR a wherein R a is an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C1-C6 alkyl (preferably H or C1-C3 alkyl), or —C(O)(C1-C6 alkyl), each group optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine, groups, or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, etc., each of which is optionally substituted; and Y C is N or CR YC where R YC is H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF)), optionally substituted O(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group, -C≡CR a wherein R ais an acetylene group which is H or a C1-C6 alkyl group (preferably C1-C3 alkyl).

[0085] The terms "aralkyl" and "heteroarylalkyl" refer to groups containing aryl or heteroaryl, respectively, as defined above, and alkyl, and / or heteroalkyl, and / or carbocyclic and / or heterocycloalkyl ring systems.

[0086] As used herein, the term "arylalkyl" refers to an aryl group, as defined above, appended to an alkyl group, as defined above. An arylalkyl group is attached to the parent moiety via an alkyl group, where the alkyl group is 1 to 6 carbon atoms. The aryl group in the arylalkyl group may be optionally substituted as described above.

[0087] The term "heterocycle" refers to a cyclic group containing at least one heteroatom, such as N, O, or S, and may be aromatic (heteroaryl) or non-aromatic. Heteroaryl moieties are therefore encompassed under the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described herein above.

[0088] Exemplary heterocycles include, among others, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolyl, and benzothiazolyl. Examples include sazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, and thiane.

[0089] Heterocyclic groups can be optionally substituted with groups selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, oxo (=O), and -SO-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like, as well as N-alkoxy-nitrogen-containing heterocycles. The term "heterocyclic" also includes bicyclic groups in which either heterocyclic ring is fused to a benzene ring or a cyclohexane ring or to another heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0090] The term "cycloalkyl" can refer to, but is not limited in any manner to, a monovalent group derived from a monocyclic or polycyclic alkyl group or cycloalkane as defined herein, for example, a saturated monocyclic hydrocarbon group having 3 to 20 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" refers to, but is not limited to, a monocyclic or polycyclic alkyl group substituted with one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, wherein these generic substituents have the same meaning as the definition of the corresponding group provided in this Description.

[0091] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom in its ring structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom in its ring structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P, and which groups contain one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, wherein these generic substituents have the same meaning as the definition of the corresponding group provided in this Description.

[0092] The term "hydrocarbyl" is intended to mean a compound containing carbon and hydrogen, which may be fully saturated, partially unsaturated, or aromatic, and includes aryl, alkyl, alkenyl, and alkynyl groups.

[0093] As used herein, the term "independently" is used to indicate that the variables that are independently applied vary independently from application to application.

[0094] The term "lower alkyl" refers to methyl, ethyl, or propyl.

[0095] The term "lower alkoxy" refers to methoxy, ethoxy, or propoxy.

[0096] therapeutic composition Described herein are therapeutic compositions comprising the compounds of the present disclosure, or pharmaceutically acceptable salts thereof.

[0097] The compounds of the present disclosure may be administered orally, parenterally, or topically, in single or divided doses. Administration of the active compound may range from continuous (intravenous drip) to several oral doses per day (e.g., QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain penetration enhancers), buccal, sublingual, and suppository administration, among other routes of administration. Enteric-coated oral tablets may be used to enhance the bioavailability of the compound from oral administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent selected and the severity of the patient's disease. The compounds of the present disclosure may also be administered as a spray, mist, or aerosol for intranasal, intratracheal, or pulmonary administration. Accordingly, the present disclosure also relates to pharmaceutical compositions comprising an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, as described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or vehicle. The compound of the present disclosure can be administered in immediate release, intermediate release, or sustained or controlled release form.Sustained or controlled release form is preferably administered orally, but can also be administered via suppository, transdermal or other topical forms.Intramuscular injection of liposome form can also be used to control or maintain the release of compound at injection site.

[0098] The compositions described herein may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled release formulations.

[0099] The compositions described herein may be administered orally, parenterally by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted container. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.

[0100] The sterile injectable form of the compositions described herein may be an aqueous or oily suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.

[0101] The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form, including but not limited to, a capsule, a tablet, an aqueous suspension, or a solution.

[0102] Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug.

[0103] The amount of compound in the pharmaceutical compositions described herein that can be combined with carrier materials to produce a dosage form will vary depending on the host and condition being treated, and the particular mode of administration. In some embodiments, compositions should be formulated to contain about 0.05 milligrams to about 750 milligrams or more, about 1 milligram to about 600 milligrams, or about 10 milligrams to about 500 milligrams of active ingredient, alone or in combination with at least one other compound according to the present disclosure.

[0104] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, and the severity of the particular disease or condition being treated.

[0105] The compounds of the present disclosure can be administered by any suitable route, such as orally, parenterally, intravenously, intradermally, subcutaneously, or topically, for example, transdermally in liquid, cream, gel, or solid form, or in aerosol form.

[0106] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient an effective dose for the desired indication, but which does not cause serious toxic effects in the patient being treated. Preferred doses of the active compound for all of the conditions mentioned herein range from about 10 ng / kg to about 300 mg / kg, from about 0.1 to about 100 mg / kg per day, or from about 0.5 to about 25 mg per kilogram of recipient body weight per day. Typical topical dosages can range from 0.01 to 5% wt / wt in a suitable carrier.

[0107] The compound is conveniently administered in any suitable unit dosage form, including but not limited to, containing less than 1 mg, between 1 mg and 3000 mg, between 5 and 500 mg of active ingredient per unit dosage form.

[0108] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001 to 30 mM, or about 0.1 to 30 μM. This may be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline solution or aqueous medium, or by bolus administration of the active ingredient. Oral administration is also suitable for producing effective plasma concentrations of the active agent.

[0109] The concentration of the active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​will also vary depending on the severity of the condition to be alleviated. It should further be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered at once, or may be divided into multiple smaller doses to be administered at varying time intervals.

[0110] Oral compositions generally will contain an inert diluent or an edible carrier. They may be enclosed in a gelatin capsule or compressed into a tablet. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be combined with an excipient and used in the form of a tablet, troche, or capsule. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition.

[0111] The active compound or its pharmaceutically acceptable salt can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.

[0112] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations may be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

[0113] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Methods for preparing such formulations will be apparent to those skilled in the art.

[0114] Liposomal suspensions can also be pharmaceutically acceptable carriers.They can be prepared according to the methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (incorporated herein in its entirety by reference).For example, liposomal preparations can be prepared by dissolving suitable lipids in an inorganic solvent, and then evaporating, leaving a thin film of dried lipid on the surface of the container.Then, an aqueous solution of active compound is added to the container.Then, the container is rotated by hand to remove lipid material from the side of the container, disperse lipid mass, and form a liposomal suspension.

[0115] The active compounds or pharmaceutically acceptable salts thereof may be mixed with other active substances that do not impair the desired action, or with substances that complement the desired action, particularly the anti-cancer agents described herein. In certain preferred aspects of the present disclosure, one or more compounds according to the present disclosure are co-administered with another bioactive agent, such as an anti-cancer agent, or a wound healing agent, including an antibiotic, as otherwise described herein.

[0116] Treatment method In some embodiments, the present disclosure provides a method of treating or ameliorating a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from Compound 81 (Compound A), Compound 163, Compound 208, Compound 209, Compound 211, or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound A.

[0118] In some embodiments, the present disclosure provides a method of treating or ameliorating a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure. [ka] is.

[0119] In some embodiments, the present disclosure provides a method of treating or ameliorating a disease or disorder disclosed herein in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure. [ka] or a pharmaceutically acceptable salt thereof.

[0120] As used herein, the terms "treat," "treating," and "treatment" refer to any action that benefits a patient, including the treatment of any disease state or condition for which the compounds may be administered that is modulated via the protein to which the compounds bind. Disease states or conditions, including cancer, that may be treated using compounds according to the present disclosure are described herein above.

[0121] In some embodiments, the disease or disorder is associated with aberrant BCL6 expression or activity.

[0122] In some embodiments, the disease or disorder is cancer associated with aberrant BCL6 expression or activity.

[0123] In some embodiments, the disease or disorder is associated with accumulation and aggregation of BCL6.

[0124] In some embodiments, the disease or disorder is a cancer associated with the accumulation and aggregation of BCL6.

[0125] In some embodiments, the disease or disorder is cancer.

[0126] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mature B-cell neoplasm, transformed follicular lymphoma, high-grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor.

[0127] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma, high-grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, and non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor.

[0128] As used herein, "angioimmunoblastic T-cell lymphoma" is also known as "AITL" or "nodal T-follicular helper (TFH)-cell lymphoma, angioimmunoblastic type."

[0129] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor.

[0130] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma, high-grade B-cell lymphoma, non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor.

[0131] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), or a solid tumor.

[0132] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma.

[0133] In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0134] In some embodiments, the cancer is transformed follicular lymphoma.

[0135] In some embodiments, the cancer is aggressive B-cell lymphoma.

[0136] In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL), where the diffuse large B-cell lymphoma (DLBCL) is selected from germinal center B-cell (GCB) DLBCL and activated B-cell (ABC) DLBCL.

[0137] In some embodiments, the cancer is germinal center B-cell (GCB) DLBCL.

[0138] In some embodiments, the cancer is activated B-cell (ABC) DLBCL.

[0139] In some embodiments, the cancer is non-Hodgkin's lymphoma, not otherwise specified.

[0140] In some embodiments, the cancer is a mature B-cell neoplasm.

[0141] In some embodiments, the cancer is a solid tumor.

[0142] In some embodiments, the cancer is a solid tumor, wherein the solid tumor is selected from breast cancer, lung cancer, ovarian cancer, neuroblastoma, and glioblastoma.

[0143] In some embodiments, the cancer is breast cancer.

[0144] In some embodiments, the cancer is lung cancer.

[0145] In some embodiments, the cancer is ovarian cancer.

[0146] In some embodiments, the cancer is neuroblastoma.

[0147] In some embodiments, the cancer is glioblastoma.

[0148] The terms "neoplasm" or "cancer" are used throughout this specification to refer to cancerous or malignant neoplasms, i.e., pathological processes that result in the formation and growth of abnormal tissue that grows by cell proliferation, often much faster than normal, and continues to grow after stimuli that would otherwise have stopped the new growth that has been initiated. Malignant neoplasms exhibit partial or complete lack of structural organization and functional coordination with normal tissue, and most invade surrounding tissues, metastasize to several sites, recur after attempted removal, and have a high probability of patient death unless appropriately treated. As used herein, the term neoplasm is used to describe all cancerous conditions and includes pathological processes associated with malignant hematopoietic cells, ascites, and solid tumors. Examples of cancers that may be treated by the compounds of the present invention, alone or in combination with at least one additional anti-cancer agent, include diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, mature B-cell neoplasms, transformed follicular lymphoma, high-grade B-cell lymphoma, germinal center B-cell (GCB) DLBCL, activated B-cell (ABC) DLBCL, non-Hodgkin's lymphoma-not otherwise specified, or solid tumors, including but not limited to breast, lung, and ovarian cancer, as well as neuroblastoma and glioblastoma.

[0149] In some embodiments, the present disclosure provides a method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure. In some embodiments, the compound is selected from the group listed in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound A. In some embodiments, the compound of the present disclosure is Compound 163 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is Compound 163. In some embodiments, the compound of the present disclosure is Compound 208, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is Compound 208. In some embodiments, the compound of the present disclosure is Compound 209, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is Compound 209. In some embodiments, the compound of the present disclosure is Compound 211, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is Compound 211. [Example]

[0150] Example 1. Compound A degrades BCL6 protein in GCB and ABC DLBCL cell lines. Degradation of BCL6 protein in DLBCL cell lines was measured by ELISA. The OCI-Ly1 cell line was treated with Compound A and its E3-binding-deficient analog for 24 hours (Figure 2A). GCB DLBCL cell lines Farage, SU-DHL-4, SU-DHL-6, and OCI-Ly7 (Figure 2B) and ABC DLBCL cell lines SU-DHL-2 and OCI-Ly10 (Figure 2C) were treated with Compound A for 24 hours. Figure 2A shows that treatment with Compound A potently degraded BCL6 protein in the OCI-Ly1 cell line compared to its E3-binding-deficient analog. Figures 2B and 2C show that treatment with Compound A potently degraded BCL6 protein in GCB and ABC DLBCL cell lines.

[0151] Example 2. Compound A inhibits proliferation of DLBCL cell lines. The antiproliferative effect of Compound A was tested on DLBCL-derived cell lines. A 9-day cell growth inhibition assay was performed using the GCB lines OCI-Ly1, OCI-Ly7, SU-DHL-4, and SU-DHL-6 (Figure 3A) and the ABC lines SU-DHL-2 and OCI-Ly10 (Figure 3B). Seven 3-fold serial dilutions of Compound A were administered at a maximum dose of 30 nM. On days 3 and 6–7, samples were split into new 48-well plates for further treatment, and 20% were split into 96-well plates for cell viability measurement using CellTiter-Glo (CTG). Split cells in the 48-well plates were harvested and cultured until day 9, at which point 20% of each sample was analyzed by CTG. Dose responses were plotted as a percentage of the vehicle (DMSO) control (Figures 3A and 3B). Graphs represent at least two independent proliferation assays per cell line. Treatment with each compound A showed a significant reduction in the proliferation of DLBCL cells, and the effect was concentration-dependent.

[0152] Example 3. Compound A inhibits tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly1. Mice bearing subcutaneous tumors were orally dosed (po) with vehicle or Compound A at 1, 3, 10, or 30 mg / kg daily for 22 days (qdx22). 3 The tumors were started with 0.001 mg / kg / day. Figure 4A shows the average growth of OCI-Ly1 tumors. Figure 4B shows the average body weight of treated mice. Statistical analysis was performed using a two-way analysis of variance: p<0.0001 (****). Error bars represent the standard error of the mean (±SEM). The data show that treatment with Compound A inhibited tumor growth in the OCI-Ly1 xenograft model derived from a DLBCL cell line, and the effect was dose-dependent.

[0153] Example 4. BCL6 protein levels in tumor lysates in OCI-Ly1 cell line xenograft tumor tissues after a time course of treatment with Compound A. Tumor lysate BCL6 protein levels in xenograft tumor tissues of the OCI-Ly1 cell line were measured after a time course of treatment with Compound A. Tumors were 200-400 mm 3 When the tumor reached 100% saturation, a single dose of Compound A was orally administered in a vehicle of 40% hydroxypropyl-b-cyclodextrin in citrate buffer at pH 3.0. Tumors were harvested at the indicated time points. Tumor tissue lysates were analyzed using Western immunoblotting and densitometry. BCL6 levels were normalized to GAPDH loading controls and expressed as a percentage of the mean BCL6 levels in the vehicle control group. The percentage of BCL6 degradation compared to vehicle is shown above each group. Cells (1 x 10 cells / mL) in 50% Matrigel + 50% RMPI-1640 (phenol red-free) were cultured at 1 x 10 cells / mL. 7 Cells / 100 μl / mouse) were implanted subcutaneously into the right flank. Figure 5 shows that treatment with Compound A rapidly degraded BCL6 protein in the OCI-Ly1 model, sustained for up to 36 hours.

[0154] Additionally, Figure 6 shows total plasma and tumor levels of Compound A after a time course of treatment with Compound A. The curves represent the average drug levels over time within each dose group for each tissue type. Individual data points show the spread of data within each group of seven mice per condition analyzed. Compound A reached maximum concentrations (C) at 4 hours in plasma and 8 hours in tumor tissue. max ) was achieved.

[0155] Example 5. Compound A inhibits tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly1. Mice bearing subcutaneous tumors were orally dosed (po) with vehicle or Compound A at 1, 3, or 10 mg / kg twice daily for 23 days (bidx23). 3The tumors were started with 1000 mg / kg of compound A. Figures 7A and 7B show that treatment with Compound A inhibited tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly1, and the effect was dose-dependent. Figure 7C shows BCL6 protein levels in tumor lysates 16 hours after the final dose, analyzed by Western blotting. BCL6 levels in individual tumors are shown in a scatter plot. The average is represented by a bar, determined by densitometry, normalized to the GAPDH loading control, and expressed as a percentage of vehicle. The percent degradation of BCL6 compared to vehicle is shown above each group. Statistical analysis was performed using a two-way ANOVA: p<0.0001 (****). Error bars represent the standard error of the mean (±SEM). Figure 7C shows that tumor growth inhibition by Compound A treatment is associated with dose-dependent degradation of BCL6 protein in the OCI-Ly1 model.

[0156] Example 6. Compound A inhibits tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly7. Mice bearing subcutaneous tumors were orally dosed (po) with vehicle or Compound A at 1, 3, 10, or 30 mg / kg daily for 13 days (qdx13). 3 The tumors were started with 1000 mg / kg of compound A. Figures 8A and 8B show that treatment with compound A inhibited tumor growth in the OCI-Ly7 xenograft model derived from a DLBCL cell line, and the effect was dose-dependent. Figure 8C shows BCL6 protein levels in tumor lysates 16 hours after the final dose, analyzed by Western blotting. BCL6 levels in individual tumors are shown in a scatter plot. The average is represented by a bar, determined by densitometry, normalized to the GAPDH loading control, and expressed as a percentage of vehicle. The percent degradation of BCL6 compared to vehicle is shown above each group. Statistical analysis was performed using a two-way ANOVA: p<0.0001 (****). Error bars represent the standard error of the mean (±SEM). Figure 8C shows that tumor growth inhibition by compound A treatment is associated with dose-dependent degradation of BCL6 protein in the OCI-Ly7 model.

[0157] Example 7. Compound A inhibits tumor growth in the DLBCL cell line-derived xenograft model SU-DHL-2. Mice bearing subcutaneous tumors were orally dosed (po) with vehicle or Compound A at 3, 10, or 30 mg / kg twice daily for 27 days (bidx27) or 30 mg / kg daily for 27 days (qdx27). 3 9A and 9B show that treatment with Compound A inhibited tumor growth in the SU-DHL-2 xenograft model derived from a DLBCL cell line, and the effect was dose-dependent. Figure 9C shows BCL6 protein levels in tumor lysates 16 hours after the final dose, analyzed by Western blotting. BCL6 levels in individual tumors are shown in a scatter plot. The average is represented by a bar, determined by densitometry, normalized to the GAPDH loading control, and expressed as a percentage of vehicle. The percent degradation of BCL6 compared to vehicle is shown above each group. Statistical analysis was performed using a two-way ANOVA: p<0.0001 (****). Error bars represent the standard error of the mean (±SEM). Figure 8C shows that tumor growth inhibition by Compound A treatment is associated with dose-dependent degradation of BCL6 protein in the SU-DHL-2 model.

[0158] Example 8. Compound A inhibits tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly10. Mice bearing subcutaneous tumors were orally dosed (po) with vehicle or Compound A at 3, 10, or 30 mg / kg twice daily for 28 days (bidx28) or 30 mg / kg daily for 28 days (qdx28). 3The tumors were started with 100 mg / kg of compound A. Figures 10A and 10B show that treatment with compound A inhibited tumor growth in the OCI-Ly10 xenograft model derived from a DLBCL cell line, and the effect was dose-dependent. Figure 10C shows BCL6 protein levels in tumor lysates 16 hours after the final administration, analyzed by Western blotting. BCL6 levels in individual tumors are shown in a scatter plot. The average is represented by a bar, determined by densitometry, normalized to the GAPDH loading control, and shown as a percentage of vehicle. The percent degradation of BCL6 compared to vehicle is shown above each group. Statistical analysis was performed using a two-way ANOVA: p<0.05 (*), p<0.0001 (****). Error bars represent the standard error of the mean (±SEM). Figure 10C shows that treatment with compound A at all dose levels degraded BCL6 protein in the OCI-Ly10 model. Example 9: TGI Table. [Table 2]

[0159] Example 10: Changes in mean tumor volume in DLBCL, Burkitt's lymphoma, and NHL-unspecified PDX model mice treated with Compound A or vehicle.

[0160] Compound A, administered orally at 30 mg / kg, induces in vivo tumor regression in patient-derived xenograft (PDX) models of DLBCL, Burkitt's lymphoma, and NHL-not otherwise specified (NOS). Results are shown in Figures 11A-11D. The DLBCL models are two germinal center-derived B-cell lymphomas: 1) high-grade B-cell lymphoma (HGBCL, LY2214) and 2) ABC / GCB (LY6934) subtypes. These models demonstrated sensitivity to Compound A, resulting in tumor regression compared to vehicle-treated controls. Compound A also induces tumor regression in models of Burkitt's lymphoma (LY3148) and NHL-not otherwise specified (LY12962). HuPrime® lymphoma xenograft models were administered orally (per os, PO) in NOD / SCID or BALB / c nude mice, four mice per group, for 21 days (QDx21). Tumor measurements were performed twice weekly. No significant weight loss was observed (not shown). Data points represent the mean per group, and error bars represent the standard error of the mean.

[0161] Example 11 Preparation of 2-[[6-[[5-chloro-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidyl)-4-methoxy-1-oxo-isoindolin-5-yl]-1-piperidyl]cyclobutoxy]-1-piperidyl]pyrimidin-4-yl]amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (Compound 72)

[0162] Step 1: Preparation of methyl 4-bromo-3-hydroxy-2-methyl-benzoate [ka]

[0163] To a solution of 2-methylpropan-2-amine (440 mg, 6.02 mmol, 0.6 mL, 1 equiv.) in dichloromethane (40 mL) at -70 °C, a solution of bromine (961 mg, 6.02 mmol, 0.3 mL, 1 equiv.) in dichloromethane (2 mL) was added dropwise and stirred at -70 °C for 1 h. Then, a solution of methyl 3-hydroxy-2-methylbenzoate (1 g, 6.02 mmol, 1 equiv.) in dichloromethane (2 mL) was added dropwise, and the resulting mixture was warmed to 25 °C and stirred for 11 h. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (200 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 150 / 1). The compound methyl 4-bromo-3-hydroxy-2-methyl-benzoate (780 mg, 3.18 mmol, 52% yield) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ:9.38(s,1H),7.46(d,J=8.4Hz,1H),7.18(d,J=8.4Hz,1H),3.81(s,3H),2.38(s,3H). MS(ESI)m / z:246.9[M+1] +

[0164] Step 2: Preparation of methyl 4-bromo-3-methoxy-2-methyl-benzoate [ka]

[0165] To a solution of methyl 4-bromo-3-hydroxy-2-methylbenzoate (780 mg, 3.18 mmol, 1 equiv.) in acetonitrile (6 mL), potassium carbonate (527 mg, 3.82 mmol, 1.2 equiv.) and iodomethane (1.36 g, 9.55 mmol, 0.5 mL, 3 equiv.) were added. The mixture was stirred at 50 °C for 5 h. LCMS showed several new peaks, indicating the desired compound. The reaction mixture was filtered, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 50 / 1). The compound methyl 4-bromo-3-methoxy-2-methyl-benzoate (740 mg, 2.86 mmol, 89% yield) was obtained as a white solid. 1 H NMR(400MHz,CDCl3)δ:7.58-7.50(m,1H),7.50-7.43(m,1H),3.91(s,3H),3.82(s,3H),2.58(s,3H).MS(ESI)m / z:259.0[M+1] +

[0166] Step 3: Preparation of methyl 4-bromo-2-(bromomethyl)-3-methoxy-benzoate [ka]

[0167] To a solution of methyl 4-bromo-3-methoxy-2-methylbenzoate (145 mg, 0.55 mmol, 1 equiv.) in carbon tetrachloride (1 mL), n-bromosuccinimide (119 mg, 0.67 mmol, 1.2 equiv.) and AIBN (2 mg, 0.02 mmol, 0.03 equiv.) were added. The mixture was stirred at 70°C under a nitrogen atmosphere for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1). The title compound was obtained as a white solid (170 mg, 0.50 mmol, 89% yield). 1 H NMR(400MHz,CDCl3)δ:7.62(dd,J=8.4,13.6Hz,2H),5.11(s,2H),4.04(s,3H),3.06(s,3H)

[0168] Step 4: Preparation of tert-butyl 5-amino-4-(5-bromo-4-methoxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate [ka]

[0169] To a solution of methyl 4-bromo-2-(bromomethyl)-3-methoxybenzoate (750 mg, 2.22 mmol, 1 equiv.) and tert-butyl 4,5-diamino-5-oxo-pentanoate (673 mg, 3.33 mmol, 1.5 equiv.) in N,N-dimethylformamide (7 mL) was added N,N-diisopropylethylamine (860 mg, 6.66 mmol, 1.16 mL, 3 equiv.). The mixture was stirred at 110 °C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 2). The compound tert-butyl 5-amino-4-(5-bromo-4-methoxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (880 mg, 2.06 mmol, 92% yield) was obtained as a white solid. MS (ESI) m / z: 427.1 [M+1] + .

[0170] Step 5: Preparation of benzyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka]

[0171] A mixture of tert-butyl 5-amino-4-(5-bromo-4-methoxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (780 mg, 1.83 mmol, 1 equiv.), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (751 mg, 2.19 mmol, 1.2 equiv.), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (118 mg, 0.18 mmol, 0.1 equiv.), and cesium fluoride (831 mg, 5.48 mmol, 0.2 mL, 3 equiv.) in dioxane (10 mL) and water (1 mL) was degassed and purged with nitrogen three times. The mixture was then stirred at 90 °C under a nitrogen atmosphere for 6 h. The reaction mixture was diluted with water (200 mL). The organic layer was extracted with ethyl acetate (100 mL × 2). The combined organic layer was washed with brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250 mm * 70 mm, 10 μm); mobile phase: [water (0.225% FA)-ACN]; B%: 50% to 75%, 17 min). The compound benzyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (900 mg, 1.60 mmol, 87% yield) was obtained as a white solid. 1 H NMR(400MHz,CDCl3)δ:7.56-7.49(m,1H),7.46-7.32(m,5H),7.30-7.23(m,1H),6.54(s,1H),5.96-5.78(m,1H),5.69(br s,1H),5.21(m,2H),4.93(dd,J=6.4,8.4Hz,1H),4.58(d,J=17.2Hz,2H),4.23-4.14(m,2H),3.84(s,3H),3.72(t,J=5.2Hz,2H),2.53(br s,2H),2.42-2.14(m,4H),1.42(s,9H).MS(ESI)m / z:564.4[M+1] + .

[0172] Step 6: Preparation of tert-butyl 5-amino-4-[4-methoxy-1-oxo-5-(4-piperidyl)isoindolin-2-yl]-5-oxo-pentanoate [ka]

[0173] To a solution of benzyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (900 mg, 1.60 mmol, 1 equiv.) in 2,2,2-trifluoroethanol (10 mL) and tetrahydrofuran (10 mL) was added palladium on activated carbon catalyst (200 mg, 10% purity) and palladium hydroxide on activated carbon catalyst (200 mg, 20% purity) under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (50 Psi) at 30 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. The compound tert-butyl 5-amino-4-[4-methoxy-1-oxo-5-(4-piperidyl)isoindolin-2-yl]-5-oxo-pentanoate (680 mg, 1.58 mmol, 98% yield) was obtained as a white solid. 1 H NMR(400MHz,CDCl3)δ:7.47(br d,J=7.6Hz,1H),7.28(d,J=7.6Hz,1H),4.82(br t,J=7.2Hz,1H),4.62-4.41(m,2H),3.96-3.96(m,2H),3.85(s,3H),3.65(q,J=7.2Hz,2H) ,2.81-2.63(m,2H),2.36-2.08(m,4H),1.75-1.65(m,2H),1.62-1.56(m,1H),1.34(s,9H).

[0174] Step 7: Preparation of benzyl 4-((1s,3s)-3-(benzyloxy)cyclobutoxy)piperidine-1-carboxylate [ka]

[0175] A mixture of cis-3-benzyloxycyclobutanol (100 g, 561.08 mmol, 1 equiv.) and benzyl 4-oxopiperidine-1-carboxylate (143.97 g, 617.19 mmol, 123.1 mL, 1.1 equiv.) in acetonitrile (2000 mL) was degassed and purged with nitrogen three times. Chloro(dimethyl)silane (53.09 g, 561.08 mmol, 1 equiv.) was then added at 0° C. The mixture was stirred at 25° C. for 12 hours under a nitrogen atmosphere. LCMS showed that the desired mass was detected. The reaction mixture was diluted with water (2 L). The organic layer was extracted with ethyl acetate (1 L × 2). The combined organic layers were washed with brine (500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=30 / 1, 20 / 1) to give the product. The title compound was obtained as a colorless oil (89 g, 225.04 mmol, 40% yield). MS (ESI) m / z: 396.3 [M+1] + .

[0176] Step 8: Preparation of benzyl 4-((1s,3s)-3-hydroxycyclobutoxy)piperidine-1-carboxylate [ka]

[0177] To a solution of benzyl 4-((1s,3s)-3-(benzyloxy)cyclobutoxy)piperidine-1-carboxylate (65 g, 164.35 mmol, 1 equiv.) in ethanol (300 mL) and tetrahydrofuran (300 mL), palladium on activated carbon (6 g, 1.44 mmol, 10% purity), palladium hydroxide on activated carbon (6 g, 8.54 mmol, 20% purity), and di-tert-butyl dicarbonate (53.80 g, 246.53 mmol, 56.6 mL, 1.5 equiv.) were added under a nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen (50 Psi) at 40 °C for 16 h. Thin-layer chromatography (petroleum ether / ethyl acetate = 1:1) showed complete consumption of the starting material and the formation of two new spots. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=50 / 1, 0 / 1). The title product was obtained as a white solid (30.8 g, 113.51 mmol, 69% yield). 1 H NMR(400MHz,CDCl3)δ:3.94-3.85(m,1H),3.82-3.71(m,2H),3.68-3.57(m,1H),3.49-3.35(m,1H ),3.08-2.92(m,2H),2.76-2.64(m,2H),1.96-1.88(m,2H),1.84-1.72(m,2H),1.54-1.37(m,11H)

[0178] Step 9: Preparation of benzyl 4-((1s,3s)-3-((tert-butylsulfonyl)oxy)cyclobutoxy)piperidine-1-carboxylate [ka]

[0179] To a solution of benzyl 4-((1s,3s)-3-hydroxycyclobutoxy)piperidine-1-carboxylate (4 g, 14.74 mmol, 1 equiv.) and triethylamine (4.47 g, 44.22 mmol, 6.16 mL, 3 equiv.) in dichloromethane (120 mL) was added trifluoromethanesulfonyl anhydride (4.57 g, 16.22 mmol, 2.68 mL, 1.1 equiv.) at 0° C. The mixture was stirred at 25° C. for 0.5 h. TLC showed the reaction was complete. The reaction was quenched with water (20 mL). The solution was extracted with dichloromethane (20 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (2-5% ethyl acetate in petroleum ether). The title compound was obtained as a yellow solid (2.5 g, 6.20 mmol, 42% yield). 1 H NMR(400MHz,CDCl3)δ:4.83(quin,J=7.2Hz,1H),3.76-3.61(m,3H),3.43-3.34(m,1H),2.99(ddd,J= 3.6,9.6,13.2Hz,2H),2.88-2.74(m,2H),2.48-2.21(m,2H),1.74-1.65(m,2H),1.45-1.36(m,11H).

[0180] Step 10: Preparation of tert-butyl 4-((1r,3r)-3-(4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-4-methoxy-1-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0181] To a solution of tert-butyl 5-amino-4-[4-methoxy-1-oxo-5-(4-piperidyl)isoindolin-2-yl]-5-oxo-pentanoate (330 mg, 0.76 mmol, 1 equiv.) and benzyl 4-((1s,3s)-3-((tert-butylsulfonyl)oxy)cyclobutoxy)piperidine-1-carboxylate (339 mg, 0.84 mmol, 1.1 equiv.) in acetonitrile (10 mL) was added N,N-diisopropylethylamine (296 mg, 2.29 mmol, 0.3 mL, 3 equiv.). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was diluted with water (100 mL). The organic layer was extracted with ethyl acetate (100 mL × 2). The combined organic layer was washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250mm*70mm, 10um); mobile phase: [water (0.225% FA)-ACN]; B%: 10% to 40%, 20 min) to obtain the title compound as a yellow oil (290mg, 0.42mmol, 55% yield). MS (ESI) m / z: 685.3 [M+1] + .

[0182] Step 11: Preparation of 3-(4-methoxy-1-oxo-5-(1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione [ka]

[0183] A mixture of tert-butyl 4-((1r,3r)-3-(4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-4-methoxy-1-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate (290 mg, 0.42 mmol, 1 equiv.) and [(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonate (245 mg, 1.06 mmol, 2.5 equiv.) in acetonitrile (10 mL) was stirred at 80° C. for 12 hours. The reaction mixture was basified with N,N-diisopropylethylamine and then concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. The title compound was obtained as a colorless gum (260 mg, 0.41 mmol, 98% yield, trifluoroacetate salt). MS (ESI) m / z: 529.3 [M+18] + .

[0184] Step 12: Preparation of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-ethyl-2-oxo-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0185] To a solution of 3-(4-methoxy-1-oxo-5-(1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione (260 mg, 0.41 mmol, 1 equiv., trifluoroacetate salt) and 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-isopropyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (181 mg, 0.41 mmol, 1 equiv.) in dimethyl sulfoxide (3 mL) was added N,N-diisopropylethylamine (161 mg, 1.25 mmol, 0.2 mL, 3 equiv.). The mixture was stirred at 120° C. for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 18%~48%, 10 min). The title compound was obtained as a white solid (47.8mg, 0.05mmol, yield 12%, purity 98%). 1 H NMR(400MHz,DMSO-d6)δ:10.9(s,1H),8.83(s,1H),8.05(s,1H),8.01-7.92(m,2H),7.69(s,2H),7.40(s,2H),7.03(s,1H),5.59-5. 19(m,1H),5.10(dd,J=5.2,13.2Hz,1H),4.70-4.60(m,1H),4.55(s,2H),4.50-4.42(m,1H),4.24-4.11(m,2H),3.91(s,3H),3.54(br s,1H),3.30(s,3H),3.27-3.19(m,2H),3.05-2.86(m,4H),2.68(d,J=4.4Hz,3H),2.65-2.59(m,2H),2.16(br s,2H),2.04-19.6(m,3H),1.88-1.76(m,4H),1.72-1.66(m,3H),1.58(d,J=7.2Hz,6H),1.43-1.33(m,2H).MS(ESI)m / z:910.2[M+1] + .

[0186] Example 12 Preparation of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide (Compound 79)

[0187] Step 1: Preparation of methyl 4-bromo-5-fluoro-2-methyl-benzoate [ka]

[0188] To a solution of 4-bromo-5-fluoro-2-methylbenzoic acid (10.50 g, 45.06 mmol, 1.00 equiv) in dimethylformamide (110 mL) was added potassium carbonate (15.57 g, 112.64 mmol, 2.50 equiv) and iodomethane (19.19 g, 135.17 mmol, 8.4 mL, 3.00 equiv) at 20 °C, and the mixture was stirred at 20 °C for 2 hours. Thin layer chromatography (dichloromethane:methanol = 10:1) showed that the reaction was complete. The mixture was filtered, and the filtrate was diluted with water (600 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (600 mL × 2), brine (600 mL × 2), dried over sodium sulfate, and then concentrated under reduced pressure to give methyl 4-bromo-5-fluoro-2-methyl-benzoate (11.00 g, 44.52 mmol, 99% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ:7.68(d,J=9.2Hz,1H),7.46(d,J=6.4Hz,1H),3.91(s,3H),2.56(s,3H).

[0189] Step 2: Preparation of methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate [ka]

[0190] To a solution of methyl 4-bromo-5-fluoro-2-methylbenzoate (11 g, 44.52 mmol, 1.00 equiv.) in dichloroethane (150 mL), N-bromosuccinimide (8.72 g, 48.98 mmol, 1.10 equiv.) and 2,2-azobisisobutyronitrile (731 mg, 4.45 mmol, 0.10 equiv.) were added at 20 °C, and the mixture was warmed to 80 °C. The mixture was stirred at 80 °C for 6 hours. Thin layer chromatography (petroleum ether:ethyl acetate = 3:1) showed the reaction was complete. The mixture was filtered, and the filtrate was diluted with saturated sodium thiosulfate (500 mL) and extracted with dichloromethane (300 mL). The organic layer was washed with water (500 mL x 2), brine (500 mL x 2), dried over sodium sulfate, and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=30:1 to 20:1) to give methyl 4-bromo-2-(bromomethyl)-5-fluoro-benzoate (13.00 g, 39.88 mmol, 90% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ:7.75-7.67(m,2H),4.89(s,2H),3.95(s,3H).

[0191] Step 3: Preparation of tert-butyl 5-amino-4-(5-bromo-6-fluoro-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate [ka]

[0192] To a solution of methyl 4-bromo-2-(bromomethyl)-5-fluorobenzoate (2.00 g, 6.14 mmol, 1.00 equiv.) in dimethylformamide (20 mL), diisopropylethylamine (3.17 g, 24.54 mmol, 4.3 mL, 4.00 equiv.) and tert-butyl 4,5-diamino-5-oxo-pentanoate (1.24 g, 6.14 mmol, 1.00 equiv.) were added at 80 °C, and the mixture was stirred at 80 °C for 12 hours. Thin layer chromatography (dichloromethane:methanol = 20:1) showed the reaction was complete. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL x 2), brine (100 mL), dried over sodium sulfate, and then concentrated under reduced pressure to give a light yellow solid. The solid was triturated with petroleum ether:ethyl acetate (80 mL, 3:1) to give tert-butyl 5-amino-4-(5-bromo-6-fluoro-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (4.50 g, 10.84 mmol, 88% yield) as a white solid, δ: 8.02 (d, J = 6.0 Hz, 1H), 7.72-7.54 (m, 2H), 7.24 (s, 1H), 4.79-4.67 (m, 1H), 4.65-4.55 (m, 1H), 4.52-4.35 (m, 1H), 2.23-2.09 (m, 3H), 2.05-1.90 (m, 1H), 1.33 (s, 9H).

[0193] Step 4: Preparation of benzyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-6-fluoro-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka]

[0194] The title compound was prepared in a similar manner to Step 5 of Example 11. The crude product was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=5:1 to 0:1) to afford benzyl 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-6-fluoro-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.20 g, 3.91 mmol, 81% yield, 98% purity) as a light brown solid. 1 H NMR(400MHz,CDCl3)δ:7.47(d,J=9.6Hz,1H),7.44-7.28(m,6H),6.40(s,1H),5.97(d,J=9.6Hz,1H),5.54(s,1H),5.19(s,2 H),4.90(dd,J=6.4,8.4Hz,1H),4.58-4.48(m,1H),4.45-4.36(m,1H),4.18(d,J=2.4Hz,2H),3.72(t,J=5.2Hz,2H),2.53(br s,2H),2.43-2.09(m,4H),1.42(s,9H).MS(ESI)m / z:552.2[M+1] + .

[0195] Step 5: Preparation of tert-butyl 5-amino-4-[6-fluoro-1-oxo-5-(4-piperidyl)isoindolin-2-yl]-5-oxo-pentanoate [ka]

[0196] The title compound was made analogously to Step 6 of Example 11. The crude product (720 mg, 1.72 mmol, 95% yield) was used in the next step without further purification. 1H NMR(400MHz,DMSO-d6)δ:7.66-7.51(m,2H),7.42(d,J=9.2Hz,1H),7.20(s,1H),4.76-4.67(m,1H),4.62-4.51(m,1H),4.47-4.36(m,1H) ),3.12-2.93(m,3H),2.66(t,J=11.2Hz,2H),2.16(s,3H),2.00-1.94(m,1H),1.78-1.55(m,4H),1.32(s,9H).MS(ESI)m / z:420.2[M+1] + .

[0197] Step 6: Preparation of tert-butyl 4-((1r,3r)-3-(4-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)cyclobutoxy)piperidine-1-carboxylate [ka]

[0198] The title compound was prepared in a similar manner to Step 10 of Example 11. The crude product was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=1:1 to dichloromethane:methanol=20:1) to give the title product as a pale yellow oil (600 mg, 0.89 mmol, 53% yield). MS (ESI) m / z: 673.3 [M+1] + .

[0199] Step 7: Preparation of 3-(6-fluoro-1-oxo-5-(1-((1r,3r)-3-(piperidin-4-yloxy)cyclobutyl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione [ka]

[0200] The title compound was prepared in the same manner as in Step 11 of Example 11. The crude product was purified by preparative high performance liquid chromatography (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.1% TFA)-ACN]; B%: 2% to 32%, 7 min) to give the title product as a white solid (200 mg, 0.33 mmol, 56% yield, trifluoroacetate salt). MS (ESI) m / z: 613.2 [M+1] + .

[0201] Step 8: Preparation of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0202] The title compound was prepared in the same manner as in Step 12 of Example 11. The crude product was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-41%, 10 min) to obtain the title product as a white solid (77.4 mg, yield 25%). 1H NMR(400MHz,DMSO-d6)δ:11.00(s,1H),8.83(s,1H),8.16(s,1H),8.05(s,1H),7.99-7.90(m,2H),7.69(s,2H),7.62(d,J=6.0Hz,1H),7.50-7 .43(m,1H),7.03(s,1H),5.64-5.18(m,1H),5.16-5.05(m,1H),4.61-4 .50(m,2H),4.47-4.39(m,1H),4.33-4.26(m,1H),4.22-4.16(m,1H),4 .15-4.07(m,2H),3.57-3.50(m,1H),3.24(t,J=10.4Hz,2H),3.02(d,J=10.4Hz,2H),2.94-2.86(m,2H),2.68(d,J=4.8Hz,3H),2.64-2.58(m, 2H),2.42-2.36(m,2H),2.21-2.14(m,2H),2.03-1.98(m,2H),1.86-1. 79(m,4H),1.77-1.69(m,4H),1.57(d,J=6.8Hz,6H),1.43-1.34(m,2H).

[0203] Example 13 Preparation of Compound A, i.e., 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide (Compound 81)

[0204] Step 1: Preparation of 4-bromo-3-fluoro-2-methyl-benzoic acid [ka]

[0205] To a solution of 4-bromo-3-fluorobenzoic acid (20.00 g, 91.32 mmol, 1.00 equiv) in tetrahydrofuran (200 mL) was added lithium triisopropylamide (2 M, 96.0 mL, 2.10 equiv) at -70 °C. The mixture was stirred at -70 °C for 1 hour. Iodomethane (38.89 g, 273.96 mmol, 17.1 mL, 3.00 equiv) was then added at -70 °C. The mixture was then warmed to 20 °C, and the mixture was stirred at 20 °C for 12 hours. The mixture was quenched with saturated ammonium chloride solution (400 mL) and extracted with ethyl acetate (400 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to give 4-bromo-3-fluoro-2-methyl-benzoic acid (16.00 g, 68.66 mmol, 75% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ: 7.55-7.47 (m, 1H), 7.46-7.36 (m, 1H), 2.42 (d, J = 2.0Hz, 3H).

[0206] Step 2: Preparation of methyl 4-bromo-3-fluoro-2-methyl-benzoate [ka]

[0207] To a solution of 4-bromo-3-fluoro-2-methyl-benzoic acid (14.00 g, 60.08 mmol, 1.00 equiv.) in methanol (100 mL) was added thionyl chloride (42.88 g, 360.46 mmol, 26.1 mL, 6.00 equiv.) at 20 °C, and the mixture was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. The residue was quenched with saturated sodium bicarbonate solution (1000 mL) and extracted with ethyl acetate (500 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate = 10:1) to give methyl 4-bromo-3-fluoro-2-methyl-benzoate (6.00 g, 24.09 mmol, 40% yield) as a colorless oil. 1H NMR (400MHz, CDCl3) δ:7.58-7.52(m,1H),7.45-7.39(m,1H),3.90(s,3H),2.53(d,J=2.6Hz,3H).

[0208] Step 3: Preparation of methyl 4-bromo-2-(bromomethyl)-3-fluoro-benzoate [ka]

[0209] To a solution of methyl 4-bromo-3-fluoro-2-methylbenzoate (6.20 g, 25.10 mmol, 1.00 equiv.) in dichloroethane (70 mL), N-bromosuccinimide (4.91 g, 27.60 mmol, 1.10 equiv.) and 2,2-azobisisobutyronitrile (412.09 mg, 2.51 mmol, 0.10 equiv.) were added at 20 °C, and the mixture was heated to 80 °C. The mixture was stirred at 80 °C for 6 hours. The mixture was filtered, and the filtrate was diluted with saturated sodium thiosulfate solution (100 mL) and extracted with dichloromethane (50 mL). The organic layer was washed with water (100 mL × 2), brine (100 mL), dried over sodium sulfate, and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=30:1 to 20:1) to give 4-bromo-2-(bromomethyl)-3-fluoro-benzoic acid metiru (7.00 g, 21.48 mmol, 86% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ:7.71-7.62(m,1H),7.62-7.51(m,1H),5.00(s,2H),3.96(s,3H).

[0210] Steps 4-9: Preparation of 2-({6-[(5-chloro-2-{4-[(1r,3r)-3-{4-[2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1-yl}cyclobutoxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide [ka]

[0211] Compound A was prepared in the same manner as in Example 12, following steps 3 to 8 using the material prepared in step 3 of this example. The crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-41%, 10 min) to give the title product as a white solid (83.5 mg, 22% yield, formate salt). 1 H NMR(400MHz,DMSO-d6)δ:11.00(s,1H),8.83(s,1H),8.18(s,1H),8.04(s,1H),7.99-7.91(m,2H),7.69(s,2H),7.61-7.47(m,2H),7.03(s ,1H),5.58-5.15(m,1H),5.11(dd,J=5.2,13.2Hz,1H),4.59-4.50(m,3H),4.37(d,J=17.4Hz,1H),4.24-4.06(m,3H),3.56-3.51(m,1H),3 .24(t,J=10.4Hz,2H),3.01(d,J=10.0Hz,2H),2.97-2.82(m,3H),2.68(d,J=4.8Hz,3H),2.60(d,J=16.0Hz,1H),2.46-2.39(m,1H),2.21- 2.13(m,2H),2.05-1.96(m,3H),1.87-1.79(m,4H),1.78-1.69(m,4H),1.57(d,J=6.8Hz,6H),1.43-1.34(m,2H).MS(ESI)m / z:748.2[M+1] + .

[0212] The contents of all references, patents, pending patent applications and published patents cited throughout this application are hereby expressly incorporated by reference.

[0213] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the present disclosure described herein. Such equivalents are intended to be encompassed by the following claims. It should be understood that the detailed examples and embodiments described herein are provided by way of example only for illustrative purposes and are not to be construed as limiting the present disclosure in any way. Various modifications or alterations in this regard will be suggested to those skilled in the art and are within the spirit and scope of the present application and are contemplated within the scope of the appended claims. For example, the relative amounts of ingredients may be changed to optimize the desired effect, additional ingredients may be added, and / or similar ingredients may be substituted for one or more of the described ingredients. Additional beneficial features and functions associated with the systems, methods, and processes of the present disclosure will be apparent from the appended claims. Furthermore, those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the present disclosure described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. 1. A method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor in a subject in need thereof, comprising administering to the subject an effective amount of a compound comprising: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof.

2. 1. A method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor in a subject in need thereof, comprising administering to the subject an effective amount of a compound comprising: 【Chemistry 2】 Or the following method: 【Transformation 3】

3. 1. A method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL) in a subject in need thereof, comprising administering to the subject an effective amount of Compound A: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

4. 1. A method of treating or ameliorating diffuse large B-cell lymphoma (DLBCL) in a subject in need thereof, comprising administering to the subject an effective amount of Compound A: 【Transformation 5】 The method of claim 1, wherein the

5. 1. A method of treating or ameliorating angioimmunoblastic T-cell lymphoma in a subject in need thereof, comprising administering to the subject an effective amount of Compound A: 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

6. 1. A method of treating or ameliorating angioimmunoblastic T-cell lymphoma in a subject in need thereof, comprising administering to said subject an effective amount of Compound A: 【Transformation 7】 The method of claim 1, wherein the

7. 1. A method of treating a solid tumor in a subject in need thereof, comprising administering to the subject an effective amount of Compound A: 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

8. 1. A method of treating a solid tumor in a subject in need thereof, comprising administering to said subject an effective amount of Compound A: 【Chemistry 9】 The method of claim 1, wherein the

9. 3. The method of claim 1 or claim 2, wherein the method is for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, high-grade B-cell lymphoma, non-Hodgkin's lymphoma, not otherwise specified, or a solid tumor.

10. 3. The method of claim 1 or claim 2, wherein the method is for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, or a solid tumor.

11. 3. The method of claim 1 or claim 2, wherein the method is for treating or ameliorating diffuse large B-cell lymphoma (DLBCL).

12. 3. The method of claim 1 or claim 2, wherein the method is for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), and the diffuse large B-cell lymphoma (DLBCL) is selected from germinal center B-cell (GCB) DLBCL and activated B-cell (ABC) DLBCL.

13. 3. The method of claim 1 or claim 2, wherein the method is for treating or ameliorating angioimmunoblastic T-cell lymphoma.

14. The method of claim 1 or claim 2, wherein the method is for treating or ameliorating transformed follicular lymphoma.

15. 3. The method of claim 1 or claim 2, wherein the method is for treating or ameliorating high-grade B-cell lymphoma.

16. 3. The method of claim 1 or claim 2, wherein the method is for treating or ameliorating non-Hodgkin's lymphoma, unspecified type.

17. 3. The method of claim 1 or claim 2, wherein the method is for treating or ameliorating a solid tumor, and the solid tumor is selected from breast cancer, lung cancer, ovarian cancer, neuroblastoma, and glioblastoma.

18. The subject is administered an effective amount of Compound A: 【Chemistry 10】 or a pharmaceutically acceptable salt thereof.

19. The subject is administered an effective amount of Compound A: 【Chemistry 11】 The method of any one of claims 9 to 17, comprising administering

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