BCL6 proteolysis modulators and related methods of use

Abstract

The present application relates to the use of compounds, such as Compound A: or a pharmaceutically acceptable salt thereof, for the treatment of various diseases or conditions, including, for example, diffuse large B-cell lymphoma (DLBCL) and vascular immunoblastic T-cell lymphoma.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 437,994, filed on January 9, 2023, and U.S. Provisional Application No. 63 / 618,208, filed on January 5, 2024, which are incorporated by reference in their entirety for all purposes. Technical Field

[0003] The present disclosure provides compounds comprising a target protein binding portion and an E3 ubiquitin ligase binding portion, and related methods of using these compounds. The compounds can be used as modulators targeting ubiquitination, such as B-cell lymphoma 6 protein (BCL6), which are degraded by the compounds of the present disclosure. Background Art

[0004] Most small molecule drugs bind enzymes or receptors in a tight and well-defined pocket. On the other hand, because the contact surface involved in protein-protein interactions is large and the grooves are shallow or the interface is flat, it is notorious that protein-protein interactions are difficult to target using small molecules. E3 ubiquitin ligases (hundreds of which are known in humans) impart substrate specificity for ubiquitination, and therefore, due to their specificity for certain protein substrates, are more attractive therapeutic targets than general proteasome inhibitors. The development of E3 ligase ligands has proven challenging, in part due to the fact that they must destroy 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, nutlin, other compounds targeting E3 ligases have been reported, but this field is still underdeveloped.

[0005] Cerebellin is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, highlighting its physiological importance. Cerebellin 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 many other proteins. Through mechanisms that have not yet been fully elucidated, cerebellin ubiquitination of target proteins leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates many developmental processes, such as the formation of limb and auditory vesicles. The end result is that this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cerebellin, DDB1 forms a complex with DDB2 that acts as a DNA damage binding protein.

[0006] Bifunctional compounds, such as those described in U.S. Patent Application Publication Nos. 2015-0291562 and 2014-0356322 (incorporated herein by reference), are used to recruit endogenous proteins to E3 ubiquitin ligases for degradation. Specifically, this disclosure provides bifunctional or proteolytic targeting chimeric (PROTAC) compounds that are useful as targeted ubiquitination modulators of a variety of polypeptides and other proteins that, following targeted ubiquitination, are degraded and / or otherwise inhibited by the bifunctional compounds.

[0007] 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 modulate BCL6 remain obstacles to the development of effective treatments. Therefore, small molecule therapeutics that target BCL6 and exploit or enhance the substrate specificity of E3 ubiquitin ligases (e.g., cerebellin) would be very useful. Summary of the Invention

[0008] In one aspect, the present application relates to a method for treating or improving diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, unspecified non-Hodgkin lymphoma or solid tumors in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, wherein the compound is:

[0009]

[0010]

[0011] or a pharmaceutically acceptable salt thereof.

[0012] In one aspect, the present application relates to a method for treating or improving diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, unspecified non-Hodgkin's lymphoma or solid tumors in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, wherein the compound is:

[0013]

[0014]

[0015] In one aspect, the present application relates to a method for treating or improving diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma or solid tumors in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, wherein the compound is:

[0016]

[0017] or a pharmaceutically acceptable salt thereof.

[0018] In one aspect, the present application relates to a method for treating or improving diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma or solid tumors in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, wherein the compound is:

[0019]

[0020]

[0021]

[0022] In one aspect, the present application relates to a method for treating or improving diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, unspecified non-Hodgkin's lymphoma or solid tumors, comprising administering to a subject an effective amount of compound A:

[0023] or a pharmaceutically acceptable salt thereof.

[0024] In one aspect, the present application relates to a method for treating or improving diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, unspecified non-Hodgkin's lymphoma or solid tumors, comprising administering to a subject an effective amount of compound A:

[0025]

[0026] In one aspect, the present application relates to a method for treating or improving diffuse large B-cell lymphoma (DLBCL), comprising administering to a subject an effective amount of compound A:

[0027] or a pharmaceutically acceptable salt thereof.

[0028] In one aspect, the present application relates to a method for treating or improving diffuse large B-cell lymphoma (DLBCL), comprising administering to a subject an effective amount of compound A:

[0029]

[0030] In one aspect, the present application relates to a method for treating or improving angioimmunoblastic T-cell lymphoma in a subject in need thereof, the method comprising administering to the subject an effective amount of compound A:

[0031] or a pharmaceutically acceptable salt thereof.

[0032] In one aspect, the present application relates to a method for treating or improving angioimmunoblastic T-cell lymphoma in a subject in need thereof, comprising administering to the subject an effective amount of compound A:

[0033]

[0034] In one aspect, the present application relates to a method of treating a solid tumor in a subject in need thereof, comprising administering to the subject an effective amount of Compound A:

[0035] or a pharmaceutically acceptable salt thereof.

[0036] In one aspect, the present application relates to a method of treating a solid tumor in a subject in need thereof, comprising administering to the subject an effective amount of Compound A:

[0037] BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The accompanying drawings, which are incorporated into and constitute a part of this specification, illustrate several embodiments of the present disclosure and, together with the specification, serve to explain the principles of the present disclosure. The accompanying drawings are only for the purpose of illustrating embodiments of the present disclosure and should not 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 illustrate exemplary embodiments of the present disclosure, wherein:

[0039] Figures 1A-1B . Demonstration of the general principle of the heterobifunctional degradable compound A disclosed herein. Figure 1A Exemplary heterobifunctional degradative compound A comprises a protein targeting moiety (PTM; rectangle), a ubiquitin ligase binding moiety (ULM; triangle), and optionally, a linker moiety (L; bold black line) that couples or tethers the PTM to the ULM. Figure 1BThe functional use of heterobifunctional degradative compound A as described herein is demonstrated. Briefly, the ULM recognizes and binds to 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 conjugating protein and, alone or through an E2 protein, catalyzes the attachment of ubiquitin (small filled ellipse) to a lysine on the target protein via an isopeptide bond. The polyubiquitinated protein (far right) is then targeted for degradation by the cell's proteasome machinery.

[0040] Figures 2A-2C Compound A degradation of BCL6 protein in germinal center B cell (GCB) and activated B cell (ABC) DLBCL cell lines. Figure 2A OCI-Ly1 was treated with Compound A and its E3 binding-deficient analog for 24 hours. Figure 2B GCBDLBCL cell lines Farage, SU-DHL-4, SU-DHL-6, and OCI-Ly7, and Figure 2C : ABC DLBCL lines SU-DHL-2 and OCI-Ly10 were treated with Compound A for 24 hours.

[0041] Figures 3A-3B Antiproliferative effect of Compound A on DLBCL-derived cell lines in a 9-day cell growth inhibition assay. Figure 3A GCB lines OCI-Ly1, OCI-Ly7, SU-DHL-4, and SU-DHL-6, and Figure 3B ABC lines SU-DHL-2 and OCI-Ly10 were dosed with a 7-point 3-fold serial dilution of Compound A with the highest dose being 30 nM.

[0042] Figure 4A Average tumor growth of the DLBCL cell line-derived xenograft model OCI-Ly1 treated with Compound A. Figure 4B Average body weight of treated mice.

[0043] Figure 5 Tumor lysate BCL6 protein levels in OCI-Ly1 cell line xenograft tumor tissues following a time course of Compound A treatment.

[0044] Figure 6 .Total Compound A plasma and tumor levels (vs. Figure 5 related).

[0045] Figure 7A Average tumor growth of the DLBCL cell line-derived xenograft model OCI-Ly1 treated with Compound A. Figure 7B Average body weight of treated mice. Figure 7C BCL6 protein levels in tumor lysates 16 h after the last dose were analyzed by Western blot.

[0046] Figure 8A Average tumor growth of the DLBCL cell line-derived xenograft model OCI-Ly7 treated with Compound A. Figure 8B Average body weight of treated mice. Figure 8C BCL6 protein levels in tumor lysates 16 h after the last dose were analyzed by Western blot.

[0047] Figure 9A Average tumor growth of the DLBCL cell line-derived xenograft model SU-DHL-2 treated with Compound A. Figure 9B Average body weight of treated mice. Figure 9C BCL6 protein levels in tumor lysates 16 h after the last dose were analyzed by Western blot.

[0048] Figure 10A Average tumor growth of the DLBCL cell line-derived xenograft model OCI-Ly10 treated with Compound A. Figure 10B Average body weight of treated mice. Figure 10C BCL6 protein levels in tumor lysates 16 h after the last dose were analyzed by Western blot.

[0049] Figures 11A-11D Shown are changes in mean tumor volume of patient-derived xenograft (PDX) mouse models of diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, and non-Hodgkin lymphoma (NHL) not otherwise specified (NOS) treated with Compound A or vehicle as described in Example 10. Data points represent the mean for each group, and error bars represent the standard error of the mean. DETAILED DESCRIPTION

[0050] 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 in 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.

[0051] 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 terms used in this specification are only used to describe specific embodiments and are not intended to limit this disclosure.

[0052] Where a range of values ​​is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise (e.g., in the case of a group containing multiple carbon atoms, in which case each number of carbon atoms falling within the range is provided), between the upper and lower limits of the range, and any other stated or intervening value within the stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges, which may independently be included in smaller ranges, are also encompassed within this disclosure, subject to any specifically excluded limitations in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of the included limits are also encompassed within this disclosure.

[0053] The following terms are used to describe the present disclosure. Where a term is not specifically defined herein, the term is given the art-recognized meaning as applied by ordinary skill in the art in the context of its use in describing the present disclosure.

[0054] As used herein and in the appended claims, 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 dictates otherwise. For example, "an element" means one element or more than one element.

[0055] As used herein in the specification and claims, the phrase "and / or" should be understood to mean "either or both" of the elements so combined, i.e., the elements are present in combination in some cases and separately in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so combined. In addition to the elements specifically identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising," a reference to "A and / or B" may, in one embodiment, refer to only A (optionally including elements other than B); in another embodiment, refer to only B (optionally including elements other than A); in yet another embodiment, refer to both A and B (optionally including other elements); and so on.

[0056] As used herein in this specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when the items in a list are separated, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one element in many elements or a list of elements, but also including more than one element and optionally other unlisted items. Only explicitly indicating the opposite term, such as "only one of..." or "exactly one of..." or when used in the claims, "consisting of..." will refer to including exactly one element in a plurality of elements or a list of elements. In general, when previously being an exclusive term such as "any one," "one of," "only one," or "exactly one," as used herein, the term "or" should only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both").

[0057] In the claims and the foregoing description, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "having," "consisting of," and the like are to be understood as open-ended, i.e., meaning 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 Office Manual of Patent Examining Procedures.

[0058] It should also be understood that in certain methods described herein that include more than one step or action, the order of the steps or actions of the method are not necessarily limited to the order in which the steps or actions of the method are recited unless the context dictates otherwise.

[0059] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins to target them for degradation. For example, the cerebellum protein E3 ubiquitin ligase, alone or in combination with an E2 ubiquitin conjugating enzyme, causes ubiquitin to attach to lysines on target proteins and subsequently targets specific protein substrates for degradation by the proteasome. Therefore, E3 ubiquitin ligases, alone or in combination with an E2 ubiquitin conjugating enzyme, are responsible for transferring ubiquitin to the target protein. Generally speaking, ubiquitin ligases involve polyubiquitination, where a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on. Polyubiquitination marks proteins for degradation by the proteasome. However, there are some ubiquitination events that are limited to monoubiquitination, in which only a single ubiquitin is added to the substrate molecule by the ubiquitin ligase. Monoubiquitinated proteins are not targeted for degradation by the proteasome, but can be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. To complicate matters further, different lysines on ubiquitin can be targeted by E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin that is recognized by the proteasome.

[0060] The term "patient" or "subject" is used throughout the specification to describe an animal, preferably a human or domesticated animal, to whom treatment, including prophylactic treatment, is provided with a composition according to the present disclosure. For treatment of those infections, conditions, or disease states that are specific to a particular animal (e.g., a human patient), the term patient refers to that particular animal, including domesticated animals such as dogs or cats or farm animals such as horses, cattle, sheep, etc. In general, in this disclosure, unless otherwise specified or implied by the context in which the term is used, the term patient refers to a human patient.

[0061] The term "effective" is used to describe an amount of a compound, composition, or component that, when used in the context of its intended use, achieves the intended result. The term effective includes all other effective amount or effective concentration terms otherwise described or used in this application.

[0062] Compounds of the present disclosure

[0063] In some embodiments, compounds of the present disclosure have the following chemical structure:

[0064] CLM-L-PTM

[0065] or a pharmaceutically acceptable salt thereof,

[0066] in:

[0067] (a) The CLM is a cerebellum protein E3 ubiquitin ligase binding moiety represented by:

[0068]

[0069] in:

[0070] W is CH2, O, CHR (e.g., CH(CH3)), C=O, NH or N;

[0071] Each X is absent or independently selected from O, S and CH2;

[0072] Z is O, S or CH2;

[0073] G is H, methyl or OH;

[0074] Each of Q1, Q2, Q3 and Q4 independently represents N or C substituted with H or R;

[0075] A is H, unsubstituted or substituted linear or branched alkyl, Cl or F;

[0076] n is an integer from 1 to 4 (e.g., 1 or 2, 1 to 3, 1, 2, 3 or 4);

[0077] each R is independently a bond, H, -OR', -NR'R", -CR'R"-, -unsubstituted or substituted linear or branched C1-C6 linear or branched alkyl (e.g., C1-C3 alkyl and / or optionally substituted with one or more halogens), unsubstituted or substituted alkoxy (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; wherein the alkoxy is optionally substituted with one or more halogens, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl), optionally substituted 4-6 membered cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, or -NO2, wherein one R is covalently attached to said L;

[0078] R' and R" are each independently selected from the bond H and a substituted or unsubstituted C1-C4 alkyl group (e.g., methyl or ethyl); and

[0079] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific;

[0080] (b) The PTM is a small molecule comprising a B-cell lymphoma 6 protein (BCL6) targeting moiety, wherein the targeting moiety is selected from:

[0081]

[0082] in:

[0083] R PTM5is H, optionally substituted linear or branched C1-C6 alkyl (e.g., methyl, ethyl or isopropyl), C1-C4 alkyl-O(C1-C3 alkyl), C1-C4 alkyl-O-, C1-C4 alkyl-NH(C1-C3 alkyl), C1-C4 alkyl-N(C1-C3 alkyl)2, optionally substituted C5-C10 aryl, optionally substituted C5-C10 heteroaryl, optionally substituted C3-C10 cycloalkyl or optionally substituted C3-C10 heterocyclyl;

[0084] Q6 and Q 16 are each independently N or CH;

[0085] Q7 and Q 14 are each independently N or CH;

[0086] X PTM1 is H, Cl or F;

[0087] X PTM2 is H, Cl, F or CN;

[0088] Q8 and Q9 is a single bond or a double bond, where

[0089] When Q8 and Q9 are connected via a single button:

[0090] Q8 is CH2; and

[0091] Q9 is CH(R PTM3 ) or N(R PTM3 );

[0092] When Q8 and Q9 are connected by a double bond:

[0093] Q8 is CH; and

[0094] Q9 is C(R PTM3 );

[0095] R PTM3 is: -OH; -Cl; -F; -CN; optionally substituted straight or branched C1-C6 alkyl, optionally substituted C1-C6 alkoxy (e.g., -OCH3 or -OCH2CH3); optionally substituted (e.g., optionally substituted with linear or branched C1-C4 alkyl, C1-C4 alkoxy, -Cl, -F, -CN, or -OH); or optionally substituted (e.g., optionally substituted with linear or branched C1-C4 alkyl, C1-C4 alkoxy, -Cl, -F, -CN, or -OH);

[0096] Each R PTM1a and R PTM2ais independently H, optionally substituted C1-C4 alkyl (e.g., CH3 or CH2CH3), optionally substituted C1-C4 alkoxy (e.g., -OCH3 or -OCH2CH3), or CH2OCH3;

[0097] Each t1 is independently 1, 2, 3, 4 or 5; and

[0098] Each t2 is independently 0, 1, 2, 3, 4 or 5;

[0099] R PTM2 is H, OH, CN, -F, -Cl, optionally substituted straight or branched C1-C4 alkyl, optionally substituted -NH2 (e.g., -N(C1-C3 alkyl)2 or -NH(C1-C3 alkyl)), optionally substituted straight or branched -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, ), each of which is optionally substituted by one or more of the following: OH, linear or branched C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl or NH2, optionally substituted -OC 3-12 monocyclic or bicyclic heterocycloalkyl (e.g., optionally substituted with one or more OH, straight or branched 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 of OH, straight or branched 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 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 C1-C6 alkyl, C1-C6 alkoxy, -CN, -F, -Cl, or NH2); and

[0100] The PTM Indicates the point of connection with said L; and

[0101] (c) L is a chemical linker group that covalently connects the CLM and the PTM, which is represented by the following formula:

[0102] -(A L ) q -,

[0103] in:

[0104] -(A L ) q - is a group connected to the CLM and the PTM;

[0105] q is an integer greater than or equal to 1;

[0106] Each A is independently selected from CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 , CO, CR L1 =CR L2 , C≡C, optionally 1-6 R L1 and / or R L2 C 3-11 Monocyclic or bicyclic cycloalkyl, optionally substituted by 1-9 R L1 and / or R L2 C 5-13 Spirocycloalkyl, optionally substituted by 1-6 R L1 and / or R L2 C 3-11 Monocyclic or bicyclic heterocyclic group, optionally substituted by 1-8 R L1 and / or R L2 C 5-13 Spiroheterocyclic group, optionally substituted by 1-6 R L1 and / or R L2 The aryl group is optionally substituted with 1 to 6 R L1 and / or R L2 a heteroaryl substituted with a group; and

[0107] Each R L1 、R L2 、R L3 、R L4 and R L5 are independently H, halogen, 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-membered or 6-membered aryl, 5-membered or 6-membered heteroaryl, C 3-11 Heterocyclic group, OC 3-8 Cycloalkyl, SC 3-8Cycloalkyl, 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, C—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(C 1-8 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 NHSO2NH2.

[0108] In some embodiments, compounds of the present disclosure have a PTM selected from the group consisting of:

[0109]

[0110] wherein the PTM Indicates the connection point with the L.

[0111] In some embodiments, compounds of the present disclosure have a PTM selected from the group consisting of:

[0112]

[0113] wherein the PTM Indicates the connection point with the L.

[0114] In some embodiments, compounds of the present disclosure have a PTM selected from the group consisting of:

[0115]

[0116] wherein the PTM Indicates the connection point with the L.

[0117] In some embodiments, compounds of the present disclosure have at least one of the following:

[0118] (a) R of PTMIIa1, PTMIIa2, PTMIIa4, PTMIIb1, PTMIIb2, PTMIIb4, PTMIIc1, PTMIIc2 and PTMIIc4 PTM2 Selected from: H, OH, NH2, -N(CH3)2, methyl, ethyl, in represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific, and Indicates the point of attachment to the aryl or heteroaryl group of the PTM;

[0119] (c) R of PTMIIa1, PTMIIa2, PTMIIa4, PTMIIb1, PTMIIb2, PTMIIb4, PTMIIc1, PTMIIc2 and PTMIIc4 PTM3 Selected from: in Indicator R PTM3 The point of attachment to the biheteroaryl or biheterocyclic ring of the PTM; or

[0120] (d) R of PTMIIa1, PTMIIa2, PTMIIa4, PTMIIb1, PTMIIb2, PTMIIb4, PTMIIc1, PTMIIc2 and PTMIIc4 PTM5 Selected from: H, methyl, CFH2, CF2H, ethyl, propyl, isopropyl, cyclopropyl, butyl, pentyl, hexyl, in Indicator R PTM5 The point of attachment to the nitrogen of the biheteroaryl or biheterocyclic ring of the PTM; or

[0121] (e) Any combination of (a), (b), (c) and (d).

[0122] In some embodiments, compounds of the present disclosure have a PTM that is:

[0123]

[0124]

[0125]

[0126] In some embodiments, compounds of the present disclosure have a PTM that is:

[0127]

[0128]

[0129] In some embodiments, compounds of the present disclosure have a PTM that is:

[0130]

[0131]

[0132] In some embodiments, compounds of the present disclosure have a PTM that is:

[0133]

[0134] In some embodiments, compounds of the present disclosure have a PTM that is:

[0135]

[0136] In some embodiments, compounds of the present disclosure have a CLM that is:

[0137]

[0138] in:

[0139] W is CH2, O, CH(C 1-3 alkyl) (e.g., CH(CH3)) or C=O;

[0140] G is H, methyl or OH;

[0141] Each of Q1, Q2, Q3 and Q4 independently represents N, CH or CR;

[0142] A is H, unsubstituted or substituted linear or branched alkyl, Cl or F;

[0143] n is an integer from 1 to 4;

[0144] R is a bond, H, -OR', -NR'R", -CR'R"-, -unsubstituted or substituted linear or branched C1-C6 linear or branched alkyl (e.g., C1-C3 alkyl and / or optionally substituted with one or more halogens), unsubstituted or substituted alkoxy (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; wherein the alkoxy is optionally substituted with one or more halogens, C1-C3 alkyl, haloalkyl, or C1-C3 fluoroalkyl), optionally substituted 4-6 membered cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, -Cl, -F, -Br, -I, -CF3, -CN, or -NO2, wherein one R is covalently attached to said L;

[0145] R' and R" are each independently selected from the bond H and a substituted or unsubstituted C1-C4 alkyl group (e.g., methyl or ethyl);

[0146] represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0147] In some embodiments, compounds of the present disclosure have a CLM that is:

[0148] in:

[0149] W is CH2, O, CH(C 1-3 alkyl) (e.g., CH(CH3)) or C=O;

[0150] A is H, methyl, or an optionally substituted straight or branched chain alkyl group;

[0151] n is an integer from 1 to 4;

[0152] R is independently selected from H, O, OH, N, NH, NH2, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl), C1-C6 alkoxy, and -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl), wherein one R or W is optionally modified to be covalently attached to a chemical linker group (L); and

[0153] Formula (g) represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0154] In some embodiments, A is H.

[0155] In some embodiments, W is CH2 or C=O.

[0156] In some embodiments, W is CH2.

[0157] In some embodiments, W is C═O.

[0158] In some embodiments, compounds of the present disclosure have L selected from:

[0159]

[0160]

[0161] in:

[0162] Each is independently a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl (e.g., a 4-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl), wherein overlapping circles indicate a spirocycle;

[0163] Each of m, n, o and p is independently 0, 1, 2, 3, 4, 5 or 6;

[0164] R L Selected from H and C 1-3 alkyl;

[0165] The linker is optionally substituted with at least one of: (i) =O and (ii) 1-4 (eg, 1, 2, 3, or 4) independently selected from C 1-3 Alkyl (e.g., methyl) and halogen (e.g., F, Cl, or Br); and

[0166] Indicates the connection point with the PTM or the CLM.

[0167] In some embodiments, compounds of the present disclosure have L selected from:

[0168]

[0169]

[0170] in:

[0171] Each is independently a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl (e.g., a 4-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl), wherein overlapping circles indicate a spirocycle;

[0172] is an 8-10 membered bridged cycloalkyl, an 8-10 membered bridged heterocycloalkyl, a 3-7 membered heterocyclyl having one or two double bonds (e.g., a 3-7 membered heterocyclyl having one or two double bonds), or a 7-10 membered fused bicyclic heterocycloalkyl (e.g., a 7-9 membered fused bicyclic heterocycloalkyl);

[0173] Each of m, n, o and p is independently 0, 1, 2, 3, 4, 5 or 6;

[0174] R L Selected from H and C 1-3 alkyl;

[0175] The linker is optionally substituted with at least one of: (i) =O and (ii) 1-4 (e.g., 1, 2, 3, or 4) independently selected from C 1-3 Alkyl (e.g., methyl), OH, and halogen (e.g., F, Cl, or Br); and

[0176] Indicates the connection point with the PTM or the CLM.

[0177] In some embodiments, compounds of the present disclosure have L selected from:

[0178]

[0179] in:

[0180] The chemical linker groups described above, excluding substitution, are optionally substituted with at least one of: (i) =O and (ii) 1-4 (e.g., 1, 2, 3, or 4) independently selected from C 1-3 Alkyl (eg, methyl) and halogen (eg, F, Cl, or Br) substitution;

[0181] *Indicates an atom (e.g., nitrogen, carbon, or oxygen) covalently attached to or shared with the CLM or the PTM;

[0182] Indicates a connection point with the PTM or the CLM; and

[0183] 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).

[0184] In some embodiments, compounds of the present disclosure have L selected from:

[0185]

[0186]

[0187] in:

[0188] The chemical linker groups described above, excluding substitution, are optionally substituted with at least one of: (i) =O and (ii) 1-4 (e.g., 1, 2, 3, or 4) independently selected from C 1-3 Alkyl (eg, methyl) and halogen (eg, F, Cl, or Br) substitution;

[0189] *Indicates an atom (e.g., nitrogen or carbon) covalently linked to or shared with the CLM or the PTM;

[0190] Indicates a connection point with the PTM or the CLM; and

[0191] 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).

[0192] In some embodiments, compounds of the present disclosure have L selected from:

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202] in:

[0203] The chemical linker groups described above, excluding substitution, are optionally substituted with at least one of: (i) =O and (ii) 1-4 (e.g., 1, 2, 3, or 4) independently selected from C 1-3 Alkyl (eg, methyl) and halogen (eg, F, Cl, or Br) substitution;

[0204] *Indicates an atom (e.g., nitrogen or carbon) covalently linked to or shared with the CLM or the PTM;

[0205] Indicates a connection point with the PTM or the CLM; and

[0206] 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).

[0207] In some embodiments, compounds of the present disclosure have L selected from:

[0208]

[0209]

[0210]

[0211]

[0212] in:

[0213] The chemical linker groups described above, excluding substitution, are optionally substituted with at least one of: (i) =O and (ii) 1-4 (e.g., 1, 2, 3, or 4) independently selected from C 1-3 Alkyl (eg, methyl) and halogen (eg, F, Cl, or Br) substitution;

[0214] *Indicates an atom (e.g., nitrogen or carbon) that is shared or covalently linked to the CLM or the PTM;

[0215] Indicates a connection point with the PTM or the CLM; and

[0216] 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).

[0217] In some embodiments, compounds of the present disclosure have L selected from:

[0218]

[0219] in:

[0220] X L is an N or CH group;

[0221] 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);

[0222] *Indicates an atom (e.g., nitrogen or carbon) that is shared or covalently linked to the CLM or the PTM;

[0223] Indicates a connection point with the PTM or the CLM; and

[0224] The chemical linker comprises 0-4 substitutions (preferably 0, 1 or 2 substitutions), each of which is independently C 1-3 Alkyl (preferably methyl).

[0225] In some embodiments, compounds of the present disclosure have L selected from:

[0226]

[0227] in:

[0228] X L is an N or CH group;

[0229] represents a stereospecific bond, one of which has the (R) configuration and the other has the (S) configuration;

[0230] *Indicates an atom (e.g., nitrogen or carbon) that is shared or covalently linked to the CLM or the PTM;

[0231] Indicates a connection point with the PTM or the CLM; and

[0232] The chemical linker comprises 0-4 substitutions (preferably 0, 1 or 2 substitutions), each of which is independently C 1-3 Alkyl (preferably methyl).

[0233] In some embodiments, compounds of the present disclosure have:

[0234] (a) A CLM that is:

[0235]

[0236] in:

[0237] The CLM Indicates the point of connection with said L; and

[0238] N* is a nitrogen atom shared with the chemical linker group;

[0239] (b) as PTM, wherein the PTM Indicates the point of connection with said L; and / or

[0240] (c) said L is selected from wherein * indicates an atom (e.g., carbon or nitrogen) covalently attached to or shared with the CLM or the PTM, and Each of indicates a connection point with the CLM or the PTM.

[0241] In some embodiments, compounds of the present disclosure have:

[0242] (a) A CLM that is:

[0243]

[0244]

[0245]

[0246]

[0247] in:

[0248] The CLM indicates the point of attachment to the L; and N* is the nitrogen atom shared with the chemical linker group;

[0249] (b) as a PTM:

[0250]

[0251]

[0252]

[0253]

[0254]

[0255] wherein the PTM Indicates the point of connection with said L; (c) L is selected from the following:

[0256]

[0257] wherein * indicates an atom (e.g., carbon, nitrogen, or oxygen) covalently attached to or shared with the CLM or the PTM, and Each of indicates a connection point with the CLM or the PTM; or

[0258] (d) Any combination of (a), (b) and (c).

[0259] In some embodiments, compounds of the present disclosure have:

[0260] (a) A CLM that is:

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271] in:

[0272] The CLM indicates the point of attachment to the L; and N* is the nitrogen atom shared with the chemical linker group;

[0273] (b) as a PTM:

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280] wherein the PTM Indicates the point of connection with said L; (c) L is selected from the following:

[0281]

[0282]

[0283]

[0284]

[0285] wherein * indicates an atom (e.g., carbon, nitrogen, or oxygen) covalently attached to or shared with the CLM or the PTM, and Each of indicates a connection point with the CLM or the PTM; or

[0286] (d) Any combination of (a), (b) or (c).

[0287] In some embodiments, the compounds of the present disclosure are selected from the list of compounds in Table 1 or pharmaceutically acceptable salts thereof:

[0288] Table 1. Compounds of the present disclosure

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405] In some embodiments, the compound of the present disclosure is Compound No. 81 (Compound A), Compound No. 163, Compound No. 208, Compound No. 209, Compound No. 211, or a pharmaceutically acceptable salt thereof.

[0406] In some embodiments, the compounds of the present disclosure are:

[0407] Compound No. 81 (Compound A) or a pharmaceutically acceptable salt thereof.

[0408] In some embodiments, the compounds of the present disclosure are:

[0409] Compound No. 81 (Compound A).

[0410] In some embodiments, the compound of the present disclosure is Compound No. 163 or a pharmaceutically acceptable salt thereof.

[0411] In some embodiments, the compound of the present disclosure is Compound No. 163.

[0412] In some embodiments, the compound of the present disclosure is Compound No. 208 or a pharmaceutically acceptable salt thereof.

[0413] In some embodiments, the compound of the present disclosure is Compound No. 208.

[0414] In some embodiments, the compound of the present disclosure is Compound No. 209 or a pharmaceutically acceptable salt thereof.

[0415] In some embodiments, the compound of the present disclosure is Compound No. 209.

[0416] In some embodiments, the compound of the present disclosure is Compound No. 211 or a pharmaceutically acceptable salt thereof.

[0417] In some embodiments, the compound of the present disclosure is Compound No. 211.

[0418] The compounds of the present disclosure can be synthesized using standard synthetic methods and procedures for preparing organic molecules and functional group transformations and manipulations, including the use of protecting groups, such as can be obtained from the relevant scientific literature or from standard reference textbooks in the field according to the present disclosure. Although not limited to any one or more sources, recognized reference textbooks for organic synthesis include: Smith, MB; March, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 5th edition; John Wiley & Sons: New York, 2001; and Greene, TW; Wuts, PGM "Protective Groups in Organic Synthesis", 3rd edition; John Wiley & Sons: New York, 1999. The synthetic methods described in U.S. Patent Application Publication No. 2022 / 0395576 and International Publication No. 2022 / 221673 are incorporated herein by reference in their entirety.

[0419] The term "independently" is used herein to indicate that variables are independently applied, varying independently from application to application.

[0420] The term "alkyl" in this context shall mean a straight-chain, branched or cyclic fully saturated hydrocarbon or alkyl group, preferably C1-C 10 , more preferably C1-C6, alternatively C1-C3 alkyl, it can be optionally substituted.The example of alkyl is methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropyl-methyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl and cyclohexyl etc.In certain embodiments, alkyl is by halogen group (At, Br, Cl, F or I) end-blocking.In certain preferred embodiments, according to compound of the present disclosure, can be used for being covalently bound to dehalogenase.These compounds generally contain the side chain (usually connected by polyethylene glycol group) of alkyl end-blocking, and the far-end of described alkyl has halogen substituent (usually chlorine or bromine), so that the compound containing this type of part is covalently bound to protein.

[0421] The term "alkenyl" refers to a linear, branched or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0422] The term "alkenyl" refers to a linear, branched or cyclic C2-C 10 (Preferably C2-C6) hydrocarbon group.

[0423] The term "alkylene" when used refers to a -(CH2) n -group (n is typically an integer from 0 to 6). When substituted, the alkylene group is preferably substituted with a C1-C6 alkyl group (including a cyclopropyl or tert-butyl group) on one or more of the methylene groups, but may also be substituted with one or more halogen groups, preferably 1 to 3 halogen groups or one or two hydroxyl groups, O-(C1-C6 alkyl) groups, or amino acid side chains as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a carbamate or alkoxy group (or other group), which is further substituted with a polyethylene glycol chain (a polyethylene glycol chain of 1 to 10, preferably 1 to 6, typically 1 to 4 ethylene glycol units), which is substituted (preferably, but not exclusively, at the distal end of the polyethylene glycol chain); an alkyl chain substituted with a single halogen group (preferably a chloro group). In other embodiments, the alkylene (typically methylene) group can be substituted with an amino acid side chain group, such as a side chain group of a natural or unnatural amino acid, for example, 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.

[0424] The term "unsubstituted" shall mean substituted only with hydrogen atoms. A carbon atom range including CO means that the carbon is absent and replaced with H. Thus, a carbon atom range of CO-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for CO, H replaces the carbon.

[0425] The term "substituted" or "optionally substituted" shall independently refer (i.e., when multiple substituents are present, each substituent is independent of the other substituents) to one or more substituents (independently up to five substituents, preferably up to three substituents, typically 1 or 2 substituents, on a moiety in a compound according to the present disclosure, and may include substituents which themselves may be further substituted) at any carbon (or nitrogen) position on the molecule in the context, and include substituents such as hydroxy, thiol, carboxyl, cyano (C≡N), nitro (NO2), halogen (preferably 1, 2 or 3 halogens, especially on alkyl, especially methyl such as trifluoromethyl), alkyl (preferably C1-C ... 10, more preferably C1-C6), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioether (C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1-C6 alkyl or aryl) including alkylene ester (so that the attachment is on the alkylene group rather than on the ester function which is preferably substituted by C1-C6 alkyl or aryl), preferably C1-C6 alkyl or aryl, halogen (preferably F or Cl), amine (including five-membered or six-membered cyclic alkylene amine, also Including C1-C6 alkylamine or C1-C6 dialkylamine, wherein the alkyl group may be substituted with one or two hydroxy groups) or optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) group (which may be optionally substituted with a polyethylene glycol chain, the polyethylene glycol chain further being bound to an alkyl group containing a single halogen, preferably chlorine, substituent), hydrazine, amine group (which is preferably substituted with one or two C1-C6 alkyl groups (including carboxamide optionally substituted with one or two C1-C6 alkyl groups)), alkanol (preferably C1-C6 alkyl or aryl), or alkanoic acid (preferably C1-C6 alkyl or aryl). Substituents according to the present disclosure may include, for example, -SiR1R2R3 groups, wherein R1 and R2 are each as described elsewhere herein, and R3 is H or C1-C6 alkyl, preferably R1, R2, R3 in this context are C1-C3 alkyl (including isopropyl or tert-butyl). Each of the above groups may be directly attached to the substituted moiety, or alternatively, the substituent may be attached via an optionally substituted -(CH2) m - or alternatively optionally substituted -(OCH2) m -、-(OCH2CH2) m -or-(CH2CH2O) m -group (which may be substituted by any one or more of the above substituents) is attached to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety). As identified above, alkylene-(CH2) m -or-(CH2) n-Groups or other chains (such as ethylene glycol chains) can be substituted at any position on the chain. Preferred substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl, which can be optionally substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halogen groups (preferably F), or side chains as otherwise described herein and optionally substituted amides (preferably formamides substituted as described above) or carbamate groups (typically with one or two C0-C6 alkyl substituents, which can be further substituted). In certain embodiments, the alkylene group (typically a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most typically methyl or O-methyl, or the side chains of amino acids as described elsewhere herein. In the present disclosure, a portion in the molecule can be optionally substituted with up to five substituents, preferably up to three substituents. Most often, in the present disclosure, a substituted portion is substituted with one or two substituents.

[0426] The term "substituted" (each substituent being independent of any other substituent) in the context in which it is used shall also mean C1-C6 alkyl, C1-C6 alkoxy, halogen, amide, carboxamide, sulfones (including sulfonamides), keto, carboxyl, C1-C6 ester (oxyester or carbonyl ester), C1-C6 keto, urethane-OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano and amine (especially including C1-C6 alkylene-NR1R2, mono- or di-C1-C6 alkyl-substituted amines, which may be optionally substituted with one or two hydroxy groups). Unless otherwise specified, each of these groups in the context contains between 1 and 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m - (wherein m and n are in this context 1, 2, 3, 4, 5 or 6), -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) nC(O)-NR1R2, -(OCH2) n OH, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CH2O) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R S 、-S(O)-R S (R S is C1-C6 alkyl or -(CH2) m In the chemical context of the defined compounds and the substituents used, the term "substituted" shall also mean optionally substituted aryl or heteroaryl or optionally substituted heterocyclyl as otherwise described herein. The alkylene group may also be substituted as otherwise disclosed herein, preferably with an optionally substituted C1-C6 alkyl group (methyl, ethyl or hydroxymethyl or hydroxyethyl being preferred, thus providing a chiral center), a side chain of an amino acid group as otherwise described herein, an amide group as described above, or a urethane group OC(O)-NR1R2 group (wherein R1 and R2 are as otherwise described herein), although many other groups may also be used as substituents. The various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents, and preferably with 1 or 2 substituents. It should be noted that in the case of compounds where substitution at a particular position of the molecule is desired (primarily for reasons of potency) but no substitution is indicated, the substituent is to be interpreted or understood to be H unless the context of the substitution suggests otherwise.

[0427] In this context, the term "aryl" or "aromatic" refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic group having a single ring (e.g., benzene, phenyl, benzyl) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.), and is capable of being bound to the compounds according to the present disclosure at any available stable position on the ring or as otherwise indicated in the presented chemical structure. In this context, other examples of aryl groups may include heterocyclic aromatic ring systems, "heteroaryl" having one or more nitrogen, oxygen, or sulfur atoms in the ring (monocyclic), such as imidazole, furanyl, pyrrole, furanyl, thiophene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazane, etc., which may be optionally substituted as described above. Heteroaryl groups that may be mentioned include 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, phenanthene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridine and pyrimidine; 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, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, etc., all of which may be optionally substituted.

[0428] The term "substituted aryl" refers to an aromatic carbocyclic group comprising at least one aromatic ring or multiple fused rings, at least one of which is aromatic, wherein the ring is substituted with one or more substituents. For example, an aryl group may comprise a substituent selected from: -(CH2) 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-OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6alkyl)amine (wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halo (preferably F, Cl) groups), OH, COOH, C1-C6alkyl, preferably CH3, CF3, OMe, OCF3, NO2 or CN groups (each of which may be substituted at the ortho, meta and / or para position, preferably the para position, of the phenyl ring), optionally substituted phenyl (the phenyl group itself is preferably linked to the PTM group, including the ULM group, via a linker group), and / or at least one of F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2 or CN groups (at the ortho, meta and / or para position, preferably the para position, of the phenyl ring), naphthyl (which may be optionally substituted), optionally substituted heteroaryl (preferably optionally substituted isoxazole (including methyl-substituted isoxazole) , optionally substituted oxazole (including methyl-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 methylimidazole), optionally substituted benzimidazole or methoxybenzimidazole, optionally substituted oxaimidazole or methyloxaimidazole, optionally substituted diazole group (including methyldiazole group), optionally substituted triazole group (including methyl-substituted triazole group), optionally substituted pyridine group (including pyridine group substituted with halo (preferably F) or methyl or oxapyridine group (wherein the pyridine group is attached to the phenyl group through 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.

[0429] "Carboxyl" refers to the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, however, these general substituents have the same meanings as those defined herein.

[0430] The term "heteroaryl" or "hetaryl" may mean, but is in no way limited to, optionally substituted quinoline (which may be attached to a 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, benzofuran, 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 1,2,3-triazole substituted with methyl, triisopropylsilyl, optionally substituted -(CH2) m -O-C1-C6 alkyl or optionally substituted (CH2) m -C(O)-O-C1-C6 alkyl), optionally substituted pyridine (2-, 3- or 4-pyridine) or a group according to the following chemical structure:

[0431]

[0432] in:

[0433] S c It is CHR SS NR URE or O;

[0434] R HET is H, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0435] R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);

[0436] R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl or -C(O)(C1-C6 alkyl)), each of which is optionally substituted by one or two hydroxyl groups or up to three halogen groups (preferably fluoro groups) or an optionally substituted heterocycle, such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and

[0437] Y C Is N or CR YC , where R YC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted alkynyl -C≡CR a , where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl).

[0438] The terms "aralkyl" and "heteroarylalkyl" refer to a group comprising an aryl or heteroaryl group, respectively, and an alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring system as defined above.

[0439] As used herein, the term "aralkyl" refers to an aryl group as defined above attached to an alkyl group as defined above. The aralkyl group is attached to the parent moiety via the alkyl group, wherein the alkyl group has from one to six carbon atoms. The aryl group in the aralkyl group may be substituted as defined above.

[0440] The term "heterocycle" refers to a cyclic group containing at least one heteroatom (e.g., N, O, or S) and can be aromatic (heteroaryl) or non-aromatic. Thus, depending on the context in which it is used, heteroaryl moieties are included under the definition of heterocycle. Exemplary heteroaryl groups are described above.

[0441] Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxol, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furanyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidine 1-Hydroxy-1-piperidinyl, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine, 1-dimethylenediamine,

[0442] The heterocyclic group may be optionally substituted by a member 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, hydroxy, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycle, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxy(═O), and -SO2-heteroaryl. Such heterocyclic groups may have a single ring or multiple fused 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, quinolinazine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indole, morpholino, piperidinyl, tetrahydrofuranyl, and the like, as well as heterocycles containing N-alkoxy-nitrogen. The term "heterocycle" also includes bicyclic groups in which any one of the heterocycles is fused to a benzene ring or a cyclohexane ring or another heterocycle (e.g., indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, and the like).

[0443] The term "cycloalkyl" may refer to, but is in no way limited to, a monovalent group derived from a monocyclic or polycyclic alkyl group or cycloalkane as defined herein, such as a saturated monocyclic hydrocarbon group having three to twenty carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" may refer to, but is in no way limited to, a monocyclic or polycyclic alkyl group, and is substituted with one or more substituents (e.g., amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo), and the meanings of these general substituents are the same as those of the corresponding groups defined in this legend.

[0444] “Heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group wherein at least one ring carbon atom in the cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S or P. “Substituted heterocycloalkyl” refers to a monocyclic or polycyclic alkyl group wherein at least one ring carbon atom in the cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S or P, and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylthiol, aryl, nitro, thiol or sulfonic acid, and the meanings of these general substituents are the same as those of the corresponding groups defined in this legend.

[0445] The term "hydrocarbyl" shall mean a compound containing carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic and includes aryl, alkyl, alkenyl and alkynyl groups.

[0446] The term "independently" is used herein to indicate that variables are independently applied, varying independently from application to application.

[0447] The term "lower alkyl" refers to methyl, ethyl or propyl.

[0448] The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.

[0449] Therapeutic compositions

[0450] Described herein are therapeutic compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0451] The compounds of the present invention can be administered in single doses or divided doses by oral, parenteral or topical routes. The scope of administration of the active compound can be from continuous (intravenous drip) to oral administration several times a day (e.g., QID), and can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which can include penetration enhancers), buccal, sublingual and suppository administration, and other routes of administration. Enteric-coated oral tablets can also be used to enhance the bioavailability of compounds from oral administration routes. The most effective dosage form will depend on the pharmacokinetics of the selected specific agent and the severity of the patient's disease. The compounds of the present invention can also be used as sprays, mists or aerosols for intranasal, intratracheal or pulmonary administration. Therefore, the present disclosure also relates to pharmaceutical compositions, which include an effective amount of the compounds of the present invention or a pharmaceutically acceptable salt thereof as described herein, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. The compounds of the present invention can also be administered in an immediate release, intermediate release or sustained or controlled release form. Sustained or controlled release forms are preferably administered orally, but may also be administered as suppositories and transdermal or other topical forms. Intramuscular injection of liposomes may also be used to control or sustain the release of the compound at the injection site.

[0452] The compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and may also be administered in a controlled-release formulation.

[0453] The compositions as described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0454] As described herein, the sterile injectable form of the composition can be an aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art using appropriate dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in a non-toxic, parenterally acceptable diluent or solvent.

[0455] The pharmaceutical compositions as described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.

[0456] Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent 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.

[0457] The amount of compound in a pharmaceutical composition as described herein that can be combined with a carrier material to prepare a single dosage form will vary depending on the host and disease being treated, the particular mode of administration, etc. In some embodiments, the composition should be formulated to contain from about 0.05 mg to about 750 mg or more, from about 1 mg to about 600 mg, or from about 10 mg to about 500 mg of active ingredient, alone or in combination with at least one other compound according to the present disclosure.

[0458] 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 employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the specific disease or condition being treated.

[0459] The compounds of the present disclosure are administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or topically, including transdermally, in liquid, cream, gel or solid form or by aerosol form.

[0460] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient an effective amount for the desired indication without causing serious toxic effects in the treated patient. Preferred dosages of the active compound for all conditions mentioned herein are in the range of about 10 ng / kg to about 300 mg / kg, about 0.1 mg / kg / day to about 100 mg / kg / day, or about 0.5 mg / kg of recipient / patient's body weight / day to about 25 mg / kg of recipient / patient's body weight / day. Typical topical dosages range from 0.01-5% wt / wt in a suitable carrier.

[0461] The compound is conveniently administered in any suitable unit dosage form including, but not limited to, those containing less than 1 mg, 1 mg to 3000 mg, or 5 mg to 500 mg of active ingredient per unit dosage form.

[0462] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001-30 mM, or about 0.1-30 μM. This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or an aqueous medium, or as a bolus injection of the active ingredient. Oral administration is also suitable for generating effective plasma concentrations of the active agent.

[0463] The concentration of the active compound in the pharmaceutical composition will depend on the absorption, distribution, inactivation and excretion rate of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage value will also vary with the severity of the condition to be alleviated. It should be further understood that for any specific subject, the specific dosage regimen should be adjusted over time according to the professional judgment of the personnel who need to use or supervise the use of the composition, and the concentration ranges shown herein are merely exemplary and are not intended to limit the scope and practice of the desired composition. The active ingredient can be used once, or can be divided into many smaller doses to be used at different time intervals.

[0464] Oral compositions will typically include an inert diluent or edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound or its prodrug derivative can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition.

[0465] The active compound or a pharmaceutically acceptable salt thereof can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, or the like.

[0466] Solutions or suspensions for parenteral, intradermal, subcutaneous or topical administration may include the following components: a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methyl paraben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate or phosphate and an agent for adjusting tonicity such as sodium chloride or glucose. The parent formulation may be enclosed in an ampoule, disposable syringe or multiple dose vial made of glass or plastic.

[0467] 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 preparation of such formulations will be apparent to those skilled in the art.

[0468] Liposomal suspensions can also be pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations can be prepared by dissolving an appropriate lipid in an inorganic solvent, which is then evaporated to leave a thin film of dry lipids on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then rotated by hand to release the lipid material from the side of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

[0469] The active compound or its pharmaceutically acceptable salt may also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as anticancer agents, as described herein, etc. In certain preferred aspects of the present disclosure, one or more compounds according to the present disclosure are co-administered with another biologically active agent, such as an anticancer agent or a wound healing agent, including an antibiotic, as described elsewhere herein.

[0470] Treatment

[0471] In some embodiments, the present disclosure provides a method for treating or improving a disease or condition 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 No. 81 (Compound A), Compound No. 163, Compound No. 208, Compound No. 209, Compound No. 211, or a pharmaceutically acceptable salt thereof.

[0472] In some embodiments, the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is Compound A.

[0473] In some embodiments, the present disclosure provides a method of treating or ameliorating a disease or condition 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. In some embodiments, the compound is

[0474] In some embodiments, the present disclosure provides a method of treating or ameliorating a disease or condition 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. In some embodiments, the compound is or a pharmaceutically acceptable salt thereof.

[0475] As used herein, the terms "treat," "treating," and "treatment" and the like refer to any action that provides a benefit to a patient to whom the compounds herein can be administered, including the treatment of any disease state or condition modulated by a protein to which the compounds herein bind. Disease states or conditions that can be treated using the compounds according to the present disclosure are shown above, including cancer.

[0476] In some embodiments, the disease or disorder is associated with aberrant BCL6 expression and or activity.

[0477] In some embodiments, the disease or disorder is cancer associated with aberrant BCL6 expression and or activity.

[0478] In some embodiments, the disease or disorder is associated with BCL6 accumulation and aggregation.

[0479] In some embodiments, the disease or disorder is a cancer associated with BCL6 accumulation and aggregation.

[0480] In some embodiments, the disease or condition is cancer.

[0481] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), a 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 lymphoma, not otherwise specified, or a solid tumor.

[0482] 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 unspecified non-Hodgkin lymphoma or a solid tumor.

[0483] As used herein, "angioimmunoblastic T-cell lymphoma" is also referred to as "AITL" or "nodal T follicular helper (TFH) cell lymphoma, angioimmunoblastic type."

[0484] 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 lymphoma, not otherwise specified, or a solid tumor.

[0485] 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 lymphoma not otherwise specified, or a solid tumor.

[0486] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), or a solid tumor.

[0487] In some embodiments, the cancer is angioimmunoblastic T-cell lymphoma.

[0488] In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0489] In some embodiments, the cancer is transformed follicular lymphoma.

[0490] In some embodiments, the cancer is high-grade B-cell lymphoma.

[0491] In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL), wherein the diffuse large B-cell lymphoma (DLBCL) is selected from germinal center B-cell (GCB) DLBCL and activated B-cell (ABC) DLBCL.

[0492] In some embodiments, the cancer is germinal center B cell (GCB) DLBCL.

[0493] In some embodiments, the cancer is activated B-cell (ABC) DLBCL.

[0494] In some embodiments, the cancer is non-Hodgkin's lymphoma, not otherwise specified.

[0495] In some embodiments, the cancer is a mature B-cell neoplasm.

[0496] In some embodiments, the cancer is a solid tumor.

[0497] 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.

[0498] In some embodiments, the cancer is breast cancer.

[0499] In some embodiments, the cancer is lung cancer.

[0500] In some embodiments, the cancer is ovarian cancer.

[0501] In some embodiments, the cancer is neuroblastoma.

[0502] In some embodiments, the cancer is glioblastoma.

[0503] The term "neoplasia" or "cancer" is used throughout this specification to refer to the pathological process that leads to the formation and growth of cancerous or malignant tumors (i.e., abnormal tissue that grows by cell proliferation), which is generally faster than normal tissue and continues to grow after the stimulus that initiated the new growth has ceased. Malignant tumors exhibit partial or complete lack of structural organization and functional coordination with normal tissue, and most invade surrounding tissues, metastasize to several sites, and may recur after attempted removal and lead to death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and includes or encompasses pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that can be treated by the compounds of the present invention, alone or in combination with at least one additional anticancer 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 lymphoma not otherwise specified, or solid tumors including, but not limited to, breast, lung, and ovarian cancers, as well as neuroblastoma and glioblastoma.

[0504] In some embodiments, the present disclosure provides a method for treating or improving 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 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 No. 163 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is Compound No. 163. In some embodiments, the compound of the present disclosure is Compound No. 208 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is Compound No. 208. In some embodiments, the compound of the present disclosure is Compound No. 209 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is Compound No. 209. In some embodiments, the compound of the present disclosure is Compound No. 211 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present disclosure is Compound No. 211.

[0505] Examples

[0506] Example 1. Compound A degrades BCL6 protein in GCB and ABC DLBCL cell lines.

[0507] Degradation of BCL6 protein in DLBCL cell lines was measured by ELISA. 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 We showed that Compound A treatment exhibited efficient BCL6 protein degradation in the OCI-Ly1 cell line compared with its E3-binding-deficient analog. Figure 2B and Figure 2C Compound A treatment demonstrated efficient BCL6 protein degradation in GCB and ABC DLBCL cell lines.

[0508] Example 2. Compound A inhibits proliferation of DLBCL cell lines.

[0509] The anti-proliferative effect of compound A on DLBCL-derived cell lines was tested. GCB lines OCI-Ly1, OCI-Ly7, SU-DHL-4 and SU-DHL-6 ( Figure 3A ) and ABC series SU-DHL-2 and OCI-Ly10 ( Figure 3B ) Cell growth inhibition assays were performed for nine days using a seven-point, three-fold serial dilution of Compound A with a maximum dose of 30 nM. On days 3 and 6-7, samples were split into new 48-well plates for reprocessing, and 20% were split into 96-well plates for cell viability measurement using CellTiter-Glo (CTG). The split cells in the 48-well plates were reprocessed and cultured until day 9, at which time 20% of each sample was analyzed by CTG. The dose response is plotted as a percentage of the vehicle (DMSO) control ( Figure 3A and Figure 3B ). The graph represents at least two independent proliferation assays for each cell line. Each Compound A treatment showed significant inhibition of DLBCL cell growth, and this effect was concentration-dependent.

[0510] Example 3. Compound A inhibits tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly1.

[0511] Vehicle or Compound A was orally (po) administered to mice bearing subcutaneous tumors at 1 mg / kg, 3 mg / kg, 10 mg / kg, or 30 mg / kg daily for 22 days (qd x 22). 3 Start dosing when Figure 4AMean OCI-Ly1 tumor growth is shown. Figure 4B The mean body weight of treated mice is shown. Statistical analysis was performed using two-way ANOVA: p < 0.0001 (****). Error bars represent standard error of the mean (± SEM). The data demonstrate that treatment with Compound A inhibited tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly1 in a dose-dependent manner.

[0512] Example 4. Tumor lysate BCL6 protein levels in OCI-Ly1 cell line xenograft tumor tissue following a time course of treatment with Compound A.

[0513] Tumor lysate BCL6 protein levels were measured in OCI-Ly1 cell line xenograft tumor tissues following a time course of treatment with Compound A. When tumors reached 200-400 mm 3 A single dose of Compound A was orally administered in a pH 3.0 citrate buffer vehicle containing 40% hydroxypropyl-b-cyclodextrin. Tumors were collected at the specified time points. Tumor tissue lysates were analyzed using a protein immunoblotting procedure and densitometry. BCL6 levels were normalized to the GAPDH loading control and expressed as a percentage (%) of the mean value of the BCL6 levels in the vehicle control group. The percentage (%) of BCL6 degradation relative to the vehicle is shown above each group. Cells (1x 10 in 50% matrigel + 50% RMPI-1640 (no phenol red) / 100 μl / mouse) were plated. 7 cells) were implanted subcutaneously in the right flank. Figure 5 Compound A treatment was shown to rapidly degrade BCL6 protein and maintain its decrease for up to 36 hours in the OCI-Ly1 model.

[0514] Additionally, Figure 6 Shown are the overall Compound A plasma and tumor levels after the time course of treatment with Compound A. The curves represent the average drug levels of each tissue type over time within each dose group. A single data point is shown to demonstrate the spread of data within seven mice per group for each assay condition. Compound A reached maximum concentrations (CA) in plasma at 4 hours and in tumor tissue at 8 hours. max ).

[0515] Example 5. Compound A inhibits tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly1.

[0516] Vehicle or Compound A was orally administered (po) to mice bearing subcutaneous tumors at 1 mg / kg, 3 mg / kg, or 10 mg / kg twice daily for 23 days (bid x 23).3 Start dosing when Figure 7A and Figure 7B Compound A treatment was shown to inhibit tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly1 in a dose-dependent manner. Figure 7C Depicted are tumor lysate BCL6 protein levels 16 hours after the last dose analyzed by Western blot. Individual tumor BCL6 levels are shown in a scatter plot, with the mean values ​​represented by bars, determined by densitometry, normalized to the GAPDH loading control, and shown as a percentage of the vehicle. The percentage (%) of BCL6 degradation relative to the vehicle is shown above each panel. Statistical analysis was performed using two-way ANOVA: p<0.0001 (****). Error bars represent standard error of the mean (± SEM). Figure 7C The results showed that the inhibition of tumor growth by Compound A treatment was associated with dose-dependent degradation of BCL6 protein in the OCI-Ly1 model.

[0517] Example 6. Compound A inhibits tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly7.

[0518] Vehicle or Compound A was orally (po) administered to mice bearing subcutaneous tumors at 1 mg / kg, 3 mg / kg, 10 mg / kg, or 30 mg / kg daily for 13 days (qd x 13). 3 Start dosing when Figure 8A and Figure 8B It was shown that treatment with Compound A inhibited tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly7 in a dose-dependent manner. Figure 8C Depicted are tumor lysate BCL6 protein levels 16 hours after the last dose analyzed by Western blot. Individual tumor BCL6 levels are shown in a scatter plot, with the mean values ​​represented by bars, determined by densitometry, normalized to the GAPDH loading control, and shown as a percentage of the vehicle. The percentage (%) of BCL6 degradation relative to the vehicle is shown above each panel. Statistical analysis was performed using two-way ANOVA: p<0.0001 (****). Error bars represent standard error of the mean (± SEM). Figure 8C The results showed that the inhibition of tumor growth by Compound A treatment was associated with dose-dependent degradation of BCL6 protein in the OCI-Ly7 model.

[0519] Example 7. Compound A inhibits tumor growth in the DLBCL cell line-derived xenograft model SU-DHL-2.

[0520] Vehicle or Compound A was orally (po) administered to mice bearing subcutaneous tumors at 3 mg / kg, 10 mg / kg, or 30 mg / kg twice daily for 27 days (bid x 27) or 30 mg / kg daily for 27 days (qd x 27). 3 Start dosing when Figure 9A and Figure 9B It was shown that treatment with Compound A inhibited tumor growth in the DLBCL cell line-derived xenograft model SU-DHL-2 in a dose-dependent manner. Figure 9C Depicted are tumor lysate BCL6 protein levels 16 hours after the last dose analyzed by Western blot. Individual tumor BCL6 levels are shown in a scatter plot, with the mean values ​​represented by bars, determined by densitometry, normalized to the GAPDH loading control, and shown as a percentage of the vehicle. The percentage (%) of BCL6 degradation relative to the vehicle is shown above each panel. Statistical analysis was performed using two-way ANOVA: p<0.0001 (****). Error bars represent standard error of the mean (± SEM). Figure 8C The results showed that the inhibition of tumor growth by Compound A treatment was associated with dose-dependent degradation of BCL6 protein in the SU-DHL-2 model.

[0521] Example 8. Compound A inhibits tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly10.

[0522] Vehicle or Compound A was orally (po) administered to mice bearing subcutaneous tumors at 3 mg / kg, 10 mg / kg, or 30 mg / kg twice daily for 28 days (bid x 28) or 30 mg / kg daily for 28 days (qd x 28). 3 Start dosing when Figure 10A and Figure 10B It was shown that treatment with Compound A inhibited tumor growth in the DLBCL cell line-derived xenograft model OCI-Ly10 in a dose-dependent manner. Figure 10C Depicted are tumor lysate BCL6 protein levels 16 hours after the last dose analyzed by Western blot. Individual tumor BCL6 levels are shown in a scatter plot, with the mean values ​​represented by bars, determined by densitometry, normalized to the GAPDH loading control, and shown as a percentage of the vehicle. The percentage (%) of BCL6 degradation relative to the vehicle is shown above each panel. Statistical analysis was performed using two-way ANOVA: p<0.05 (*), p<0.0001 (****). Error bars represent standard error of the mean (± SEM). Figure 10CCompound A treatment was shown to degrade BCL6 protein in the OCI-Ly10 model at all dose levels.

[0523] Example 9: TGI table.

[0524] Table 2. Compounds of the invention showing >75% TGI in a BCL6 sensitive tumor xenograft model (OCI-Ly1).

[0525] Compound number Ly-1 TGI@10mg / kg (BID) Compound No. 81 (Compound A) 100％ Compound No. 163 95％ Compound No. 208 77％ Compound No. 209 104％ Compound No. 211 87％

[0526] Example 10: Changes in mean tumor volume in DLBCL, Burkitt's lymphoma, and unspecified NHL models in PDX mice treated with Compound A or vehicle.

[0527] Compound A, administered orally at 30 mg / kg, induced in vivo tumor regression in patient-derived DLBCL, Burkitt's lymphoma, and not otherwise specified NHL (NOS) xenograft (PDX) models. Figures 11A-11D Two DLBCL models representing germinal center-derived B-cell lymphomas, 1) high-grade B-cell lymphoma (LY2214) and 2) ABC / GCB (LY6934) subtypes, showed sensitivity to Compound A, resulting in tumor regression compared to vehicle-treated controls. Compound A also induced tumor regression in models of Burkitt's lymphoma (LY3148) and NHL NOS (LY12962). In NOD / SCID or BALB / c nude mice, the results were published in the journal Cell Reports. Lymphoma xenograft model, 4 / group, oral (oral, PO) administration every day, continued 21 days (QD x 21), and obtained tumor measurement results twice a week. No significant weight loss was observed (not shown). Data points represent the mean value of each group, and error bars represent the standard error of the mean value.

[0528] Example 11: Preparation of 2-[[6-[[5-chloro-2-[4-[3-[4-[2-(2,6-dioxo-3-piperidinyl)4-methoxy-1-oxo-isoindolin-5-yl]-1-piperidinyl]cyclobutyloxy]-1-piperidinyl]pyrimidin-4-yl]amino]-1-isopropyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide (Compound 72)

[0529] Step 1: Preparation of 4-bromo-3-hydroxy-2-methyl-benzoic acid methyl ester

[0530]

[0531] At -70 DEG C, to a solution of 2- methylpropane-2-amine (440mg, 6.02mmol, 0.6mL, 1 equivalent) in dichloromethane (40mL) was added dropwise a solution of bromine (961mg, 6.02mmol, 0.3mL, 1 equivalent) in dichloromethane (2mL), and the mixture was stirred at -70 DEG C for 1 hour. Then, a solution of 3- hydroxy-2-methyl-benzoic acid methyl ester (1g, 6.02mmol, 1 equivalent) in dichloromethane (2mL) was added dropwise, and the resulting mixture was warmed to 25 DEG C and stirred for 11 hours. The reaction mixture was diluted with water (200mL) and extracted with dichloromethane (200mL x 2). The combined organic phase 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). Compound 4-bromo-3-hydroxy-2-methyl-benzoic acid methyl ester (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] +

[0532] Step 2: Preparation of 4-bromo-3-methoxy-2-methyl-benzoic acid methyl ester

[0533]

[0534] To a solution of 4- bromo- 3- hydroxy -2- methyl - benzoic acid methyl esters (780mg, 3.18mmol, 1 equivalent) in acetonitrile (6mL) is added potassium carbonate (527mg, 3.82mmol, 1.2 equivalents) and iodomethane (1.36g, 9.55mmol, 0.5mL, 3 equivalents). The mixture is stirred at 50 DEG C for 5 hours. Several new peaks are shown on LCMS, and the desired compound is detected. The reaction mixture is filtered and diluted with water (100mL), and extracted with ethyl acetate (100mL x 2). The combined organic phases are washed with brine (200mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 0 to 50 / 1). Compound 4- bromo- 3- methoxy -2- methyl - benzoic acid methyl esters (740mg, 2.86mmol, 89% yield) is obtained as a white solid. 1H 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] +

[0535] Step 3: Preparation of 4-bromo-2-(bromomethyl)-3-methoxy-benzoic acid methyl ester

[0536]

[0537] To a solution of 4-bromo-3-methoxy-2-methyl-benzoic acid methyl ester (145 mg, 0.55 mmol, 1 equivalent) in carbon tetrachloride (1 mL) is added n-bromosuccinimide (119 mg, 0.67 mmol, 1.2 equivalents) and AIBN (2 mg, 0.02 mmol, 0.03 equivalents). The mixture is stirred at 70 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture is diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases are washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 0 to 10 / 1). The title compound (170 mg, 0.50 mmol, 89% yield) is obtained as a white solid. 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)

[0538] Step 4: Preparation of tert-butyl 5-amino-4-(5-bromo-4-methoxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate

[0539]

[0540] To a solution of 4- bromo- 2- (bromomethyl) -3- methoxy- benzoic acid methyl ester (750mg, 2.22mmol, 1 equivalent) and 4,5- diamino -5- oxo- t-butyl pentanoate (673mg, 3.33mmol, 1.5 equivalents) in N, N- dimethylformamide (7mL) is added N, N- diisopropylethylamine (860mg, 6.66mmol, 1.16mL, 3 equivalents). The mixture is stirred at 110 ° C for 1 hour. The reaction mixture is diluted with water (100mL) and extracted with ethyl acetate (100mL x 2). The combined organic phases are washed with brine (200mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 2). The compound 5-amino-4-(5-bromo-4-methoxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester (880 mg, 2.06 mmol, 92% yield) was obtained as a white solid. MS (ESI) m / z: 427.1 [M+1] + .

[0541] Step 5: Preparation of 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester

[0542]

[0543] A mixture of 5-amino-4-(5-bromo-4-methoxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoic acid tert-butyl ester (780 mg, 1.83 mmol, 1 eq), 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 eq), di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (118 mg, 0.18 mmol, 0.1 eq) and cesium fluoride (831 mg, 5.48 mmol, 0.2 mL, 3 eq) in dioxane (10 mL) and water (1 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred under a nitrogen atmosphere at 90 ° C for 6 hours. The reaction mixture was diluted with water (200 mL). The organic layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 10 um); mobile phase: [water (0.225% FA)-ACN]; B%: 50%-75%, 17 minutes). The compound 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (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] + .

[0544] Step 6: Preparation of tert-butyl 5-amino-4-[4-methoxy-1-oxo-5-(4-piperidinyl)isoindolin-2-yl]-5-oxo-pentanoate

[0545]

[0546] Under a nitrogen atmosphere, to a solution of 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-4-methoxy-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (900 mg, 1.60 mmol, 1 equivalent) in 2,2,2-trifluoroethanol (10 mL) and tetrahydrofuran (10 mL) was added palladium / activated carbon catalyst (200 mg, 10% purity) and palladium hydroxide / activated carbon catalyst (200 mg, 20% purity). The suspension was degassed and purged with hydrogen three times. The mixture was stirred at 30 ° C under hydrogen (50 Psi) for 12 hours. 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 5-amino-4-[4-methoxy-1-oxo-5-(4-piperidinyl)isoindolin-2-yl]-5-oxo-pentanoic acid tert-butyl ester (680 mg, 1.58 mmol, 98% yield) was obtained as a white solid. 1 HNMR(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).

[0547] Step 7: Preparation of benzyl 4-((1s,3s)-3-(benzyloxy)cyclobutyloxy)piperidine-1-carboxylate

[0548]

[0549] A mixture of cis-3-benzyloxycyclobutanol (100g, 561.08mmol, 1 equivalent) and benzyl 4-oxopiperidine-1-formate (143.97g, 617.19mmol, 123.1mL, 1.1 equivalents) in acetonitrile (2000mL) is degassed and purged with nitrogen 3 times, and then chloro(dimethyl)silane (53.09g, 561.08mmol, 1 equivalent) is added at 0°C. The mixture is stirred at 25°C for 12 hours under a nitrogen atmosphere. LCMS shows that the desired mass is detected. The reaction mixture is diluted with water (2L). The organic layer is extracted with ethyl acetate (1L×2). The combined organic layer is washed with brine (500mL). The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain a residue. The residue is purified by silica gel chromatography (petroleum ether / ethyl acetate=30 / 1,20 / 1) to obtain 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] + .

[0550] Step 8: Preparation of benzyl 4-((1s,3s)-3-hydroxycyclobutyloxy)piperidine-1-carboxylate

[0551]

[0552] Under a nitrogen atmosphere, to a solution of benzyl 4-((1s, 3s)-3-(benzyloxy)cyclobutyloxy)piperidine-1-carboxylate (65 g, 164.35 mmol, 1 equivalent) in ethanol (300 mL) and tetrahydrofuran (300 mL) was added palladium / activated carbon catalyst (6 g, 1.44 mmol, 10% purity), palladium hydroxide / activated carbon catalyst (6 g, 8.54 mmol, 20% purity) and di-tert-butyl dicarbonate (53.80 g, 246.53 mmol, 56.6 mL, 1.5 equivalents). The suspension was degassed and purged with hydrogen three times. The mixture was stirred at 40 ° C under hydrogen (50 Psi) for 16 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 1: 1) indicated that the starting material was completely consumed and two new spots were formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate=50 / 1, 0 / 1) to obtain the title product (30.8 g, 113.51 mmol, 69% yield) in white. 1H 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)

[0553] Step 9: Preparation of benzyl 4-((1s,3s)-3-((tert-butylsulfonyl)oxy)cyclobutyloxy)piperidine-1-carboxylate

[0554]

[0555] At 0 ° C, to a solution of 4- ((1s, 3s) -3- hydroxycyclobutyloxy) piperidine -1- carboxylic acid benzyl ester (4g, 14.74mmol, 1 equivalent) and triethylamine (4.47g, 44.22mmol, 6.16mL, 3 equivalents) in dichloromethane (120mL) was added trifluoromethanesulfonic anhydride (4.57g, 16.22mmol, 2.68mL, 1.1 equivalents). The mixture was stirred at 25 ° C for 0.5 hours. TLC shows that the reaction is complete. The reaction is quenched with water (20mL). The solution is extracted with dichloromethane (20mL x 2). The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue is purified by silica gel chromatography (2-5% ethyl acetate / petroleum ether). The title compound (2.5g, 6.20mmol, 42% yield) is obtained as a yellow solid. 1 HNMR (400MHz, CDCl3) δ: 4.83 (quin, J = 7.2 Hz, 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).

[0556] 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)cyclobutyloxy)piperidine-1-carboxylate

[0557]

[0558] To a solution of tert-butyl 5-amino-4-[4-methoxy-1-oxo-5-(4-piperidinyl)isoindolin-2-yl]-5-oxo-pentanoate (330 mg, 0.76 mmol, 1 eq) and benzyl 4-((1s,3s)-3-((tert-butylsulfonyl)oxy)cyclobutyloxy)piperidine-1-carboxylate (339 mg, 0.84 mmol, 1.1 eq) in acetonitrile (10 mL) was added N,N-diisopropylethylamine (296 mg, 2.29 mmol, 0.3 mL, 3 eq). 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 x 2). The combined organic layers were washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 10 um); mobile phase: [water (0.225% FA)-ACN]; B%: 10%-40%, 20 minutes) to obtain the title compound (290 mg, 0.42 mmol, 55% yield) as a yellow oil. MS (ESI) m / z: 685.3 [M+1] + .

[0559] 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

[0560]

[0561] 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)cyclobutyloxy)piperidine-1-carboxylate (290 mg, 0.42 mmol, 1 eq) and [(1R,4S)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid (245 mg, 1.06 mmol, 2.5 eq) 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 (260 mg, 0.41 mmol, 98% yield, trifluoroacetate) was obtained as a colorless gum. MS (ESI) m / z: 529.3 [M+18] + .

[0562] 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}cyclobutyloxy]piperidin-1-yl}pyrimidin-4-yl)amino]-1-ethyl-2-oxo-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide

[0563]

[0564] 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 eq, trifluoroacetate) and 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-isopropyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide (181 mg, 0.41 mmol, 1 eq) in dimethyl sulfoxide (3 mL) was added N,N-diisopropylethylamine (161 mg, 1.25 mmol, 0.2 mL, 3 eq). 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 minutes). The title compound (47.8 mg, 0.05 mmol, 12% yield, 98% purity) was obtained as a white solid. 1H 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] + .

[0565] 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}cyclobutyloxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide (Compound 79)

[0566] Step 1: Preparation of 4-bromo-5-fluoro-2-methyl-benzoic acid methyl ester

[0567]

[0568] At 20 ° C, to a solution of 4-bromo-5-fluoro-2-methyl-benzoic 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), 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.times.2), brine (600 mL.times.2), dried over sodium sulfate, and then concentrated under reduced pressure to give 4-bromo-5-fluoro-2-methyl-benzoic acid methyl ester (11.00 g, 44.52 mmol, 99% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: 7.68 (d, J = 9.2 Hz, 1H), 7.46 (d, J = 6.4 Hz, 1H), 3.91 (s, 3H), 2.56 (s, 3H).

[0569] Step 2: Preparation of 4-bromo-2-(bromomethyl)-5-fluoro-benzoic acid methyl ester

[0570]

[0571] At 20 ° C, to a solution of 4-bromo-5-fluoro-2-methyl-benzoic acid methyl ester (11 g, 44.52 mmol, 1.00 equivalent) in dichloroethane (150 mL), N-bromosuccinimide (8.72 g, 48.98 mmol, 1.10 equivalent) and 2,2-azobisisobutyronitrile (731 mg, 4.45 mmol, 0.10 equivalent) were added, 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 that 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 obtain a residue. The residue was purified by silica gel column chromatography (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).

[0572] Step 3: Preparation of tert-butyl 5-amino-4-(5-bromo-6-fluoro-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate

[0573]

[0574] At 80 DEG C, to a solution of 4-bromo-2-(bromomethyl)-5-fluoro-benzoic acid methyl ester (2.00g, 6.14mmol, 1.00 equivalent) in dimethylformamide (20mL), diisopropylethylamine (3.17g, 24.54mmol, 4.3mL, 4.00 equivalent) and 4,5-diamino-5-oxo-pentanoic acid tert-butyl ester (1.24g, 6.14mmol, 1.00 equivalent) were added, and the mixture was stirred at 80 DEG C for 12 hours. Thin layer chromatography (dichloromethane: methanol = 20: 1) showed that the reaction was complete. The mixture was diluted with water (100mL) and extracted with ethyl acetate (100mL). The organic layer was washed with water (100mL x 2mL), brine (100mL), dried over sodium sulfate, and then concentrated under reduced pressure to obtain 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).

[0575] Step 4: Preparation of 4-[2-(4-tert-butoxy-1-carbamoyl-4-oxo-butyl)-6-fluoro-1-oxo-isoindolin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester

[0576]

[0577] The title compound was prepared in analogy to Example 11, step 5. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1 to 0:1) to give 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. 1H 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] + .

[0578] Step 5: Preparation of tert-butyl 5-amino-4-[6-fluoro-1-oxo-5-(4-piperidinyl)isoindolin-2-yl]-5-oxo-pentanoate

[0579]

[0580] The title compound was prepared analogously to Example 11, Step 6. The crude product (720 mg, 1.72 mmol, 95% yield) was used in the next step without further purification. 1 H 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),4.4 7-4.36(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] + .

[0581] 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)cyclobutyloxy)piperidine-1-carboxylate

[0582]

[0583] The title compound was prepared similarly to Example 11, step 10. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1 to dichloromethane:methanol=20:1) to give the title product (600 mg, 0.89 mmol, 53% yield) as a light yellow oil. MS (ESI) m / z: 673.3 [M+1] + .

[0584] 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

[0585]

[0586] The title compound was prepared similarly to Example 11, Step 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%-32%, 7 minutes) 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] + .

[0587] 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}cyclobutyloxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide

[0588]

[0589] The title compound was prepared in analogy to Example 11, Step 12. The crude product was purified by preparative high-performance liquid chromatography (column: Phenomenex Synergi C18 150*25 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-41%, 10 min) to give the title product (77.4 mg, 25% yield) as a white solid. 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).

[0590] Example 13: Preparation of Compound A, ie, 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}cyclobutyloxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide (Compound 81)

[0591] Step 1: Preparation of 4-bromo-3-fluoro-2-methyl-benzoic acid

[0592]

[0593] To a solution of 4- bromo -3- fluoro- benzoic acid (20.00 g, 91.32 mmol, 1.00 equivalent) in tetrahydrofuran (200 mL) was added lithium diisopropylamide (2 M, 96.0 mL, 2.10 equivalents) at -70 ° C, and the mixture was stirred at -70 ° C for 1 hour. Then, iodomethane (38.89 g, 273.96 mmol, 17.1 mL, 3.00 equivalents) was added at -70 ° C. Then, the mixture was 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 obtain 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).

[0594] Step 2: Preparation of 4-bromo-3-fluoro-2-methyl-benzoic acid methyl ester

[0595]

[0596] At 20 ° C, thionyl chloride (42.88 g, 360.46 mmol, 26.1 mL, 6.00 equiv) was added 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), and the mixture was stirred at 20 ° C for 1 hour. The mixture was concentrated under reduced pressure to obtain 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 obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 4-bromo-3-fluoro-2-methyl-benzoic acid methyl ester (6.00 g, 24.09 mmol, 40% yield) as a colorless oil. 1 H 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).

[0597] Step 3: Preparation of 4-bromo-2-(bromomethyl)-3-fluoro-benzoic acid methyl ester

[0598]

[0599] At 20 ° C, to a solution of 4-bromo-3-fluoro-2-methyl-benzoic acid methyl ester (6.20g, 25.10mmol, 1.00 equivalent) in dichloroethane (70mL), N-bromosuccinimide (4.91g, 27.60mmol, 1.10 equivalent) and 2,2-azobisisobutyronitrile (412.09mg, 2.51mmol, 0.10 equivalent) were added, and the mixture was warmed 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 (100mL) and extracted with dichloromethane (50mL). The organic layer was washed with water (100mL x 2), brine (100mL), dried over sodium sulfate, and then concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=30:1 to 20:1) to give methyl 4-bromo-2-(bromomethyl)-3-fluoro-benzoate (7.00 g, 21.48 mmol, 86% yield) as a colorless oil. 1 HNMR(400MHz, CDCl3)δ:7.71-7.62(m,1H),7.62-7.51(m,1H),5.00(s,2H),3.96(s,3H).

[0600] Step 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}cyclobutyloxy]piperidin-1-yl}pyrimidin-4-yl)amino]-2-oxo-1-(propan-2-yl)-1,2-dihydroquinolin-3-yl}oxy)-N-methylacetamide

[0601]

[0602] Using the material prepared in step 3 of this example, compound A was prepared according to steps 3-8 in a manner similar to that in Example 12. The crude product was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150*25 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-41%, 10 minutes) to give the title product (83.5 mg, 22% yield, formate salt) as a white solid. 1H 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] + .

[0603] The contents of all references, patents, pending patent applications, and issued patents cited throughout this application are expressly incorporated herein by reference.

[0604] Those skilled in the art will recognize or be able to ascertain many equivalents to the specific embodiments of the disclosure described herein using only routine experimentation. These equivalents are intended to be covered by the following claims. It should be understood that the detailed examples and embodiments described herein are given for illustrative purposes only and are in no way to be considered as limitations of the present disclosure. Various modifications or variations thereof will be considered by those skilled in the art and are included within the spirit and scope of this application and are considered to be within the scope of the appended claims. For example, the relative amounts of the ingredients may be changed to optimize the desired effect, other ingredients may be added, and / or one or more of the ingredients may be replaced with similar ingredients. Other advantageous features and functions associated with the systems, methods, and processes of the present disclosure will be apparent from the following claims. In addition, those skilled in the art will recognize or be able to ascertain many equivalents to the specific embodiments of the disclosure described herein using only routine experimentation. These equivalents are intended to be covered by the following claims.

Claims

1. A method for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, unspecified non-Hodgkin lymphoma, or solid tumors in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, wherein the compound is: or a pharmaceutically acceptable salt thereof.

2. A method for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, transformed follicular lymphoma, high-grade B-cell lymphoma, unspecified non-Hodgkin's lymphoma, or solid tumors in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound, wherein the compound is:

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

4. A method for treating or improving diffuse large B-cell lymphoma (DLBCL) in a subject in need thereof, the method comprising administering to the subject an effective amount of Compound A:

5. A method for 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: or a pharmaceutically acceptable salt thereof.

6. A method for 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:

7. 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: or a pharmaceutically acceptable salt thereof.

8. 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:

9. The method according to claim 1 or claim 2, wherein the method is used to treat or improve diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma, high-grade B-cell lymphoma, unspecified non-Hodgkin's lymphoma or solid tumors.

10. The method according to claim 1 or claim 2, wherein the method is used to treat or improve diffuse large B-cell lymphoma (DLBCL), angioimmunoblastic T-cell lymphoma or solid tumors.

11. The method according to claim 1 or claim 2, wherein the method is used to treat or improve diffuse large B-cell lymphoma (DLBCL).

12. The method according to claim 1 or 2, wherein the method is used to treat or improve diffuse large B-cell lymphoma (DLBCL), wherein the diffuse large B-cell lymphoma (DLBCL) is selected from germinal center B cell (GCB) DLBCL and activated B cell (ABC) DLBCL.

13. The method according to claim 1 or claim 2, wherein the method is used to treat or ameliorate angioimmunoblastic T-cell lymphoma.

14. The method according to claim 1 or claim 2, wherein the method is used to treat or ameliorate transformed follicular lymphoma.

15. The method according to claim 1 or claim 2, wherein the method is used to treat or ameliorate high-grade B-cell lymphoma.

16. The method according to claim 1 or claim 2, wherein the method is used to treat or ameliorate unspecified non-Hodgkin's lymphoma.

17. The method according to claim 1 or claim 2, wherein the method is used to treat or improve solid tumors, wherein the solid tumors are selected from breast cancer, lung cancer, ovarian cancer, neuroblastoma and glioblastoma.

18. The method according to any one of claims 9 to 17, comprising administering to the subject an effective amount of Compound A: or a pharmaceutically acceptable salt thereof.

19. The method according to any one of claims 9 to 17, comprising administering to the subject an effective amount of Compound A:

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