BCL6 bifunctional degradation agent

Abstract

The present disclosure provides a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-b), or (I-c)) or a pharmaceutically acceptable salt thereof that induces degradation of a BCL6 protein. These compounds are useful, for example, in the treatment of cancer in a subject (e.g., a human). The disclosure also provides compositions containing a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-b), or (I-c)), or a pharmaceutically acceptable salt thereof, as well as methods of using and preparing these compositions.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 580,215, filed September 1, 2023; U.S. Provisional Application Serial No. 63 / 607,012, filed December 6, 2023; U.S. Provisional Application Serial No. 63 / 624,171, filed January 23, 2024; and U.S. Provisional Application Serial No. 63 / 665,670, filed June 28, 2024, each of which is incorporated herein by reference in its entirety. sequence list

[0002] This application includes a sequence list, which has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML file, created on August 26, 2024, is named TLS-055WO_SL.xml and has a size of 2,665 bytes. Technical Field

[0003] This disclosure provides compounds of formula (I) (e.g., formula (Ia), (I-a1), (Ib), or (Ic)) that induce the degradation of BCL6 protein, or pharmaceutically acceptable salts thereof. These compounds can be used, for example, to treat cancer in a subject (e.g., a human). This disclosure also provides compositions containing compounds of formula (I) (e.g., formula (Ia), (I-a1), (Ib), or (Ic)) or pharmaceutically acceptable salts thereof, and methods for using and preparing these compositions. Background Technology

[0004] B-cell lymphoma 6 (BCL6) is a transcriptional repressor involved in the formation and maintenance of germinal centers (GCs) within lymphoid follicles. This protein controls GC function and coordinates the activity of signaling mediators during GC B-cell maturation. More than 1000 known or presumed BCL6 target genes exist, including MYC, BCL2, genes associated with DNA damage responses (e.g., ATR, TP53), and cell cycle checkpoint control genes (e.g., CDKN1A, CDKN1B). BCL6 is expressed in the darker cells of GCs, where somatic hypermutation is permitted to generate high-affinity B-cell receptors. Overexpression or loss of control of BCL6 (e.g., through translocation) can allow the maintenance of BCL6's pro-hypoplastic function and the elimination of its antitumor function. Summary of the Invention

[0005] This article provides compounds of formula (I):

[0006]

[0007] Formula (I)

[0008] Or its pharmaceutically acceptable salt, wherein:

[0009] TBM is selected from the following groups: (T1) and (T2):

[0010] (T1)

[0011] (T2); and

[0012] Where X 1 X 3 m3, R 1 R 2a R 4 R 5 R 6 X a L, ring C, and X are as defined in this paper.

[0013] This article also provides pharmaceutical compositions comprising a compound of formula (I) (e.g., formula (Ia), (I-a1), (Ib) or (Ic)) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0014] This article provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., (Ia), (I-a1), (Ib) or (Ic)) provided herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0015] This article also provides BCL6 protein that is non-covalently bound to a compound of formula (I) (e.g., formula (Ia), (I-a1), (Ib) or (Ic)) or a pharmaceutically acceptable salt thereof.

[0016] This article also provides ternary complexes comprising BCL6 protein, a compound of formula (I) (e.g., formula (Ia), (I-a1), (Ib) or (Ic)) or a pharmaceutically acceptable salt thereof, and cereblon (CRBN) E3 ligase protein (also referred to herein as CRBN protein) or a portion thereof.

[0017] To facilitate understanding of the disclosure set forth herein, numerous additional terms are provided. Generally, the nomenclature used herein, and the laboratory procedures described in organic chemistry, medicinal chemistry, and pharmacology, are those well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Every patent, patent application, published application, and other publication mentioned throughout this specification and its appendices is incorporated herein by reference in its entirety. In the event of any conflict between this disclosure and any content incorporated herein by reference, this disclosure shall prevail.

[0018] Details of one or more embodiments of the present invention are set forth in the following drawings and description. Further features and advantages of the invention will be understood from these descriptions and drawings, as well as the claims. Detailed Implementation

[0019] This disclosure provides compounds of formula (I) (e.g., formula (Ia), (I-a1), (Ib), or (Ic)) that induce the degradation of BCL6 protein, or pharmaceutically acceptable salts thereof. These compounds can be used, for example, to treat cancer. This disclosure also provides compositions containing compounds of formula (I) (e.g., formula (Ia), (I-a1), (Ib), or (Ic)) or pharmaceutically acceptable salts thereof, and methods for using and preparing these compositions.

[0020] Upon antigen stimulation, germinal centers (GCs) form in lymphoid follicles, and B cells in the darker areas of the GCs undergo rapid proliferation and somatic hypermutation. Their immunoglobulin variable genes, as well as other genes including BCL6, generate high-affinity B cell receptors. BCL6 is generally considered the 'master regulator' of the GC response. In some cancers, BCL6 can be mutated, translocated, and / or its expression can be upregulated. See, for example, Leeman-Neill and Bhagat, Expert Opinion on Therapeutic Targets 22.2 (2018): 143-152, doi: 10.1080 / 14728222.2018.1420782; Mlynarczyk and Melnick. Immunological Reviews 288.1 (2019): 214-239, doi:10.1111 / imr.12755.

[0021] The BCL6 protein possesses multiple domains, including the BTB domain, the RD2 domain, and a DNA-binding domain. The N-terminal BTB domain is the homodimerization site of BCL6, and the monomer interface forms a "side groove," which is the binding site for endogenous co-repressors of BCL6, such as SMRT, NCOR, and BCOR. See, for example, Cardenas, Mariano G. et al., Clinical Cancer Research 23.4 (2017): 885-893, doi: 10.1158 / 1078-0432.CCR-16-2071.

[0022] Compounds that induce the degradation of target proteins are sometimes referred to as heterobifunctional compounds, PROTACs, or degrading agents. These compounds typically consist of a moiety that binds to the target protein and a moiety that binds to a ubiquitin E3 ligase (sometimes called an E3 ligase or simply E3), these two moieties optionally separated by a linker. It is believed that, in order to induce degradation, heterobifunctional compounds induce the formation of a ternary complex between the target protein, the compound, and the E3 ligase. Following the formation of the ternary complex is the ubiquitination of the target protein and its degradation by the proteasome. Several E3 ligases have been used as partner E3 ligases of heterobifunctional degrading agents. In this paper, the cereblon (CRBN) E3 ligase (also referred to herein as the CRBN protein) is used.

[0023] Degradation of target proteins can have potential advantages over small-molecule inhibition, such as that of the target protein. One potential advantage is that the duration of action of heterobifunctional compounds is often based on the rate of resynthesis of the target protein. Another potential advantage is that many heterobifunctional compounds are believed to be released from ubiquitinated target protein-E3 ligase complexes and can be used to form additional ternary complexes; this is sometimes referred to as the “catalytic” conversion of heterobifunctional compounds. In some cases, degradation of target proteins can also be more advantageous than small-molecule inhibition because degradation can attenuate the scaffold function of the target protein, which small molecules cannot. It is also generally accepted that a high affinity for the target protein is not always required for the formation of ternary complexes.

[0024] Heterobifunctional compounds are further described in the following publications: for example, international publications WO 2021 / 077010; WO 2022 / 221673; WO 2023 / 212147; WO 2024 / 151557; WO 2023 / 114460; McCoulll, William et al., ACSChemical Biology 13.11 (2018): 3131-3141, doi: 10.1021 / acschembio.8b00698; Chamberlain and Hamann, Nature Chemical Biology 15.10 (2019): 937-944, doi:10.1038 / s41589-019-0362-y; Li and Song, Journal of Hematology & Oncology 13(2020), doi: 10.1186 / s13045-020-00885-3; Wu et al., Nature Structural & Molecular Biology 27.7 (2020): 605-614, doi: 10.1038 / s41594-020-0438-0; Dong et al., Journal of Medicinal Chemistry 64.15 (2021): 10606-10620, doi: 10.1021 / acs.jmedchem.1c00895; Yang et al., Targeted Oncology 16.1 (2021): 1-12, doi:10.1007 / s11523-020-00782-2.

[0025] Compound implementation plan

[0026] This article provides compounds of formula (I):

[0027]

[0028] Formula (I)

[0029] Or its pharmaceutically acceptable salt, wherein:

[0030] TBM is selected from the following groups: (T1) and (T2):

[0031] (T1)

[0032] (T2)

[0033] X1 It is arbitrarily divided by 1 to 3 R c Replacement C 2-6 alkylene, wherein the C 2-6 The CH2 group of the alkylene group is optionally X 2 Substitute;

[0034] X 2 Choose from the following groups: -O-, -N(R) d - and -S(O) 0-2 -;

[0035] m3 is 0 or 1;

[0036] X 3 It is arbitrarily selected by 1 to 3 Rs c Replacement C 1-3 Alkylene;

[0037] R 1 Choose from the following groups: H, halogenated group, and R. b1 ;

[0038] R 2a Choose from the following groups: H, halogenated group, cyano group, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0039] Each R 4 Choose independently from the following groups: H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0040] R 5 Choose from the following groups: -OH, -NH2, -R 5A -OR 5A and -NR 5A R f ,in:

[0041] R 5A Choose from the following groups:

[0042] Optionally by 1 to 3 R c Replacement C 1-6 Alkyl groups; and

[0043] -(C 0-3 (alkylene)-R b1 Wherein C 0-3 Alkylene is optionally surrounded by 1 to 2 R c replace;

[0044] Xa Choose from the following groups: N and CR Xa ;

[0045] R 6 and R Xa Independently select from the following groups: H, halogenated group, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy groups, CN, and -C≡CH;

[0046] L is attached to aa or bb –(L) A ) n1 -,in:

[0047] n1 is an integer from 1 to 5; and

[0048] Each L A Choose independently from the following groups: L A1 L A3 and L A4 ,in:

[0049] L A 0 to 2 L A It is L A1 ;

[0050] L A 0 to 2 L A It is L A3 ;and

[0051] L A 1 to 3 L A It is L A4 ,

[0052] Each L A1 Independently select from the following groups: -CH2-, -CHR L -and-C(R) L )2-, where:

[0053] Each R L Choose independently from the following groups: halogenated, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -(C 0-3 alkylene)-(C 3-5 cycloalkyl), -(C 0-3 (alkylene)-(4-6-membered heterocyclic) and optionally surrounded by 1 to 6 R c Replacement C 1-6 alkyl;

[0054] Each L A3Independently select from the following groups: -N(R) d )-、-N(R b -、-O-、-S(O) 0-2 - and C (=O);

[0055] Each L A4 Choose independently from the following groups:

[0056] (a)C 3-15 Cycloalkyl or 4 to 15-membered heterocyclic groups, each of which is optionally substituted by 1 to 6 substituents independently selected from the group consisting of: R a and R b ;and

[0057] (b) Phenylidene or 5- to 6-membered heteroaryl groups, each of which is optionally substituted by 1 to 3 substituents independently selected from the group consisting of: R a and R b ;

[0058] Ring C can be selected from the following groups: , and ,in:

[0059] c1 is 0, 1, or 2;

[0060] Each R Yb Independently select free R a and R b The group formed;

[0061] R Ya Choose from the following groups: H, R a and R b ;and

[0062] yy represents the attachment point to L;

[0063] X is CH or N;

[0064] Each R a Choose independently from the following groups:

[0065] (a) Halogenated group;

[0066] (b) Cyano group;

[0067] (c)-OH;

[0068] (d) Oxide group;

[0069] (e) Optionally assigned to 1 to 6 R c Replacement C 1-6 Alkoxy;

[0070] (f)-NR d R e ;

[0071] (g)C(=O)C 1-6 alkyl;

[0072] (h)C(=O)OC 1-6 alkyl;

[0073] (i)C(=O)N(R f )2;

[0074] (j)S(O) 0-2 (C 1-6 alkyl);

[0075] (k)S(O) 0-2 (C- 1-6 (halogenated alkyl); and

[0076] (l)C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne groups, each optionally surrounded by 1 to 6 R groups c replace;

[0077] Each R b Independently select from the following groups: -(L b ) b -R b1 and -R b1 ,in:

[0078] Each b is independently 1, 2, or 3;

[0079] Each L b Choose independently from the following groups: -O-, -N(H)-, -N(C)-. 1-3 Alkyl)-, -S(O) 0-2 - C (=O) and C 1-3 Alkylene; and

[0080] Each R b1 Choose independently from the following groups: C 3-6 Cycloalkyl and 4 to 8-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. g replace;

[0081] Each R c Choose independently from the following groups: halogenated, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e C(=O)C1-6 Alkyl, C(=O)OC 1-6 Alkyl, C(=O)N(R) f 2. S(O) 0-2 (C 1-6 Alkyl groups and S(O) 0-2 (C- 1-6 (Halogenated alkyl);

[0082] Each R d and R e Independently select from the following groups: H, C (=O)C 1-6 Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Haloalkyl, C(=O)N(R) f 2. S(O) 1-2 (C 1-6 Alkyl groups), S(O) 1-2 (C- 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f )2 and optionally by 1 to 3 R h Replacement C 1-6 alkyl;

[0083] Each R f Independently select from the following groups: H and optionally selected by 1 to 3 Rs. h Replacement C 1-6 alkyl;

[0084] Each R g Independently select from the following groups: R h , Oxide group, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0085] Each R h Independently select from the following groups: halogenated, cyano, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl) and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

[0086] Certain combinations of heteroatoms (such as N, O, S, or halogen groups) define compounds that are less stable under physiological conditions. Examples include (1) compounds containing acetals or animal bonds; (2) compounds containing acyclic NO, NN, or NS(O)O bonds; and (3) compounds containing OO, OS(O). 0-2 N-halogenated groups, O-halogenated groups, and S(O) 0-2 Compounds with -halogenated groups. Therefore, such compounds are not preferred.

[0087] As used in this article, "acyclic bond" refers to a chemical bond that is not part of a ring. Examples include... and The NO bond in the ring. To avoid confusion, acyclic NO, NN, or NS(O)0 bonds (i.e., those bonds that are not part of a ring, e.g., in...) or (I) is less preferred, but compounds of formula (I) may include NO, NN, or NS(O)O bonds that form part of a ring (e.g., (NN bond in the text).

[0088] In some implementations of equation (I), the TBM is selected from the group consisting of: (T1) and (T2):

[0089] (T1)

[0090] (T2)

[0091] X 1 It is arbitrarily selected by 1 to 3 Rs c Replacement C 2-6 alkylene, wherein the C 2-6 The CH2 group of the alkylene group is optionally X 2 Substitute;

[0092] X 2 Choose from the following groups: -O-, -N(R) d - and -S(O) 0-2 -;

[0093] m3 is 0 or 1;

[0094] X 3 It is arbitrarily selected by 1 to 3 Rs c Replacement C 1-3 Alkylene;

[0095] R 1 Choose from the following groups: H and halogenated groups.

[0096] R 2aChoose from the following groups: H, halogenated group, cyano group, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy and C 1-3 Halogenated alkoxy groups;

[0097] Each R 4 Choose independently from the following groups: H, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0098] R 5 Choose from the following groups: -OH, -NH2, -R 5A -OR 5A and -NR 5A R f ,in:

[0099] R 5A Choose from the following groups:

[0100] Optionally by 1 to 3 R c Replacement C 1-6 Alkyl groups; and

[0101] -(C 0-3 (alkylene)-R b1 Wherein C 0-3 Alkylene is optionally surrounded by 1 to 2 R c replace;

[0102] X a Choose from the following groups: N and CR Xa ;

[0103] R 6 and R Xa Independently select from the following groups: H, halogenated group, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy groups, CN, and -C≡CH;

[0104] L is attached to aa or bb –(L) A ) n1 -,in:

[0105] n1 is an integer from 1 to 5; and

[0106] Each L A Choose independently from the following groups: L A1 L A3 and L A4 ,in:

[0107] L A0 to 2 L A It is L A1 ;

[0108] L A 0 to 2 L A It is L A3 ;and

[0109] L A 1 to 3 L A It is L A4 ,

[0110] Each L A1 Independently select from the following groups: -CH2-, -CHR L -and-C(R) L )2-, where:

[0111] Each R L Choose independently from the following groups: halogenated, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -(C 0-3 alkylene)-(C 3-5 cycloalkyl), -(C 0-3 (alkylene)-(4-6-membered heterocyclic) and optionally surrounded by 1 to 6 R c Replacement C 1-6 alkyl;

[0112] Each L A3 Independently select from the following groups: -N(R) d )-、-N(R b -、-O-、-S(O) 0-2 - and C (=O);

[0113] Each L A4 Choose independently from the following groups:

[0114] (a)C 3-15 Cycloalkyl or 4 to 15-membered heterocyclic groups, each of which is optionally substituted by 1 to 6 substituents independently selected from the group consisting of: R a and R b ;and

[0115] (b) Phenylidene or 5- to 6-membered heteroaryl groups, each of which is optionally substituted by 1 to 3 substituents independently selected from the group consisting of: R a and R b ;

[0116] Ring C can be selected from the following groups: , and ,in:

[0117] c1 is 0, 1, or 2;

[0118] Each R Ya and R Yb Independently select free R a and R b The group formed; and

[0119] yy represents the attachment point to L;

[0120] X is CH or N;

[0121] Each R a Choose independently from the following groups:

[0122] (a) Halogenated group;

[0123] (b) Cyano group;

[0124] (c)-OH;

[0125] (d) Oxide group;

[0126] (e) Optionally assigned to 1 to 6 R c Replacement C 1-6 Alkoxy;

[0127] (f)-NR d R e ;

[0128] (g)C(=O)C 1-6 alkyl;

[0129] (h)C(=O)OC 1-6 alkyl;

[0130] (i)C(=O)N(R f )2;

[0131] (j)S(O) 0-2 (C 1-6 alkyl);

[0132] (k)S(O) 0-2 (C- 1-6 (halogenated alkyl); and

[0133] (l)C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne groups, each optionally surrounded by 1 to 6 R groups c replace;

[0134] Each R b Independently select from the following groups: -(Lb ) b -R b1 and -R b1 ,in:

[0135] Each b is independently 1, 2, or 3;

[0136] Each L b Choose independently from the following groups: -O-, -N(H)-, -N(C)-. 1-3 Alkyl)-, -S(O) 0-2 - C (=O) and C 1-3 Alkylene; and

[0137] Each R b1 Choose independently from the following groups: C 3-6 Cycloalkyl and 4 to 8-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. g replace;

[0138] Each R c Choose independently from the following groups: halogenated, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e C(=O)C 1-6 Alkyl, C(=O)OC 1-6 Alkyl, C(=O)N(R) f 2. S(O) 0-2 (C 1-6 Alkyl groups and S(O) 0-2 (C- 1-6 (Halogenated alkyl);

[0139] Each R d and R e Independently select from the following groups: H, C (=O)C 1-6 Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Haloalkyl, C(=O)N(R) f 2. S(O) 1-2 (C 1-6 Alkyl groups), S(O) 1-2 (C- 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f )2 and optionally by 1 to 3 R h Replacement C 1-6 alkyl;

[0140] Each R f Independently select from the following groups: H and optionally selected by 1 to 3 Rs. h Replacement C 1-6 alkyl;

[0141] Each R g Independently select from the following groups: R h , Oxide group, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0142] Each R h Independently select from the following groups: halogenated, cyano, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl) and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

[0143] In some implementations of formula (I), TBM is (T1).

[0144] In some implementations of equation (I), TBM is (T1a):

[0145] (T1a)

[0146] Where X 1a It is arbitrarily selected by 1 to 3 Rs c Replacement C 1-4 Alkylene.

[0147] In some implementations of equation (I), TBM is (T1a-1):

[0148] (T1a-1)

[0149] Where X 1a It is arbitrarily selected by 1 to 3 Rs c Replacement C 2-4 Alkylene.

[0150] In some implementations of equation (I), TBM is (T1a-2):

[0151] (T1a-2)

[0152] Where R X1 It is methyl or H.

[0153] In some implementations of equation (I), each R 4 It's H.

[0154] In some implementations of formula (I), R 5 Yes -NR 5A R f In some such implementations, R 5A It is C 1-3 Alkyl group. For example, R 5 It can be -NH(Me).

[0155] In some implementations of equation (I), TBM is (T1a-1a):

[0156] (T1a-1a)

[0157] Where R X1 It is methyl or H.

[0158] In some implementations of formula (I), TBM is (T2).

[0159] In some implementations of equation (I), TBM is (T2-a):

[0160] (T2-a)

[0161] Where m3 is 1; X 3 It is C 1-3 Alkylene; and R 1 It's H.

[0162] In some implementations of formula (I), R 2a It's H.

[0163] In some implementations of formula (I), X a It is N.

[0164] In some implementations of formula (I), R 6 It is a halogenated group. For example, R 6 It can be -Cl.

[0165] In some implementations of equation (I), L is –(L A ) n1 -,in:

[0166] n1 is an integer from 2 to 4; and

[0167] Each L A Choose independently from the following groups: L A1 L A3 and L A4,in:

[0168] L A 0 to 2 L A It is L A1 ;

[0169] L A 0 to 2 L A It is L A3 ;and

[0170] L A 2 to 3 L in A It is L A4 ,in:

[0171] Each L A4 C is independent 3-10 Cycloalkyl or 4 to 12-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. a Replace, of which:

[0172] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl groups, OH groups, and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl; and

[0173] Each R L Independently select from the following groups: -F, -OH, and optionally 1 to 3 R... c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 -F atoms) 1-3 alkyl).

[0174] In some implementations of equation (I), L is –(L A ) n1 -,in:

[0175] n1 is an integer from 2 to 4; and

[0176] Each L A Choose independently from the following groups: L A1 and L A4 ,in:

[0177] L A 0 to 2 L A It is L A1 ;and

[0178] L A 2 to 3 L in A It is L A4 ,in:

[0179] Each L A4 Independently, they are 4 to 12-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. a Replace, of which:

[0180] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl groups, OH groups, and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl; and

[0181] Each R L Independently select from the following groups: -F, -OH, and optionally 1 to 3 R... c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 -F atoms) 1-3 alkyl).

[0182] In some implementations of equation (I), L is -L A4a -L A1 -L A4b - bb ,in:

[0183] L A4a and L A4b Each is an independently selected L A4 ,and

[0184] bb represents the attachment point to ring C.

[0185] In some implementations, L A4a and L A4b Independently, it is optional to be controlled by 1 to 3 Rs a Substituted 4 to 12 nitrogen-containing heterocyclic groups; and each R L Independently select from the following groups: -F, -OH, and optionally 1 to 3 R... c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 -F atoms) 1-3 Alkyl group). In some embodiments, L A4a and L A4b Each contains one or two cyclic nitrogen atoms and no other cyclic heteroatoms. In some embodiments, L A4a and / or L A4b Each R existing on a Choose independently from the following groups: -F and C, which may be replaced by 1 to 3 Fs. 1-3 Alkyl groups (e.g., -CH3).

[0186] In some implementations, L A4a and L A4b Each is independently and arbitrarily assigned to 1 to 3 Rs a The selected monocyclic 4- to 6-membered nitrogen-containing heterocyclic group is substituted. In some embodiments, L A4a and L A4b One of them is 1,4-piperidinyl; and L A4a and L A4b The other one is independently selected from the group consisting of: 1,4-piperidinyl and 1,4-piperazinyl, wherein each of the 1,4-piperidinyl or 1,4-piperazinyl is optionally surrounded by 1 to 2 R... a Replacement. In some implementations, L A4a and L A4b Each contains one or two cyclic nitrogen atoms and no other cyclic heteroatoms. In some embodiments, L A4a and / or L A4b Each R existing on a Choose independently from the following groups: -F and C, which may be replaced by 1 to 3 Fs. 1-3 Alkyl groups (e.g., -CH3).

[0187] In some implementations, L A4a and L A4b One of them is arbitrarily selected by 1 to 3 Rs a Substituted monocyclic 4- to 6-membered nitrogen-containing heterocyclic groups; and L A4a and L A4b The other one is arbitrarily selected by 1 to 3 Rs. a Substituted bicyclic spirocyclic 6 to 12 (e.g., 10 to 12) nitrogen-containing heterocyclic sub-groups. In some embodiments, L A4b It is arbitrarily selected by 1 to 3 Rs a Substituted monocyclic 4- to 6-membered nitrogen-containing heterocyclic groups; and L A4a It is arbitrarily selected by 1 to 3 Rs a Substituted bicyclic spirocyclic 6 to 12 (e.g., 10 to 12) nitrogen-containing heterocyclic sub-groups. In some embodiments, L A4b It is optional to be 1 to 2 R a Substituted 1,4-piperidine; and L A4a It is optional to be 1 to 2 R a The substituted bicyclic spirocyclic 10- to 12-membered nitrogen-containing heterocyclic group. In some embodiments, L A4a and L A4b Each contains one or two cyclic nitrogen atoms and no other cyclic heteroatoms. In some embodiments, L A4a and / or L A4b Each R existing on aChoose independently from the following groups: -F and C, which may be replaced by 1 to 3 Fs. 1-3 Alkyl groups (e.g., -CH3).

[0188] In some implementations of formula (I), L A1 It is -CH2-.

[0189] In some implementations of formula (I), L A1 Yes - CHR L -, where R L C is C that can be arbitrarily replaced by 1 to 3 Fs. 1-3 Alkyl (e.g., R) L It is -CH3).

[0190] In some implementations of formula (I), ring C is selected from the group consisting of: and .

[0191] In some implementations of formula (I), ring C is selected from the group consisting of: , , , and .

[0192] In some implementations of formula (I), R Ya It is arbitrarily selected by 1 to 3 Rs c Replacement C 1-6 Alkyl; and

[0193] Each R Yb Choose independently from the following groups: -F and C, which may be replaced by 1 to 3 -F groups. 1-3 alkyl.

[0194] In some implementations of equation (I), each R Yb Yes, it is -F.

[0195] In some implementations of formula (I), R Ya C is a C that is optionally replaced by 1 to 3 -F. 1-3 Alkyl groups, and each R Yb Yes, it is -F.

[0196] In some implementations of formula (I), R Ya It is a methyl group.

[0197] In some implementations of formula (I), R Ya It is methyl; and each R Yb Yes, it is -F.

[0198] In some implementations of formula (I), ring C is selected from the group consisting of: , , , and .

[0199] In some implementations of formula (I), X is CH.

[0200] In some embodiments, the compound of formula (I) is the same as the compound of formula (Ia):

[0201]

[0202] Formula (Ia)

[0203] Or its pharmaceutically acceptable salt, wherein:

[0204] X 1a It is arbitrarily selected by 1 to 3 Rs c Replacement C 2-4 Alkylene;

[0205] L A4a and L A4b Independently, it is optional to be controlled by 1 to 3 Rs a Substituted 4- to 12-membered nitrogen-containing heterocyclic groups;

[0206] L A1 It is CH -2 or CHR L ,

[0207] R L Choose from the following groups: -F, -OH, and optionally surrounded by 1 to 3 R groups. c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 -F atoms) 1-3 alkyl);

[0208] Ring C can be selected from the following groups: and .

[0209] c1 is 0, 1, or 2;

[0210] R Ya It is arbitrarily selected by 1 to 3 Rs c Replacement C 1-6 alkyl;

[0211] Each R Yb Choose independently from the following groups: -F and C, which may be replaced by 1 to 3 -F groups. 1-3 Alkyl; and

[0212] yy indicates that it is related to LA4b Attachment point.

[0213] In some implementations of equation (Ia), each R 4 It's H.

[0214] In some implementations of formula (Ia), R 5 Yes -NR 5A R f In some implementations, R 5A It is C 1-3 Alkyl group. For example, R 5 It can be -NH(Me).

[0215] In some embodiments, the compound of formula (I) is a compound of formula (I-a1):

[0216]

[0217] Equation (I-a1)

[0218] Or its pharmaceutically acceptable salt.

[0219] in:

[0220] R X1 It is methyl or H;

[0221] L A4a and L A4b Independently, it is optional to be controlled by 1 to 3 Rs a Substituted 4- to 12-membered nitrogen-containing heterocyclic groups;

[0222] L A1 It is CH -2 or CHR L ,

[0223] R L Choose from the following groups: -F, -OH, and optionally surrounded by 1 to 3 R groups. c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 -F atoms) 1-3 alkyl);

[0224] L A4a and / or L A4b Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl groups, OH groups, and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl;

[0225] Ring C can be selected from the following groups: and .

[0226] c1 is 0, 1, or 2;

[0227] R Ya It is arbitrarily selected by 1 to 3 Rs c Replacement C 1-6 alkyl;

[0228] Each R Yb Choose independently from the following groups: -F and C, which may be replaced by 1 to 3 -F groups. 1-3 Alkyl; and

[0229] yy indicates that it is related to L A4b Attachment point.

[0230] In some implementations of formula (Ia) or (I-a1), R 2a It's H.

[0231] In some implementations of formula (Ia) or (I-a1), X a It is N.

[0232] In some implementations of formula (Ia) or (I-a1), R 6 It is a halogenated group (e.g., -Cl).

[0233] In some implementations of formula (Ia) or (I-a1), c1 is 0 or 1.

[0234] In some implementations of formula (Ia) or (I-a1), R Ya C is a C that is optionally replaced by 1 to 3 -F. 1-3 Alkyl groups, and each R Yb Yes, it is -F.

[0235] In some implementations of formula (Ia) or (I-a1), R Ya It is a methyl group.

[0236] In some embodiments of formula (Ia) or (I-a1), ring C is selected from the group consisting of: , , , and .

[0237] In some implementations of formula (Ia) or (I-a1), L A4a -L A1 -L A4b Part of it is ,in:

[0238] m4 and m5 are independently 0, 1 or 2;

[0239] Each R a4 and R a5 Choose independently from the following groups: -F, CN, C 1-3 Alkyl groups, OH groups, and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl; and

[0240] bb represents the attachment point to ring C. For example, Part can be .

[0241] In some implementations of formula (Ia) or (I-a1), L A4a -L A1 -L A4b Part of it is ,in:

[0242] m4 and m5 are independently 0, 1 or 2;

[0243] Each R a4 Choose independently from the following groups: -F, CN, C 1-3 Alkyl groups, OH groups, and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl;

[0244] Each R a5 Independently, C is optionally replaced by 1 to 3 Fs. 1-3 Alkyl; and

[0245] bb represents the attachment point to ring C. For example, Part can be .

[0246] In some implementations of formula (Ia) or (I-a1), L A4a -L A1 -L A4b Part of it is ,in:

[0247] m4 and m5 are independently 0, 1 or 2;

[0248] Each R a4 Independently, C is optionally replaced by 1 to 3 Fs. 1-3 alkyl;

[0249] Each R a5 Choose independently from the following groups: -F, CN, C 1-3 Alkyl groups, OH groups, and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl; and

[0250] bb represents the attachment point to ring C. For example, Part can be .

[0251] In some embodiments, the compound of formula (I) is the compound of formula (Ib):

[0252]

[0253] Formula (Ib)

[0254] Or its pharmaceutically acceptable salt, wherein:

[0255] L A4a and L A4b Independently, it is optional to be controlled by 1 to 3 Rs a Substituted 4- to 12-membered nitrogen-containing heterocyclic groups;

[0256] L A1 It is CH -2 or CHR L ,

[0257] R L Choose from the following groups: -F, -OH, and optionally surrounded by 1 to 3 R groups. c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 -F atoms) 1-3 alkyl);

[0258] c1 is 1 or 2;

[0259] R Ya It is arbitrarily selected by 1 to 3 Rs c Replacement C 1-6 Alkyl; and

[0260] Each R Yb Choose independently from the following groups: -F and C, which may be replaced by 1 to 3 -F groups. 1-3 alkyl.

[0261] In some embodiments, the compound of formula (Ib) is not compound number R239 or R240 as depicted in Table R1, or a pharmaceutically acceptable salt thereof.

[0262] In some implementations of formula (Ib), one or more of (1)-(3) apply:

[0263] (1)L A4a and L A4b Independently, it is optional to be controlled by 1 to 3 Rs a Substituted 4- to 6-membered monocyclic nitrogen-containing heterocyclic groups;

[0264] (2)L A4a and L A4b Independently, it is optional to be controlled by 1 to 3 Rsa Substituted 4 to 12 nitrogen-containing heterocyclic groups; and / or

[0265] (3) c1 is 2.

[0266] In some implementations of formula (Ib), Some selections are made from the following groups: , and .

[0267] In some implementations of formula (Ib), L A4a -L A1 -L A4b Part of it is ,in:

[0268] m4 and m5 are independently 0, 1 or 2;

[0269] Each R a4 and R a5 Choose independently from the following groups: -F, CN, C 1-3 Alkyl groups, OH groups, and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl; and

[0270] bb means with The attachment point. In some implementations, m5 is 0; and m4 is 0 or 1 (e.g., 0).

[0271] In some implementations of formula (Ib), L A1 It is CH2.

[0272] In some embodiments, the compound of formula (I) is the compound of formula (Ic):

[0273]

[0274] Formula (Ic)

[0275] Or its pharmaceutically acceptable salt, wherein:

[0276] m4 and m5 are independently 0, 1 or 2;

[0277] Each R a4 and R a5 Choose independently from the following groups: -F, CN, C 1-3 Alkyl groups, OH groups, and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl;

[0278] L A1 It is CH -2 or CHR L ,

[0279] Where R L Choose from the following groups: -F, -OH, and optionally surrounded by 1 to 3 R groups. c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 -F atoms) 1-3 alkyl);

[0280] c1 is 0, 1, or 2;

[0281] R Ya It is arbitrarily selected by 1 to 3 Rs c Replacement C 1-6 Alkyl; and

[0282] Each R Yb Choose independently from the following groups: -F and C, which may be replaced by 1 to 3 -F groups. 1-3 alkyl.

[0283] In some embodiments, the compound of formula (Ic) is not compound numbered R242, R242a, R242b, R212 or R167 as depicted in Table R1, or a pharmaceutically acceptable salt thereof.

[0284] In some implementations of formula (Ic), one or more of (1)-(3) apply:

[0285] (1) m4 is 1 or 2, where each R a4 Independently, C is optionally replaced by 1 to 3 Fs. 1-3 alkyl;

[0286] (2) m5 is 1 or 2; and / or

[0287] (3) c1 is 1 or 2.

[0288] In some implementations of equation (Ic), m4 is 0; and m5 is 0.

[0289] In some implementations of equation (Ic), m4 is 1 or 2, where each R a4 Independently, C is optionally replaced by 1 to 3 Fs. 1-3 Alkyl group; and m5 is 0.

[0290] In some implementations of formula (Ic), L A1 It is CH2.

[0291] In some implementations of formula (Ic), c1 is 0.

[0292] In some implementations of formula (Ic), c1 is 1 or 2.

[0293] In some implementations of formula (Ic), Some selections are made from the following groups: , and .

[0294] In some implementations of formula (Ib) or (Ic), R Ya It is a methyl group.

[0295] In some implementations of formula (Ib) or (Ic), each R Yb Yes, it is -F.

[0296] In some implementations of formula (Ib) or (Ic), R 5 Yes -NR 5A R f .

[0297] In some implementations of formula (Ib) or (Ic), R 5 It is -NH(Me).

[0298] In some implementations of formula (Ib) or (Ic), R 2a It's H.

[0299] In some implementations of formula (Ib) or (Ic), m3 is 1; and X 3 It is C 1-3 Alkylene.

[0300] In some implementations of formula (Ib) or (Ic), R 1 It's H.

[0301] In some implementations of formula (Ib) or (Ic), –(X 3 ) m3 -R 1 It is isopropyl.

[0302] In some implementations of formula (Ib) or (Ic), R 6 It is -Cl.

[0303] In some implementations of formula (Ib) or (Ic), X a It is N.

[0304] In some implementations of formula (Ib) or (Ic), R 5 It is -NH(Me); R 6 It is -Cl; and X a It is N. In some implementations, m3 is 1; X 3 It is C 1-3 Alkylene; and R1 It's H.

[0305] In some implementations of formula (Ib) or (Ic), X is CH.

[0306] In some embodiments, the compounds of formula (I) are selected from the group consisting of compounds in table C1 or pharmaceutically acceptable salts thereof.

[0307] Table C1

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319] Notes :

[0320] In certain compounds in Table C1 or Table R1, one or more stereoisomer source centers are indicated by “V3000 enhanced stereochemical symbols” (see: support.collaborativedrug.com / hc / en-us / articles / 360020872171-Advanced-Stereochemistry-Registration-Atropisomers-Mixtures-Unknowns-and-Non-Tetrahedral-Chirality, accessed December 23, 2022, and Accelrys Chemical Representation Guide, Accelrys Software Inc., 2014, each incorporated herein by reference in its entirety). Using this stereochemical symbol, certain stereoisomer source centers are indicated by “abs”, “&x”, or “orx”, where x is an integer (e.g., 1 or 2). For the avoidance of doubt, the stereochemical symbols in Table C1 or Table R1 have the following meanings:

[0321] (1) When the stereoisomer source center (e.g., the stereoisomer source carbon) is depicted with a "flat" bond in the structural formula (i.e., the chemical bonds at the stereoisomer source center are not depicted with wedges or dashed lines), each stereoisomer source center can independently adopt the (R)- or (S)- configuration. For example, the structure This refers to (S)-(1-methylpyrrolidone-2-yl)methanol, (R)-(1-methylpyrrolidone-2-yl)methanol, or mixtures thereof. As another non-limiting example, the structure... It means: (3S,5S)-5-methylpiperidine-3-carboxylic acid; (3R,5S)-5-methylpiperidine-3-carboxylic acid; (3S,5R)-5-methylpiperidine-3-carboxylic acid; (3R,5R)-5-methylpiperidine-3-carboxylic acid; or mixtures thereof.

[0322] When using wedges and dashed lines to depict the center of a stereoisomorphic source or multiple stereoisomorphic source centers, the following symbols are used:

[0323] (2) When the stereoisomeric source center is denoted by "abs" or when it is not denoted by an enhanced stereochemical symbol (e.g., "abs", "&x", or "orx"), the stereoisomeric source center has the absolute configuration as described in the structural formula. For example, two structures and It refers to (S)-(1-methylpyrrolidone-2-yl)methanol.

[0324] (3) When the stereoheterogeneous source center is represented by "orx" in the structural formula, the stereoheterogeneous source center has been split, but the configuration at the stereoheterogeneous source center has not yet been determined. For example, the structure... It refers to a stereoisomer selected from the group consisting of (S)-(1-methylpyrrolidone-2-yl)methanol and (R)-(1-methylpyrrolidone-2-yl)methanol.

[0325] (4) When two or more stereoheterogeneous source centers are represented by "orx" in the structural formula, each of these stereoheterogeneous source centers is split, but the configuration at the stereoheterogeneous source center is not yet determined. Specifically:

[0326] a. For any pair of stereoheterogeneous source centers denoted by “orx” in the structural formula, each stereoheterogeneous source center is independently defined according to (3) (see above) when the numerical parts in the symbols are different (e.g., the two stereoheterogeneous source centers are denoted by “or1” and “or2” respectively). For example, the structural This refers to a stereoisomer selected from the following groups: , , and .

[0327] b. For any pair of stereoisomer source centers denoted by "orx" in the structural formula, when the numerical parts of the symbols are the same (e.g., each stereoisomer source center is denoted by "or1"), the structural formula refers to a stereoisomer having the relative stereochemistry described in the structural formula at these stereoisomer source centers, but the absolute configuration of these stereoisomer source centers has not yet been determined. For example, structural... It refers to one of the two "cis" stereoisomers: or As another example, structure It refers to one of the "trans" stereoisomers: or .

[0328] (5) When two or more stereoisomer source centers are represented by "&x" in the structural formula, the structural formula refers to a mixture of stereoisomers with different configurations at the stereoisomer source centers. Specifically:

[0329] a. For any pair of stereoisomer source centers denoted by "&x" in a structural formula, when the numerical parts of the symbols differ (e.g., the two stereoisomer source centers are denoted by "&1" and "&2" respectively), the structural formula refers to a mixture of stereoisomers at these two stereoisomer source centers, wherein the configuration at each stereoisomer source center can vary independently from one another. For example, structural... It refers to a mixture of four stereoisomers: , , and .

[0330] b. For any pair of stereoisomer source centers denoted by “&x” in the structural formula, when the numerical parts in the symbols are the same (e.g., each of the two stereoisomer source centers is denoted by “&1”), the structural formula refers to a mixture of stereoisomers at these two or more stereoisomer source centers, wherein the relative configurations are as described in the structural formula. For example, structural... It refers to a mixture of "cis" stereoisomers: and As another example, structure It refers to a mixture of "trans" stereoisomers: and .

[0331] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compounds depicted in Table C1 of U.S. Provisional Application Serial No. 63 / 580,215, filed September 1, 2023; Table C1 of U.S. Provisional Application Serial No. 63 / 607,012, filed December 6, 2023; Table C1 of U.S. Provisional Application Serial No. 63 / 624,171, filed January 23, 2024; and Table C1 of U.S. Provisional Application Serial No. 63 / 665,670, filed June 28, 2024; each Table C1 is incorporated herein by reference in its entirety.

[0332] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not a compound or a pharmaceutically acceptable salt thereof in Table C1 of International Patent Application PCT / US / 23 / 67918, filed June 5, 2023, the entire text of Table C1 of International Patent Application PCT / US / 23 / 67918 is incorporated herein by reference.

[0333] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is not one of the compounds or a pharmaceutically acceptable salt thereof depicted in Table R1.

[0334] Table R1

[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] In some embodiments, compounds of formula (I) (e.g., formula (Ia), (I-a1), (Ib), or (Ic)) or pharmaceutically acceptable salts thereof are expressed at EC50 concentrations of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 50 Reduces cell viability in cell lines expressing BCL6 protein. In some embodiments, the compound is administered at EC50 concentrations of less than 200 nM (e.g., less than 150 nM, less than 100 nM, less than 10 nM, less than 1 nM). 50 It reduces cell viability in cell lines expressing BCL6 protein. For example, the compound can be present in EC50 concentrations of about 0.1 nM to about 100 nM, about 0.1 nM to about 50 nM, about 1 nM to about 50 nM, about 1 nM to about 20 nM, or about 0.1 nM to about 1 nM. 50 It reduces cell viability in cell lines expressing BCL6 protein.

[0372] In some embodiments, compounds of formula (I) (e.g., formula (Ia), (I-a1), (Ib), or (Ic)) or pharmaceutically acceptable salts thereof are expressed at DC concentrations of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 50 Inducing the degradation of BCL6 protein in cell lines expressing BCL6 protein. In some embodiments, a compound of formula (I) (e.g., formula (Ia), (I-a1), (Ib), or (Ic)) or a pharmaceutically acceptable salt thereof is used in DC at less than 200 nM (e.g., less than 150 nM, less than 100 nM, less than 10 nM, less than 1 nM). 50 Induces the degradation of BCL6 protein in cell lines expressing BCL6 protein. For example, the compound can be expressed in DC concentrations of about 0.1 nM to about 100 nM, about 0.1 nM to about 50 nM, about 1 nM to about 50 nM, about 1 nM to about 20 nM, or about 0.1 nM to about 1 nM. 50 Degradation of BCL6 protein in cell lines expressing BCL6 protein.

[0373] In some embodiments, a compound of formula (I) (e.g., formula (Ia), (I-a1), (Ib), or (Ic)) or a pharmaceutically acceptable salt thereof is used in a concentration of less than 70% (e.g., less than 50%, less than 30%, less than 20%, or less than 10%) of Y. min Inducing the degradation of BCL6 protein in cell lines expressing BCL6 protein. In some embodiments, a compound of formula (I) (e.g., formula (Ia), (I-a1), (Ib), or (Ic)) or a pharmaceutically acceptable salt thereof is used in a concentration of less than 50% (e.g., less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%) of Y. min Inducing the degradation of BCL6 protein in cell lines expressing BCL6 protein. In some embodiments, a compound of formula (I) (e.g., formula (Ia), (I-a1), (Ib), or (Ic)) or a pharmaceutically acceptable salt thereof is used in a concentration of less than 30% (e.g., less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%) of Y. min Induces the degradation of BCL6 protein in cell lines expressing BCL6 protein. For example, the compound can be administered at about 1% to about 70% (e.g., about 5% to about 50% or about 10% to about 30%) of Y. min Degradation of BCL6 protein in cell lines expressing BCL6 protein.

[0374] This article also provides BCL6 protein that is non-covalently bound to a compound of formula (I) (e.g., formula (Ia), (I-a1), (Ib) or (Ic)) or a pharmaceutically acceptable salt thereof.

[0375] This article also provides ternary complexes comprising BCL6 protein, a compound of formula (I) (e.g., formula (Ia), (I-a1), (Ib) or (Ic)) or a pharmaceutically acceptable salt thereof, and CRBN protein or a portion thereof.

[0376] Chemical definition

[0377] The term "halogenated group" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0378] The term "oxo group" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.

[0379] The term "alkyl" refers to a saturated acyclic hydrocarbon group, which can be straight-chain or branched and contains a specified number of carbon atoms. For example, C 1-10This indicates that the group may have 1 to 10 carbon atoms (including the terminal number). The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. As used in this context, the term "saturated" means that only single bonds exist between the carbon atoms in the composition, and other available valence bonds are occupied by hydrogen and / or other substituents as defined herein.

[0380] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halogroups (e.g., -CF3, -CHF2, or -CH2F).

[0381] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH3).

[0382] The term "alkylene" refers to a divalent alkyl group (e.g., -CH2-). Similarly, terms such as "cycloalkylene" and "heterocyclic alkylene" refer to divalent cycloalkyl and heterocyclic groups, respectively. To avoid confusion, in "cycloalkylene" and "heterocyclic alkylene," the two groups can be on the same ring carbon atom (e.g., gemini, such as...). or Or on different ring atoms (e.g., cyclic carbon and / or nitrogen atoms (e.g., adjacent cyclic carbon and / or nitrogen atoms)) (e.g., , , , ).

[0383] The term "alkenyl" refers to an acyclic hydrocarbon chain that can be straight-chain or branched, having one or more carbon-carbon double bonds. The alkenyl moiety contains a specified number of carbon atoms. For example, C 2-6 This indicates that the group can have 2 to 6 carbon atoms (including the terminal number). The alkenyl group can be unsubstituted or substituted by one or more substituents.

[0384] The term "alkynyl" refers to an acyclic hydrocarbon chain that can be straight-chain or branched, having one or more carbon-carbon triple bonds. The alkynyl moiety contains a specified number of carbon atoms. For example, C 2-6 This indicates that the group can have 2 to 6 carbon atoms (including the terminal number). The alkynyl group can be unsubstituted or substituted by one or more substituents.

[0385] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group with 6 to 20 carbon atoms, wherein at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic aromatic ring system, a 10-carbon bicyclic aromatic ring system, or a 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and so on.

[0386] As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons, 3 to 10 ring carbons, or 3 to 6 ring carbons, wherein the cycloalkyl group may optionally be substituted. As used in this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms. Examples of saturated cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyl groups may have any degree of unsaturation, provided that one or more double bonds are present in the cycloalkyl group, the rings in the ring system are not aromatic, and the partially unsaturated cycloalkyl group is generally not fully saturated. Examples of partially unsaturated cycloalkyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkyl groups may include multiple fused rings and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl groups include: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and so on. Cycloalkyl groups also include spirocyclic (e.g., spirocyclic bicyclic groups in which the two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl groups include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, etc.

[0387] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10, or 15 ring atoms; wherein at least one ring in the system contains one or more heteroatoms, which are independently selected from the group consisting of N, O, and S (including oxidized forms, such as: or And at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, such as tetrahydroisoquinolinyl, for example, tetrahydroquinolinyl). In some embodiments, the heteroaryl group contains one to four (e.g., one, two, or three) cyclic heteroatoms, each independently selected from the group consisting of N, O, and S (including oxidized forms, such as: or The heteroaryl group can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thiophene, pyridinyl, furanyl, oxazolyl, oxadiazolyl, pyrroloyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl-benzothiophene, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cenylyl, indazole, indolyl, isoquinolinyl, isothiazolyl, naphridinyl, purine, thiophene-pyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl Thiophene[2,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[4,3-b]pyridyl, tetrazolyl, benzodihydropyranyl, 2,3-dihydrobenzo[b][1,4]dioxacyclohexenyl, benzo[d][1,3]m-dioxacyclopentyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindololinyl, etc. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furanyl, pyrazolyl, imidazolyl, isoindololinyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, heteroaryl groups also include aryl lactams, aryl cycloureas, or their intercalated alkene analogs, wherein each cyclic nitrogen adjacent to the carbonyl group is a tertiary nitrogen (i.e., all three valence bonds are occupied by non-hydrogen substituents), such as pyridones (e.g., , , or ), pyrimidinones (e.g., or ), pyridazinone (e.g., or ), pyrazinone (e.g., or ) and imidazolids (e.g., One or more of the following, wherein each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (i.e., the oxo group (i.e., "=O") in this text is a component of the heteroaryl ring).

[0388] The term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system having 3 to 15 ring atoms (e.g., 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 15-membered tricyclic ring systems). In the case of a monocyclic ring system, it has 1 to 3 heteroatoms; in the case of a bicyclic ring system, it has 1 to 6 heteroatoms; or in the case of a tricyclic or polycyclic ring system, it has 1 to 9 heteroatoms selected from O, N, and S (including oxidized forms, such as: or (For example, carbon atoms and, if they are monocyclic, bicyclic, or tricyclic ring systems, one to three, one to six, or one to nine heteroatoms of N, O, S, or P), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. As used in this context, the term “saturated” means that only single bonds exist between the constituent ring atoms, and other available valence bonds are occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclic groups include piperazine, pyrrolyl, dioxane, morpholinyl, tetrahydrofuranyl, and so on. Partially unsaturated heterocyclic groups may have any degree of unsaturation, provided that one or more double bonds are present in the heterocyclic group, the rings in the ring system are not aromatic, and the partially unsaturated heterocyclic group is generally not completely saturated. Examples of partially unsaturated heterocyclic groups include, but are not limited to, tetrahydropyridinyl, dihydropyrazine, dihydropyridinyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiopheneyl.

[0389] Heterocyclic groups may include multiple fused rings and bridged rings. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, 3- Azabicyclo[3.2.1]octyl, 2-oxabicyclo[1.1.0]butyl, 2-oxabicyclo[2.1.0]pentyl, 2-oxabicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 7-oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1]heptyl, 7-oxabicyclo[4.2.0]octyl, 2-oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl, etc. Heterocyclic groups also include spirocyclic groups (e.g., spirocyclic bicyclic groups in which the two rings are connected by only one atom). Non-limiting examples of spirocyclic heterocyclic groups include 2-azaspiro[2.2]pentyl, 4-azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, 1,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl, 2,5-diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, and 2-oxaspiro. [2.2]pentyl, 4-oxaspiro[2.5]octyl, 1-oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6-oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, 1-oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl, etc.

[0390] As used herein, a nitrogen-containing heterocyclic group refers to a heterocyclic group having one to two cyclic nitrogen atoms and 0 to two additional cyclic heteroatoms selected from the group consisting of: O and S (including oxidized forms, such as: or Nitrogen-containing heterocyclic groups can be monocyclic, bicyclic, or polycyclic as defined elsewhere herein. Examples of monocyclic nitrogen-containing heterocyclic groups include aziridine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like. Examples of bicyclic nitrogen-containing heterocyclic groups include 7-azaspiro[3.5]nonyl, 1,7-diazaspiro[4.5]decyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonyl, 2,6-diazaspiro[3.3]heptyl, and the like.

[0391] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation attributable to the ring itself; for example, one or more double or triple bonds between the constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and so on.

[0392] To avoid confusion, unless otherwise stated, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclic, heterocyclic alkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) containing a sufficient number of ring atoms to form bicyclic or higher-order ring systems (e.g., tricyclic, polycyclic ring systems), it should be understood that such rings and cyclic groups encompass those having fused rings, including those where the fusion point is located at: (i) on adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a zero-atom bridge (e.g., ...) (ii) Monocyclic atoms (spirofused ring systems) (e.g., , or ), or (iii) a continuous array of ring atoms (bridged ring systems with all bridge lengths > 0) (e.g., , or ).

[0393] Furthermore, the atoms constituting the compounds of this embodiment are intended to include all isotopic forms of these atoms. As used herein, isotopes include those atoms with the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0394] Furthermore, the compounds generally or specifically disclosed herein are intended to include all tautomer forms. Therefore, for example, those containing: The compounds include those containing: The tautomer form. Similarly, the tautomer form described as having a pyridyl or pyrimidinyl moiety optionally substituted with a hydroxyl group includes a pyridinone or pyrimidinone.

[0395] The compounds described herein can encompass a wide range of stereochemical forms. This also includes diastereomers and optical isomers (e.g., mixtures of enantiomers, including racemic mixtures), as well as individual enantiomers and diastereomers arising from the structural asymmetry of certain compounds. Unless otherwise specified, when a disclosed compound is named or described by not specifying its stereochemical structure and has one or more chiral centers, it should be understood to represent all possible stereoisomers of that compound.

[0396] Treatment

[0397] Indications

[0398] This article provides methods for inducing the degradation of the BCL6 protein. For example, this article provides compounds that can induce the degradation of the BCL6 protein and can be used to treat or prevent cancer. Exemplary compounds that bind to BCL6 are described in the following literature: for example, Cerchietti, Leandro C. et al., Cancer Cell 17.4 (2010): 400-411, doi:10.1016 / j.ccr.2009.12.050; Cardenas, Mariano G. et al., The Journal of Clinical Investigation 126(9) (2016): 3351-3362, doi: 10.1172 / JCI85795; Kerres, Nina et al., Cell Reports 20.12 (2017): 2860-2875, doi: 10.1016 / j.celrep.2017.08.081; Yasui, Takeshi et al., Bioorganic & Medicinal Chemistry 25.17 (2017): 4876-4886, doi: 10.1016 / j.bmc.2017.07.037; Kamada, Yusuke et al., Journal of Medicinal Chemistry 60.10 (2017): 4358-4368, doi: 10.1021 / acs.jmedchem.7b00313; McCoulll, William et al., ACS Chemical Biology 13.11 (2018): 3131-3141, doi: 10.1021 / acschembio.8b00698; Guo, Weikai et al., Journal of Medicinal Chemistry 63.2(2020): 676-695, doi: 10.1021 / acs.jmedchem.9b01618; Teng, Mingxing et al., ACSMedicinal Chemistry Letters 11.6 (2020): 1269-1273, doi: 10.1021 / acsmedchemlett.0c00111; Pearce, Andrew C. et al., Journal of Biological Chemistry297.2 (2021): 100928, doi: 10.1016 / j.jbc.2021.100928; Ding, Shu, Yu Rao and Qianjin Lu, Cellular & Molecular Immunology (2022): 1-3, doi: 10.1038 / s41423-022-00882-1; Xing, Y. et al., Cancer Letters (2022), doi: 10.1016 / j.canlet.2021.12.035; Huckvale, R. et al., Journal of Medicinal Chemistry (2022), doi: 10.1021 / acs.jmedchem.1c02175; Davis, O. et al., Journal of Medicinal Chemistry (2022), doi: 10.1021 / acs.jmedchem.1c02174; International Published WO 2008 / 066887; WO2010 / 008436; WO 2014 / 204859; WO 2018 / 215798; WO 2018 / 215801; WO 2018 / 219281; WO2019 / 119138; WO 2019 / 119144; WO 2019 / 119145; WO 2019 / 153080; WO 2019 / 197842; WO2020 / 104820; WO 2021 / 074620; WO 2021 / 077010; WO 2022 / 221673; WO 2023 / 212147; and WO2023 / 114460. .

[0399] The term “compounds provided herein” refers to compounds of formula (I) disclosed herein (e.g., formula (Ia), (I-a1), (Ib) or (Ic)).

[0400] The degradation efficacy of the compounds or their pharmaceutically acceptable salts described herein can be obtained via DC. 50 The value is used to determine this. As used in this article, DC... 50 This refers to the concentration of a compound or its pharmaceutically acceptable salt provided herein that results in a 50% reduction in the concentration of a protein (e.g., BCL6 protein) in cells compared to the protein concentration prior to contact with the compound provided herein or its pharmaceutically acceptable salt, or compared to the protein concentration in cells not contacted with the compound provided herein or its pharmaceutically acceptable salt. As measured under substantially similar conditions, a lower DC... 50 Compounds with higher DC values ​​relative to those with higher DC values 50Compounds with high degradation values ​​are more effective degradation inducers. In some embodiments, DC... 50 Values ​​can be obtained in vitro or in vivo (e.g., in tumor cells expressing BCL6 protein, such as cell lines like A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2; see also, for example, Cardenas, Mariano G. et al., Clinical Cancer Research 23.4(2017): 885-893, doi: 10.1158 / 1078-0432.CCR-16-2071 and international publication WO The assays disclosed in WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673 are used (e.g., using HiBiT assays). In some embodiments, cell lines that are independent of BCL6 and / or do not have significant expression of BCL6 can be used as controls (e.g., Toledo, H929, MM.1S, or OPM2).

[0401] The degradation efficacy of the compounds or their pharmaceutically acceptable salts described herein can be measured via EC. 50 The value is used to determine this. As used in this article, EC 50 This refers to the concentration of a compound or its pharmaceutically acceptable salt that, compared to the protein concentration prior to contact with the compound provided herein or its pharmaceutically acceptable salt, or to the protein concentration in cells not contacted with the compound provided herein or its pharmaceutically acceptable salt, results in a 50% reduction in the concentration of a protein (e.g., BCL6 protein) relative to the trough concentration of proteins in the cell. As measured under substantially similar conditions, a lower EC 50 Compounds with higher EC values ​​relative to those with higher EC values 50 The compound with the highest value is a more effective degradation inducer. In some implementations, EC... 50Values ​​can be obtained in vitro or in vivo (e.g., in tumor cells expressing BCL6 protein, such as cell lines like A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2; see also, for example, Cardenas, Mariano G. et al., Clinical Cancer Research 23.4 (2017): 885-893, doi: 10.1158 / 1078-0432.CCR-16-2071 and international publication WO The assays disclosed in WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673 are used (e.g., using HiBiT assays). In some embodiments, cell lines that are independent of BCL6 and / or do not have significant expression of BCL6 can be used as controls (e.g., Toledo, H929, MM.1S, or OPM2).

[0402] The degradation efficacy of the compounds or their pharmaceutically acceptable salts described herein can be obtained through Y. min The value is used to determine this. As used in this article, Y... min This refers to the ratio, expressed as a percentage, of the trough concentration of a protein (e.g., BCL6 protein) in a cell to the protein concentration prior to contact with the compound provided herein or its pharmaceutically acceptable salts, or to the protein concentration in cells not contacted with the compound provided herein or its pharmaceutically acceptable salts. As used herein, D max It is 1-Y min Y min It can be measured by HiBiT determination (e.g., as described in Example B1). As measured under substantially similar conditions, it has a lower Y... min Compounds with higher Y values ​​are relative to those with higher Y values. min Compounds with this value are more effective degradation inducers. In some embodiments, Y... minValues ​​can be obtained in vitro or in vivo (e.g., in tumor cells expressing BCL6 protein, such as cell lines like A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2; see also, for example, Cardenas, Mariano G. et al., Clinical Cancer Research 23.4 (2017): 885-893, doi: 10.1158 / 1078-0432.CCR-16-2071 and international publication WO). The assays disclosed in WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673 are used (e.g., using HiBiT assays). In some embodiments, cell lines that are independent of BCL6 and / or do not have significant expression of BCL6 can be used as controls (e.g., Toledo, H929, MM.1S, or OPM2).

[0403] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts exhibit less than 70% (e.g., less than 50% or less than 30%) of Y in HiBiT-based degradation assays (e.g., assays as described in Example B1). min In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts exhibit less than 50% (e.g., less than 30%) of Y in HiBiT-based degradation assays. min In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts exhibit less than 30% Yg in HiBiT-based degradation assays. min .

[0404] In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof exhibit less than 70% (e.g., less than 50% or less than 30%) of Y in the assay described in Example B1. min In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof exhibit less than 50% (e.g., less than 30%) of Y in the assay described in Example B1. min In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof exhibit less than 30% Y in the assay described in Example B1. min .

[0405] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts exhibit about 0% to about 70% (e.g., about 0% to about 50%, about 30% to about 50%, or about 0% to about 30%) of Y in a HiBiT-based degradation assay (e.g., the assay described in Example B1). min In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts exhibit about 0% to about 50% (e.g., about 30% to about 50% or about 0% to about 30%) of Y in a HiBiT-based degradation assay. min In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts exhibit approximately 0% to approximately 30% γ-ray dilution in HiBiT-based degradation assays. min .

[0406] In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof exhibit about 0% to about 70% (e.g., about 0% to about 50%, about 30% to about 50%, or about 0% to about 30%) of Y in the assay described in Example B1. min In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof exhibit about 0% to about 50% (e.g., about 30% to about 50% or about 0% to about 30%) of Y in the assay described in Example B1. min In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof exhibit about 0% to about 30% γ in the assay described in Example B1. min .

[0407] The effects of protein degradation typically increase over time, but the occurrence of degradation (e.g., determined by the percentage of degradation compared to a control or parameter Y) is not always consistent with the rate of degradation. min DC 50 and / or D max The degradation rate (represented by the protein resynthesis rate) is affected by the degradation rate. Therefore, degradation can be examined after a specified time period (such as 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 5 days, 10 days, or longer). For example, degradation can be expressed as the percentage of degradation after 24 hours.

[0408] Exemplary assays for verifying the degradation-inducing mechanisms of compounds such as those provided herein are known in the art and described, for example, in Wu et al., Nature Structural & Molecular Biology 27.7 (2020): 605-614, doi: 10.1038 / s41594-020-0438-0.

[0409] Degradation assays can be used to quantify the on-target and off-target degradation induction of compounds, such as those provided herein. Exemplary assays include quantitative Western blotting, other immunoassays (e.g., MesoScale Discovery (MSD) immunoassays), homogeneous time-resolved fluorescence (HTRF), and HiBiT. In some embodiments, cells can be contacted with the compounds provided herein or their pharmaceutically acceptable salts, incubated, and then lysates can be prepared for gel electrophoresis (e.g., SDS-PAGE), followed by Western blotting and quantification compared to a control (e.g., a DMSO-treated control). As another example, cell lines can be engineered to express HiBiT-tagged BCL6 protein, and the amount of fluorescence observed when a complementary LgBiT peptide is added can be compared between cells treated with the compounds provided herein or their pharmaceutically acceptable salts and a control (e.g., a DMSO-treated control). See, for example, Example B1. In some implementations, the off-target degradation induction of protein eukaryotic peptide chain releasing factor GTP binding subunits ERF3A (GSPT1), Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and / or casein kinase I isoform α (CK1α) can be evaluated. See also, for example, international publications WO2018 / 215798; WO 2018 / 215801; WO 2020 / 104820; McCoulll, William et al., ACS Chemical Biology 13.11 (2018): 3131-3141, doi: 10.1021 / acschembio.8b00698; Bellenie, Benjamin R. et al., Journal of Medicinal Chemistry 63.8 (2020): 4047-4068, doi:10.1021 / acs.jmedchem.9b02076; Lloyd, Matthew G et al., Journal of Medicinal Chemistry 64.23 (2021): 17079-17097, doi: 10.1021 / acs.jmedchem.1c00946.

[0410] The binding affinity of the compounds or their pharmaceutically acceptable salts to BCL6 described herein can be assessed, for example, by binding to IC6. 50 or K i Value (e.g., using competitive determination) or by K D The value (e.g., using a biophysical assay) is used to determine the binding IC50. As determined under substantially similar conditions, a lower binding IC50 value is observed. 50Compounds with high binding IC values ​​are relative to compounds with high binding IC values. 50 Compounds with higher binding K values ​​are more effective binders. As determined under substantially similar conditions, those with lower binding K values... i Compounds with a high binding K value are relative to compounds with a high binding K value. i Compounds with higher K values ​​are more effective conjugates. Similarly, as determined under substantially similar conditions, compounds with lower K values... D Compounds with higher K values ​​are relative to those with higher K values. D Compounds with higher values ​​are more effective conjugates. K D The values ​​can be determined by surface plasmon resonance (SPR) or biolayer interferometry; see, for example, Guo, Weikai et al., Journal of Medicinal Chemistry 63.2 (2020): 676-695, doi: 10.1021 / acs.jmedchem.9b01618; Lloyd, Matthew G. et al., Journal of Medicinal Chemistry 64.23 (2021): 17079-17097, doi: 10.1021 / acs.jmedchem.1c00946, and international publications WO2019 / 153080; WO 2019 / 119144; and WO 2019 / 119145.

[0411] The ability of the compounds described herein, or their pharmaceutically acceptable salts, to inhibit BCL6 can be used with IC50. 50 The value is determined by measurement. If measured under substantially similar conditions, a lower IC50 value indicates a lower IC50. 50 Compounds with higher IC values ​​are relative to those with higher IC values. 50 Compounds with high values ​​are more effective inhibitors. For example, IC50... 50The value can be calculated using FRET (e.g., homogeneous time-resolved fluorescence (HTRF)) assays, in which a labeled (e.g., His-labeled) BCL6 protein and a labeled (e.g., fluorophore-labeled (e.g., Alexa-Fluor633)) co-repressor peptide (e.g., BCOR) are incubated in the presence of the compound provided herein or a pharmaceutically acceptable salt thereof. Subsequently, the FRET ratio (relative to an appropriate control) can be measured using an appropriate FRET pair (e.g., an antibody recognizing the labeled BCL6 protein (e.g., an anti-His-terbium cavitation compound)). See, for example, international publications WO 2018 / 108704; WO 2018 / 215798; WO 2019 / 197842; WO 2020 / 104820; WO 2021 / 074620. As another example, an enzyme-linked immunosorbent assay (ELISA) can be used to calculate the IC50 using a labeled (e.g., biotinylated) co-repressor peptide (e.g., BCOR) immobilized on a substrate and a labeled (e.g., FLAG-labeled) BCL6 (e.g., its domains, such as the BTB domain). 50 The IC50 value is defined as follows: the compound provided herein, or a pharmaceutically acceptable salt thereof, can be used to prevent the interaction between the co-repressor peptide and BCL6, and the interaction between the co-repressor peptide and BCL6 can be measured using an antibody against a BCL6 construct (e.g., an anti-FLAG antibody). See, for example, Kamada, Yusuke et al., Journal of Medicinal Chemistry 60.10 (2017): 4358-4368, doi: 10.1021 / acs.jmedchem.7b00313. As yet another example, the IC50 value can be calculated using fluorescence polarization assays of fluorescently labeled co-repressor peptides (e.g., SMRT). 50 The values, wherein the compounds provided herein, or pharmaceutically acceptable salts thereof, can be used to prevent the interaction between the co-repressor peptide and BCL6. See, for example, International Publication WO 2019 / 119144. As another example, BRET (Bioluminescent Resonance Energy Transfer) assays can be used to calculate cellular IC50 values. 50 The value can be obtained by inserting a vector encoding BCL6 and a co-repressor peptide (e.g., SMRT) fused to NanoLuc or HaloTag into cells. Cells can be treated with the compounds provided herein or their pharmaceutically acceptable salts to determine the effect of the compounds on inhibiting BCL6-co-repressor interactions. See, for example, international publications WO 2018 / 215798 and WO 2019 / 197842. In another example, a luciferase assay can be used to calculate the IC50 value for inhibiting BCL6 repressor function. 50The method involves engineering cells to express luciferase under the control of one or more BCL6 repressor sites, and incubating the cells with the compounds provided herein or their pharmaceutically acceptable salts to determine the effect of the compounds on BCL6 repressor function. See, for example, international publications WO 2019 / 119144; WO 2019 / 119145; WO 2019 / 153080.

[0412] Another exemplary way to evaluate the effects of the compounds presented herein or their pharmaceutically acceptable salts is to measure the induction (e.g., fold increase) of genes typically repressed by BCL6 (e.g., p53, ATR, CXCR3, CD69, and CDKN1A) using methods such as RT-PCR. See, for example, Guo, Weikai et al., Journal of Medicinal Chemistry 63.2 (2020): 676-695, doi: 10.1021 / acs.jmedchem.9b01618.

[0413] Exemplary assays for determining the potency of the compounds provided herein or their pharmaceutically acceptable salts include measuring the effect of the compounds provided herein or their pharmaceutically acceptable salts on cell proliferation and / or viability. Cell proliferation assays can be performed in various forms, including 2D and 3D. Similarly, proliferation assays can be performed using any suitable cell line, including, for example, A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2. In some implementations, cell lines that are independent of BCL6 and / or do not exhibit significant expression of BCL6 can be used as controls (e.g., Toledo, H929, MM.1S, or OPM2). As an illustrative example, a 3D cell proliferation assay may include growing cells in 3D medium, contacting the cells with the compounds provided herein or their pharmaceutically acceptable salts, and using appropriate reagents (e.g., CELLTITER-GLO). ®3D) Cell proliferation is measured, and then the signal from the experiment using the compound provided herein or a pharmaceutically acceptable salt thereof is compared with the signal from a control experiment (e.g., lacking the compound provided herein or a pharmaceutically acceptable salt thereof). As another illustrative example, 2D cell proliferation assays may include plating cells onto a growth surface, optionally allowing the cells to grow for a period of time, contacting the cells with the compound provided herein or a pharmaceutically acceptable salt thereof, and using appropriate reagents (e.g., CELLTITER-GLO). ® Cell proliferation is measured, and then the signals from experiments using the compounds provided herein or their pharmaceutically acceptable salts are compared with signals from control experiments (e.g., experiments lacking the compounds provided herein or their pharmaceutically acceptable salts). Additional cell viability assays include the MTT assay (based on the colorimetric determination of the reduction of the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to insoluble purple formazan), and other similar assays based on relevant tetrazolium salts, ATPlite assays, and other methods known in the art. See, for example, Example B2. See also, for example, Guo, Weikai et al., Journal of Medicinal Chemistry 63.2 (2020):676-695, doi: 10.1021 / acs.jmedchem.9b01618; McCoulll, William et al., ACS Chemical Biology 13.11 (2018): 3131-3141, doi: 10.1021 / acschembio.8b00698; Lloyd, Matthew G. et al., Journal of Medicinal Chemistry 64.23 (2021): 17079-17097, doi:10.1021 / acs.jmedchem.1c00946; Bellenie, Benjamin R. et al., Journal of Medicinal Chemistry 63.8 (2020): 4047-4068, doi: 10.1021 / acs.jmedchem.9b02076; and international publications WO 2018 / 215798; WO 2018 / 215801; WO 2018 / 219281; WO 2019 / 119145; WO 2019 / 153080; and WO 2020 / 104820.

[0414] Cell viability assays can be used to measure the effect of the compounds provided herein or their pharmaceutically acceptable salts on cell death. For example, cells expressing the BCL6 protein (e.g., A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2 cells) can be incubated with different concentrations of the compounds provided herein or their pharmaceutically acceptable salts, and then exposed to an assay reagent (e.g., using CELLTITER-GLO). ® A cell viability assay kit is used to determine cell viability. In some embodiments, the effect on cell viability can be compared with cell lines that are independent of BCL6 and / or do not have significant expression of BCL6 (e.g., Toledo, H929, MM.1S, or OPM2).

[0415] Cell viability assays can be used to measure the effect of the compounds described herein or their pharmaceutically acceptable salts, in combination with other therapeutic agents, on cell death. For example, cells expressing the BCL6 protein (e.g., A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2 cells) can be incubated (e.g., from 316 nM semi-logarithmic dilution to 1 nM) in a 7×7 dose matrix at various concentrations (e.g., from 316 nM to 1 nM) of the compounds provided herein or their pharmaceutically acceptable salts and additional therapeutic agents (e.g., any other therapeutic agents described herein) and then exposed to an assay reagent (e.g., using CELLTITER-GLO). ®A cell viability assay kit is used to determine cell viability. Combination activity can be assessed using a Bliss-independent model: negative values ​​indicate antagonistic effects, positive values ​​indicate synergistic effects, and zero values ​​indicate additive activity. Bliss scores in the dose matrix can be summed to obtain a "Bliss Sum" value, reflecting the overall synergistic activity of the compounds provided herein or their pharmaceutically acceptable salts and additional therapeutic agents in each cell line. In some embodiments, cell lines that are BCL6-independent and / or do not have significant BCL6 expression can be used as controls (e.g., Toledo, H929, MM.1S, or OPM2).

[0416] As another example, the potency and / or efficacy of the compounds provided herein or their pharmaceutically acceptable salts can be evaluated in animal models, such as cell line-derived (CDX) xenograft models (e.g., using established cancer cell lines such as DB, DoHH2, OCI-Ly1, OCI-Ly7, RL, Pfeiffer, SU-DHL-5, SU-DHL-6, WSU-DLCL2, REH, BALL-1, RS4; 11. SEMK2, KOPN8, NALM-6, KASUMI-2, RCH-ACV, SUP-B15, BV-173, TOM-1, NALM-20, NALM-21, MUTZ-5, or MHH-CALL-4 (e.g., OCI-Ly1, OCI-Ly7, SU-DHL-5, SU-DHL-6, WSU-DLCL2, DB, RL, Pfeiffer, or DoHH2)), genetically engineered mouse models (GEMM), or patient-derived xenograft (PDX) models. For example, PDX models can be developed in immunodeficient mice (e.g., athymic nude mice, distant hybrid homozygous mice (e.g., Cr1:NU(NCr)-Foxn1)). nu ) or Fox Chase SCID (CB17 / Icr-Prkdc scid The procedure was performed on mice (IcrIcoCrl). Mice could be female mice aged 6 to 12 weeks at the time of tumor transplantation, with free access to food and water. Approximately 70 mg of tumor was transplanted subcutaneously into the right side of each mouse. Tumors were measured weekly after transplantation, and once the tumor volume reached 150 mm², the tumor was considered complete. 3 Up to 300mm 3Mice can be randomly assigned to treatment and control groups. In some embodiments, one or more experimental groups may be added to evaluate pharmacokinetics and / or pharmacodynamics. Mice can be treated with the compounds provided herein or their pharmaceutically acceptable salts (e.g., administered via IP or PO) and optional additional therapies or therapeutics (e.g., any other therapies or therapeutics described herein). Throughout the study, the health status, weight, and tumor volume of the mice can be recorded weekly. Treatment can begin after 28 days or when the tumor reaches 1 cm. 3 Mice were euthanized, and tumors could be evaluated (e.g., by tumor weight, by tumor volume). At the end of each study, the optimal response for each treatment group could be calculated. The optimal response was defined as Δvolume over t ≥ 10 days. tThe minimum value. The optimal response can be compared between the control and treatment groups to determine if the treatment group is better than the control group. In some implementations, tumor samples can also be collected at the end of each study, and relevant proteins (e.g., BCL6) can be measured to determine if the treatment group has a better protein regulatory profile compared to the control group. In some implementations, tumor samples and / or blood samples can also be collected at the end of each study, and altered gene expression activities (e.g., altered ARID3A, ARID3B, ATR, B2M, BANK1, BATF, BCL11A, BCL2, BCL2A1, BLIMP1, BML1, CASP8, CCND1, CCND2, CCR6, CCR7, CD38, CD44, CD69, CDKN1A, CDKN1B, CFLAR / FLIP, CHEK1, CXCR4, CXCR5, DR5, EBI2, ETV6, FCMR, FGD4, ID2, IFITM1, I Expression levels of FITM2, IFNAR2, IFNGR1, IL10, IL10RB, IL7R, CXCL10, IRF1, IRF4, IRF7, IRF9, JAK3, JARID2, JUN, KLF2, LITAF, MCL1, MIP-1a, MYC, MYD88, NFKBIE, NOTCH2, PDL1, PIM1, PPP3R1, PRDM1, PTEN, S1PR1, SHP1, STAT1, STAT3, STAT5A, TLR1, TLR4, TLR7, TLR9, TNF-R2, TOX, TP53, ZEB2, and / or ZNF608. For pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples can be obtained from mice at the same or different time points as in efficacy studies. For example, for pharmacokinetic studies, tumor and / or blood samples from mice can be obtained on day 1, day 3 and / or day 5, collected at 6 hours, 12 hours and / or 24 hours after administration, and relevant proteins can be measured in tumor samples, and pharmacokinetic studies can be performed on blood samples or portions thereof (e.g., plasma).In some implementations, the PDX is B-cell acute lymphoblastic leukemia (B-ALL) (e.g., Philadelphia chromosome-positive B-ALL, Philadelphia chromosome-negative B-ALL, or B-ALL with MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion), or non-Hodgkin lymphoma. Lymphoma (e.g., mature B-cell tumors such as Burkitt lymphoma (BL), large B-cell lymphomas such as diffuse large B-cell lymphoma without specific indications (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) such as HGBCL-MYC / BCL-2 with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL) or high-grade B-cell lymphoma NOS (HBGCL-NOS)), follicular lymphoma (FL), mantle cell lymphoma (MCL) or transformation of indolent B-cell lymphoma), peripheral T Primary cutaneous T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)) or primary cutaneous T-lymphoproliferative or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorders, mycosis fungoides, Sezary syndrome). Models of cutaneous γ-δ T-cell lymphoma (also known as Sézary syndrome or primary cutaneous γ-δ T-cell lymphoma). See, for example, Guo, Weikai et al., Journal of Medicinal Chemistry 63.2 (2020): 676-695, doi: 10.1021 / acs.jmedchem.9b01618; and Alaggio, Rita et al., Leukemia 36.7 (2022):1720-1748, doi: 10.1038 / s41375-022-01620-2.

[0417] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, exhibit activity in models of autoimmune diseases or symptoms. Exemplary assays can be found, for example, in international publications WO 2020 / 014599 and WO 2021 / 074620.

[0418] In some embodiments, the ability of the compounds provided herein or their pharmaceutically acceptable salts to regulate (e.g., reduce) Ig antibody production (e.g., IgA antibody production, IgE antibody production, and / or IgG antibody production), regulate (e.g., reduce) Ig antibody affinity (e.g., IgA antibody affinity, IgE antibody affinity, and / or IgG antibody affinity), and / or regulate (e.g., reduce) germinal center formation in animals (e.g., mice) excited with T-cell-dependent antigens (e.g., keyhole limpethaemocyanin (KLH) or sheep erythrocytes (SRBCs)). For example, KLH can be administered to mice (e.g., C57BL / 6 mice), followed by administration of the compounds provided herein or their pharmaceutically acceptable salts for a period of time (e.g., 14 days). After sacrifice, KLH-specific IgG from serum samples from mice can be analyzed by, for example, ELISA. Similarly, germinal centers can be detected using immunohistochemical staining, for example, peanut lectin (PNA). See, for example, Example 1 of WO 2020 / 014599.

[0419] In some embodiments, the ability of the compounds provided herein or pharmaceutically acceptable salts thereof to modulate (e.g., reduce) the number of germinal center B cells in an animal (e.g., a mouse) after immunization with an antigen can be evaluated. For example, an animal (e.g., a mouse) can be immunized with a specific antigen formulated in an adjuvant (such as Complete Freund's Adjuvant (CFA) or alum), and after a period of time (e.g., 8 days), the animal can be sacrificed and the spleen harvested. The spleen can be processed into a suspension and cultured in the presence of the compounds provided herein or pharmaceutically acceptable salts thereof. The cells can then be analyzed, for example, the number of germinal center B cells (e.g., by flow cytometry using lineage markers GL7 and CD95). See, for example, WO 2021 / 074620.

[0420] In some implementations, the ability of the compounds provided herein or their pharmaceutically acceptable salts to improve or prevent one or more symptoms, biomarkers or other signs of an autoimmune disease or condition can be evaluated in animal models of autoimmune diseases or conditions.

[0421] Experimental autoimmune encephalitis (EAE) can be used as an animal model for inflammatory diseases of the central nervous system, including multiple sclerosis (MS) and neuromyelitis optica. In some cases, EAE can be induced in animals (e.g., mice), for example via recombinant human myelin oligodendrocyte glycoprotein (MOG) or fragments thereof (e.g., MOG). 1-125 Immunotherapy with myelin basic protein and / or proteolipoproteins. After induction of EAE, animals can be treated with the compounds described herein or their pharmaceutically acceptable salts. Animals can be evaluated by, for example, the severity of EAE, B-cell exhaustion, or both. See, for example, Constantinescu, Cris S. et al. British Journal of Pharmacology 164.4 (2011): 1079-1106, doi:10.1111 / j.1476-5381.2011.01302.x; Monson, Nancy L. et al. PloS One 6.2 (2011):e17103, doi: 10.1371 / journal.pone.0017103.

[0422] In some embodiments, the autoimmune disease or condition is an antidrug or antitherapy antibody. In some embodiments, the autoimmune disease or condition is an antidrug antibody. In some embodiments, the antidrug antibody is an antibody against an antibody drug (e.g., an anti-TNFα antibody drug). In some embodiments, the autoimmune disease or condition is an antitherapy antibody. In some embodiments, the antitherapy antibody is an antibody against an enzyme replacement therapy (e.g., factor VII replacement therapy, α-galactosidase replacement therapy, or α-glucosidase replacement therapy). In some embodiments, the antitherapy antibody is an antibody against a gene therapy (e.g., AAV-based gene therapy). See, for example, Vaisman-Mentesh, Anna et al. Frontiers in Immunology 11 (2020): 1951j, doi: 10.3389 / fimmu.2020.01951; Lenders, Malte, and Eva Brand. Drugs 81.17 (2021): 1969–1981, doi: 10.1007 / s40265-021-01621-y; Rana, Jyoti, Maite Melero Munoz, and Moanaro Biswas. Cellular Immunology (2022): 104641, doi: 10.1016 / j.cellimm.2022.104641; and Butterfield, John SS et al. Cellular Immunology (2023): 104742, doi: 10.1016 / j.cellimm.2023.104742.

[0423] In some implementations, the autoimmune disease or symptom is antisynergistic syndrome. For example, a model of antisynergistic syndrome can be induced in susceptible mice (e.g., C57BL / 6, B6.G7, and / or NOD.Idd3 / 5) by immunization with histyl-tRNA synthetase (e.g., mouse histyl-tRNA synthetase or human histyl-tRNA synthetase) or fragments thereof. Treatment with the compounds provided herein or pharmaceutically acceptable salts thereof may be initiated at the time of immunization and sustained for a period of time (e.g., short-term (e.g., 10-14 days) or long-term (e.g., 8-16 weeks)), after which the mice may be sacrificed. The production of histyl-tRNA synthetase-specific antibodies in mice (e.g., via immunoprecipitation, ELISA, and / or flow cytometry), tissue (e.g., lung and / or muscle) inflammation (e.g., by pathological examination), or combinations thereof can be evaluated. See, for example, Katsumata, Yasuhiro et al. Journal of Autoimmunity 29.2-3 (2007): 174-186, doi:10.1016 / j.jaut.2007.07.005; Ascherman, Dana P. Current Rheumatology Reports 17 (2015), doi: 10.1007 / s11926-015-0532-1; and Konishi, Risa, Yuki Ichimura and Naoko Okiyama. Immunological Medicine 46.1 (2023): 9-14, doi: 10.1080 / 25785826.2022.2137968.

[0424] In some implementations, the autoimmune disease or symptom is arthritis (e.g., rheumatoid arthritis or inflammatory arthritis). For example, a mouse model of rheumatoid arthritis (CIA) can be induced in susceptible mice (e.g., DBA / 1 or HLA-DR) by immunization with type II collagen (CII), or collagen-induced arthritis (CIA). Treatment with the compounds provided herein or their pharmaceutically acceptable salts can be initiated at the time of immunization and continue for a period of time (e.g., 6 weeks). Clinical scores in mice (e.g., inflammation of the arthritic limb, paw thickness, paw volume (e.g., using an organ filling measure) or combinations thereof) can be evaluated, for example. The production of CII-specific antibodies, B-cell depletion, or combinations thereof. See, for example, Example 2 of WO 2020 / 014599; Brand, David D. et al. Nature Protocols 2.5 (2007): 1269-1275, doi:10.1038 / nprot.2007.173. Other animal models of arthritis (e.g., inflammatory arthritis) are known in the art, such as K / BxN mice. In some embodiments, such mice may be treated with the compounds provided herein or pharmaceutically acceptable salts thereof, and evaluated, for example, in a manner similar to that of CII-immunized mice, or additionally, titrated with autoantibodies, such as those against glucose-6-phosphate isomerase. See, for example, Huang, Haochu, Christophe Benoist, and Diane Mathis. Proceedings of the National Academy of Sciences 107.10 (2010): 4658-4663, doi: 10.1073 / pnas.1001074107; and Pigott, Elizabeth, and Laura Mandik-Nayak. Arthritis & Rheumatism 64.7 (2012): 2169-2178, doi: 10.1002 / art.34406.

[0425] In some implementations, the autoimmune disease or symptom is graft-versus-host disease (e.g., chronic graft-versus-host disease). In some cases, animal models of graft-versus-host disease can be established in animals (e.g., mice) conditioned with high-dose cyclophosphamide and lethal total body irradiation (TBI), which are then rescued from bone marrow with bone marrow optionally including allogeneic spleen cells or purified T cells. The compounds provided herein or their pharmaceutically acceptable salts may then be administered for a period of time. The animals can be evaluated by, for example, pulmonary function tests, by immunohistochemistry assessing the presence of autoantibodies, or by examining germinal centers in spleen sections, including, for example, examining B cell depletion (e.g., germinal center B cell depletion). See, for example, Srinivasan, Mathangi et al. Blood, The Journal of the American Society of Hematology 119.6 (2012): 1570-1580, doi: 10.1182 / blood-2011-07-364414; and az, Katelyn et al. Blood, The Journal of the American Society of Hematology 133.1 (2019): 94-99, doi: 10.1182 / blood-2018-03-839993. Also see, for example, Dubovsky, Jason A. et al. The Journal of Clinical Investigation 124.11 (2014): 4867-4876, doi:10.1172 / JCI75328.

[0426] In some implementations, the autoimmune disease or symptom is IgG4-related disease (IgG4-RD). In some cases, animal models of IgG4-RD can be generated by injecting mice with IgG (e.g., IgG1 and / or IgG4) derived from human IgG4-RD patients. Such mice can be treated with the compounds provided herein or pharmaceutically acceptable salts thereof. Animals can be evaluated by measuring, for example, pancreatic and / or salivary tissue damage, B cell depletion, or both. See, for example, Shiokawa, Masahiro et al., Gut 65.8 (2016): 1322-1332, doi: 10.1136 / gutjnl-2015-310336. In some cases, animal models of IgG4-RD can be generated by knocking in a mutation (such as LATY136F) in the linker (LAT) for T cell activation. Such mice can be treated with the compounds provided herein or pharmaceutically acceptable salts thereof. Animals can be evaluated by measuring, for example, pancreatic and / or salivary tissue damage, B cell depletion, or both. See, for example, Yamada, Kazunori et al., PLoS One 13.6 (2018): e0198417, doi: 10.1371 / journal.pone.0198417.

[0427] In some implementations, the autoimmune disease or symptom is lupus (e.g., systemic lupus erythematosus). In some cases, the animal model of lupus is the MRL / lpr mouse, which can exhibit high expression of Tfh-related molecules (such as ICOS, PD-1, BCL6, and IL-21) and produce autoantibodies against nuclear components, developing nephritis, arthritis, and skin lesions. Such mice can be treated with the compounds provided herein or their pharmaceutically acceptable salts. Animals can be evaluated, for example, by measuring B cell depletion (e.g., germinal center B cell depletion), identifying the presence and / or severity of glomerulonephritis, autoantibody titers (e.g., anti-RNA antibody titers, anti-nuclear antibody titers, and / or anti-dsDNA antibody titers), IL-21 expression, and / or the amount of activated CD4+ T cells. See, for example, Ahuja, Anupama et al., *The Journal of Immunology* 179.5 (2007):3351-3361, doi: 10.4049 / jimmunol.179.5.3351; Shen, Chunxiu et al., *Journal of Cellular and Molecular Medicine* 25.17 (2021): 8329-8337, doi: 10.1111 / jcmm.16785; and Marinov, Anthony D. et al., *Arthritis & Rheumatology* 73.5 (2021):826-836, doi: 10.1002 / art.41608. Other animal models of lupus are known in the art, such as the NZB / W mouse, which can be treated with the compounds provided herein or their pharmaceutically acceptable salts, and evaluated in a manner similar to that of the MRL / lpr mouse. See, for example, Wang, Wensheng et al., The Journal of Immunology 192.7(2014): 3011-3020, doi: 10.4049 / jimmunol.1302003; and Kansal, Rita et al., Science Translational Medicine 11.482 (2019): eaav1648, doi: 10.1126 / scitranslmed.aav1648.

[0428] In some implementations, the autoimmune disease or symptom is myasthenia gravis (e.g., muscle-specific tyrosine kinase (MuSK) positive myasthenia gravis). For example, animal models of MuSK positive myasthenia gravis (e.g., rat, mouse, or rabbit models) can be generated by immunizing the animal with a purified chimeric protein containing the extracellular domain of MuSK (e.g., the extracellular domain of MuSK and the Fc region of IgG1). Following immunization, the animal is treated with the compounds provided herein or their pharmaceutically acceptable salts, and the animal (e.g., rat, mouse, or rabbit) can be evaluated, for example, by measuring clinical scores (e.g., grasping and / or lifting heavy objects while observing tremor, kyphosis, muscle strength, and signs of fatigue), body weight, complex muscle action potentials (e.g., using electromyography), anti-MuSK antibodies, B cell exhaustion, or combinations thereof. See, for example, Shigemoto, Kazuhiro et al., The Journal of Clinical Investigation 116.4 (2006):1016-1024, doi: 10.1172 / JCI21545. As another example, animal models of MuSK-positive myasthenia gravis (e.g., rat, mouse, or rabbit models) can be generated by immunizing animals with a purified protein containing the extracellular domain of MuSK (e.g., the extracellular domain of MuSK with or without a tag, as in the case of His tags). Following immunization, the animals are treated with the compounds provided herein or their pharmaceutically acceptable salts, and can be evaluated, for example, by measuring clinical scores (e.g., grasping and / or lifting heavy objects while observing tremor, kyphosis, muscle strength, and signs of fatigue), body weight, complex muscle action potentials (e.g., using electromyography), anti-MuSK antibodies, B-cell exhaustion, or combinations thereof. See, for example, Mori, Shuuichi et al., The American Journal of Pathology 180.2 (2012): 798-810, doi: 10.1016 / j.ajpath.2011.10.031; and Reuveni, Debby et al., Frontiers in Immunology 11 (2020): 403, doi: 10.3389 / fimmu.2020.00403.As another example, animal models of myasthenia gravis (e.g., rat, mouse, or rabbit models) can be generated by immunizing animals with acetylcholine receptors or recombinant acetylcholine receptor proteins or fragments thereof from the electro-organs of electric rays (e.g., *Torpedo californica*) or electric eels (e.g., *Electrophorus electricus*). Treatment with the compounds provided herein or their pharmaceutically acceptable salts can, for example, begin about 4 weeks after immunization, but sometimes earlier or later. Animals (e.g., rats, mice, or rabbits) can be evaluated, for example, by measuring clinical scores (e.g., grasping and / or lifting heavy objects while observing tremor, kyphosis, muscle strength, and signs of fatigue), body weight, complex muscle action potentials (e.g., using electromyography), anti-acetylcholine receptor antibodies, B-cell exhaustion, or combinations thereof. See, for example, Mori, Shuuichi et al., The American Journal of Pathology 180.2 (2012): 798-810, doi: 10.1016 / j.ajpath.2011.10.031; Xin, Ning et al., Molecular and Cellular Neuroscience 58 (2014): 85-94, doi: 10.1016 / j.mcn.2013.12.006; and Losen, Mario et al., Experimental Neurology 270 (2015): 18-28, doi: 10.1016 / j.expneurol.2015.03.010.

[0429] In some embodiments, the autoimmune disease or symptom is multiple sclerosis (MS). In some embodiments, MS is clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), or secondary progressive MS (SPMS). In some embodiments, the animal model of MS may be based on an echogenic encephalopathy (EAE), such as a relapsing-remitting EAE in SJL / J mice (e.g., via protein lipoprotein (PLP)). 139-151 Chronic EAE in C57BL / 6J mice (e.g., via MOG) 35-55 EAEs in immunized or transgenic mice (e.g., via expression of MOG) 35-55T cell clones or B cell heavy chain knock-in mice with specific Vα and Vβ chains. In some embodiments, the animal (e.g., mouse) model is generated via infection with a small RNA virus (such as Theiler's murine encephalitis virus). In some embodiments, the animal (e.g., mouse) model is generated by feeding C57BL / 6 mice with copper phosphate (e.g., 0.2%, for 6 weeks). In some embodiments, the animal (e.g., mouse) model is generated via lysophosphatidylcholine injection (e.g., in SJL / J mice). Following treatment with the compounds provided herein or their pharmaceutically acceptable salts, the animal's myelin-specific T cell levels, B cell depletion, reduction in inflammatory lesions, axonal degeneration, protection or reversal of copper phosphate or lysophosphatidylcholine-induced demyelination, or combinations thereof, can be analyzed, for example. See, for example, Procaccini, Claudio et al., European Journal of Pharmacology 759 (2015): 182-191, doi:10.1016 / j.ejphar.2015.03.042.

[0430] In some embodiments, the autoimmune disease or symptom is neuromyelitis optica (NMO). In some cases, animal models of NMO involve administration of an antibody against astrocyte aquaporin-4 (AQP4), referred to as AQP4-IgG or NMO-IgG, to various CNS tissues, such as the brain. In some embodiments, the antibody is administered to animals suffering from EAE. AQP4-IgG can be recombinant or derived from human NMO patients. Following treatment with the compounds provided herein or their pharmaceutically acceptable salts, the slowing or reversal of astrocyte demyelination, the number of macrophages, the number of activated microglia, the number of activated neutrophils, B cell depletion, or combinations thereof, can be analyzed, for example, in euthanized animals. See, for example, Bennett, Jeffrey L. et al., Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society 66.5(2009): 617-629, doi: 10.1002 / ana.21802; Saini, Harleen et al., BMC Neurology 13.1(2013), doi: 10.1186 / 1471-2377-13-104; Oji, Satoru et al., PloS One 11.3 (2016):e0151244, doi: 10.1371 / journal.pone.0151244; Peschl, Patrick et al., Journal of Neuroinflammation 14.1 (2017), doi: 10.1186 / s12974-017-0984-5; and Duan, Tianjiao and Alan S. Verkman. Brain Pathology 30.1 (2020): 13-25, doi: 10.1111 / bpa.12793.

[0431] In some implementations, the autoimmune disease or symptom is pemphigus (e.g., pemphigus vulgaris). In some cases, an animal model of pemphigus (e.g., a mouse) can be generated by adoptive transfer of peripheral lymphocytes from Dsg3 knockout animals to immunodeficient but desmosome core glycoprotein 3-expressing recipient mice to create an artificial immune state in the recipient animals. In some cases, an animal model of pemphigus (e.g., a mouse) with an MHC class II-null background expressing the pemphigus-associated HLA-DRB1*0402 allele can be generated, which produces anti-human DSG3 antibodies after immunization with recombinant human DSG3. After treating these models with the compounds provided herein or their pharmaceutically acceptable salts, the animal's B cell repertoire can be analyzed, for example, for anti-desmosome core glycoprotein B cell clones, B cell depletion, or both. See, for example, Kasperkiewicz, Michael et al., Nature Reviews Disease Primers 3.1 (2017): 17071, doi: 10.1038 / nrdp.2017.71.

[0432] In some implementations, the autoimmune disease or symptom is Sjogren's syndrome. In some cases, the animal model of Sjogren's syndrome is the NOD mouse, which sometimes undergoes further genetic manipulation or hybridization (e.g., NOD.B10.H2). bOr C57BL / 6.NOTDc3.NODc1t) to summarize the symptoms of the syndrome. Such mice can be treated with the compounds provided herein or their pharmaceutically acceptable salts. The animal's salivary and lacrimal gland secretion rates, salivary protein content, autoantibodies against exocrine gland proteins (e.g., anti-Sjögren's syndrome A (SSA) antibodies, anti-Sjögren's syndrome B (SSB) antibodies, and / or anti-muscarinic acetylcholine 3 receptor (M3R) antibodies), B cell depletion, or combinations thereof can be evaluated, for example. Robinson, Christopher P. et al. Arthritis & Rheumatism 41.1 (1998): 150-156, doi:10.1002 / 1529-0131(199801)41:1<150::AID-ART18>3.0.CO; 2-T; Cha, Seunghee et al. Arthritis & Rheumatism 46.5 (2002): 1390-1398, doi: 10.1002 / art.10258; and Ohno, Seiji et al. Autoimmunity 45.7 (2012): 540-546, doi: 10.3109 / 08916934.2012.710860. Other animal models of Sjögren's syndrome are known in the art and include, for example, NFS / sld mice, IQI / Jic mice, Aly / aly mice, and mice immunized with M3R peptides, which in some cases can be evaluated using the same parameters as NOD mice. See, for example, Iizuka, Mana et al., Journal of Autoimmunity 35.4 (2010): 383-389, doi: 10.1016 / j.jaut.2010.08.004; and Park, Young-Seok, Adrienne E Gauna, and Seunghee Cha. Current Pharmaceutical Design 21.18 (2015): 2350-2364, doi: 10.2174 / 1381612821666150316120024.

[0433] The pharmacokinetic parameters of the compounds provided herein or their pharmaceutically acceptable salts can be evaluated in animal models, such as mouse, rat, canine, or non-human primate models (e.g., cynomolgus monkeys). Pharmacokinetic (PK) studies can be performed in animal models (e.g., male CD1 mice) via two exemplary routes of delivery: intravenous (IV) injection and oral (PO), e.g., oral tube feeding. Animals in the IV group (e.g., n=3) are allowed free access to food and water; animals in the PO group are allowed free access to food or are fasted for 6–8 hours prior to administration. The compounds provided herein or their pharmaceutically acceptable salts can be formulated into solutions for the IV route and solutions or suspensions for the PO route. On each day of administration in the experiment, for the IV route, the compound provided herein or a pharmaceutically acceptable salt thereof may be administered via intravenous injection (e.g., at 1 mg / kg), or for the PO route, via oral tube feeding (e.g., at 3 mg / kg to 300 mg / kg, 3 mg / kg to 90 mg / kg, or 3 mg / kg to 10 mg / kg, such as 10 mg / kg or 30 mg / kg). In some cases, animals may be orally pre-administered with a cytochrome P450 inhibitor (e.g., 1-aminobenzotriazole) prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof (e.g., 16 hours prior). Blood samples may be collected by continuous exsanguination at multiple time points (e.g., for single-dose studies, at 8 time points from 0.83 hours to 24 hours after administration). At each time point, blood (it should be understood that the volume of the blood sample will vary depending on the species) may be collected (e.g., via a vein, such as the saphenous vein in mice) in a tube containing an anticoagulant (e.g., K2EDTA). Blood samples can be placed on wet ice and centrifuged (e.g., at 2000×g for 4-10 minutes) to obtain plasma samples. Plasma samples can be diluted (e.g., with an equal volume of pH 3.0 phosphate buffer or an equal volume of pH 5.0 sodium citrate) and submitted to LC-MS / MS for analysis. Pharmacokinetic parameters, including clearance (CL) and volume of distribution (V), can be analyzed. d ), maximum plasma concentration (C max ), time to maximum plasma concentration (t) max ), half-life (t) 1 / 2 The area under the curve (AUC) and oral bioavailability (%F) can be calculated using a non-compartmental model.

[0434] In some implementations, pharmacokinetic parameters of the compounds provided herein or their pharmaceutically acceptable salts can be measured in rat models (e.g., the Sprague-Dawley rat model). Exemplary implementations are as follows.

[0435] The compounds described herein or their pharmaceutically acceptable salts are administered orally (e.g., via tube feeding) once daily to rats (e.g., male Sbergdolly rats aged 7–9 weeks) for several days (e.g., 3 days). The compounds described herein or their pharmaceutically acceptable salts are administered in solution or suspension formulations (e.g., 10% DMA / 45% PHOSAL 50 PG / 40% MIGLYOL). ® 810 N / 5% polysorbate 80 was administered to rats at given dose levels (e.g., 1 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 30 mg / kg, 50 mg / kg, or 100 mg / kg). Rats had free access to food and water.

[0436] Blood samples (e.g., 150 µL per sample) were collected from rats at predetermined intervals (e.g., 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, 38 hours, 49 hours, 52 hours, 60 hours, 72 hours, 96 hours, and / or 120 hours) following administration of the first dose. Blood was sampled via jugular vein puncture, and the blood samples (e.g., with K2EDTA as an anticoagulant) were temporarily placed on ice and then centrifuged over 30 minutes (e.g., at 4°C and 6000 RPM for 5 minutes). Plasma samples were placed on dry ice. After the last sampling, all samples were stored at -80°C or analyzed shortly after collection. The concentration of the compounds described herein or their pharmaceutically acceptable salts can be measured in acidified plasma samples (e.g., diluted 1:1 v / v with pH 3 phosphate buffer), the concentration of which can be determined (e.g., via LC / MS / MS). For example, acidified plasma samples were prepared for analysis using protein precipitation (e.g., by adding methanol) and an internal standard was incorporated at a known concentration. The incorporated sample was mixed, centrifuged, and the supernatant was used in the LC / MS / MS method. The LC / MS / MS method used was KINETEX. ® A C18 2.6 μm 100 Å (50 mm * 2.10 mm) column was used, with water (0.1% formic acid (FA)) as the first mobile phase and acetonitrile (0.1% FA) as the second mobile phase. Multiple reaction monitoring was used to measure the analytes of interest. The following pharmacokinetic parameters were determined using the concentrations of the compounds described herein or their pharmaceutically acceptable salts in plasma samples: t 1 / 2 (hr), t max (hr), C max (ng / mL), AUC last (hr*ng / mL), AUC Inf (hr*ng / mL), AUC Extr (%) MRT Inf(hr), AUC Inf / D(hr*kg*ng / mL / mg)、%F、AUC 0-24 (hr*ng / mL) and AUC 48-72 (hr*ng / mL).

[0437] At least one blood sample (e.g., collected 72 hours after the first dose) is used for clinical chemistry, and the levels of one or more of the following are determined: TBA (μmol / L), AST (U / L), ALT (U / L), GLU (mmol / L), ALP (U / L), BUN (mmol / L), CREA (μmol / L), CHOL (mmol / L), TG (mmol / L), CK (U / L), Ca (mmol / L), P (mmol / L), TBIL (μmol / L), ALB (g / L), TP (g / L), K (mmol / L), Na (mmol / L), Cl (mmol / L), A / G, and GLB (g / L).

[0438] Clinical observations, body weight, and food consumption in rats were monitored during administration and for three days after administration was discontinued. Rats were then sacrificed, and any macroscopic abnormalities were roughly assessed.

[0439] In some implementations, pharmacokinetic parameters of the compounds provided herein or their pharmaceutically acceptable salts can be measured in mouse models (e.g., the Balb / c model). Exemplary implementations are as follows.

[0440] The compounds described herein or their pharmaceutically acceptable salts were administered orally twice daily (e.g., via tube feeding) to mice (e.g., male Balb / c mice aged 9–11 weeks) for several days (e.g., 10 days). The compounds described herein or their pharmaceutically acceptable salts were also administered in solution or suspension formulations (e.g., 10% DMA / 45% PHOSAL 50 PG / 40% MIGLYOL). ® The product (810 N / 5% polysorbate 80) was administered to mice at given dose levels (e.g., 1 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 30 mg / kg, 50 mg / kg, or 100 mg / kg). Mice had free access to food and water.

[0441] Blood samples (e.g., 30 µL per sample) were collected from mice at predetermined intervals (e.g., 14, 12, 16, 24, 64, 136, 220, 228, 232, and 240 hours after administration of the first dose) (not every mouse will be sampled at every time point). Blood was sampled via saphenous vein puncture, and the blood samples (e.g., with K2EDTA as an anticoagulant) were temporarily placed on ice and then centrifuged over 30 minutes (e.g., at 4°C and 4600 RPM for 5 minutes). Plasma samples were acidified and placed on dry ice. After the last sampling, all samples were stored at -80°C or analyzed shortly after collection. The concentrations of the compounds described herein or their pharmaceutically acceptable salts, as measured herein, can be determined (e.g., via LC / MS / MS) in the acidified plasma samples (e.g., diluted 1:1 v / v with pH 3 phosphate buffer). For example, acidified plasma samples are prepared for analysis using protein precipitation (e.g., by adding acetonitrile) and an internal standard is incorporated at a known concentration. The incorporated sample is mixed, centrifuged, and the supernatant is used in an LC / MS / MS method. The LC / MS / MS method uses an ACQUITY UPLC BEH C18 1.7 μm (2.1*50 mm) column with a first mobile phase of 5 mM NH4OAC (0.05% FA or 0.1% FA) and a second mobile phase of acetonitrile (0.1% FA). Multiple reaction monitoring is used to measure the analyte of interest. The following pharmacokinetic parameters are determined using the concentrations of the compounds described herein or their pharmaceutically acceptable salts in the plasma sample: t 1 / 2 (hr), t max (hr), C max (ng / mL), AUC last (hr*ng / mL), AUC Inf (hr*ng / mL), AUC Extr (%) MRT Inf (hr), AUC Inf / D (hr*kg*ng / mL / mg) and %F.

[0442] Clinical observations, body weight, and food consumption in mice were monitored during administration and for three days after administration was discontinued. Mice were then sacrificed and any macroscopic abnormalities were roughly assessed.

[0443] In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 4%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 10%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 20%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 30%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 40%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 60%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 80%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is from about 4% to about 90% (e.g., from about 4% to about 80%, from about 4% to about 60%, from about 4% to about 40%, from about 4% to about 20%, from about 4% to about 10%, from about 20% to about 40%, from about 40% to about 60%, from about 60% to about 80%, or from about 70% to about 90%). In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is from about 4% to about 20%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is from about 20% to about 40%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is from about 40% to about 60%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is from about 50% to about 80%.

[0444] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are not substrates of human cytochrome P450 enzymes. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are not substrates of human cytochrome P450 enzymes, wherein ≥25% clearance is attributed to the enzyme. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are not inhibitors and / or inducers of one or more human cytochrome P450 enzymes. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are not inhibitors and / or inducers of one or more human cytochrome P450 enzymes, wherein the IC50 of one or more human cytochrome P450 enzymes is... 50 and / or EC 50 The concentrations were significantly greater than the estimated free fraction concentrations of the compounds or their pharmaceutically acceptable salts provided in this article at clinically relevant doses.

[0445] Exemplary human cytochrome P450 enzymes include those from the CYP1, CYP2, and CYP3 families. Among them, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2J2, CYP2S1, CYP2E1, CYP3A4, and CYP3A5 are known drug-metabolizing enzymes. In some embodiments, no single cytochrome P450 enzyme is responsible for the elimination of 25% or more of the compounds provided herein or their pharmaceutically acceptable salts. Cytochrome P450 inhibitory and / or inducing activities can be determined using appropriate in vitro assays, such as those described in the guidance document “In Vitro Drug Interaction Studies – Drug Interactions Mediated by Cytochrome P450 Enzymes and Transporters” provided by the USFDA in January 2020, and similarly those described in the ICH M12 guidance document completed in May 2024. For example, the evaluation of cytochrome P450 inhibition can be performed in an in vitro study in a reversible and time-dependent manner. In in vitro inhibition studies, the ratio of the intrinsic clearance values ​​of the probe substrate for the enzymatic pathway in the absence and presence of the compound provided herein or its pharmaceutically acceptable salt can be calculated based on these in vitro results; for reversible inhibition, this ratio is referred to as R1, where R1 = 1 + (I max,u / K i,u ), and I max,u This is the predicted maximum unbound plasma concentration in humans of the compound provided herein or its pharmaceutically acceptable salt, and K i,u This is the unbound inhibition constant determined in vitro. Specifically, in the case of CYP3A, although the enzyme is also expressed at significant levels in the intestine, R can be calculated. 1,gut , where R 1,gut =1 + (I gut + K i,u ), and where I gut This is the predicted human intestinal lumen concentration of the compound or its pharmaceutically acceptable salt provided in this article, calculated as a human oral dose / 250 mL. The time-dependent inhibition ratio R² can be calculated similarly, where R² = (k... obs + k deg ) / k deg And Kobs is through k obs = (k inact *I max,u ) / (K I,u + *I max,u The observed (epistemological first-order) inactivation rate of affected cytochrome P450 was calculated, k. degK is the apparent first-order degradation rate constant of the affected cytochrome P450. I,u It is the unbound concentration of the compound provided herein or its pharmaceutically acceptable salt that causes half-maximal inactivation, and k inact This is the maximum deactivation rate constant. Using R1 and R... 1,gut These equations, along with R2, can be used to evaluate the potential of the compounds presented herein or their pharmaceutically acceptable salts as inhibitors of cytochrome P450, and the potential for drug-drug interaction (DDI) can be further investigated using mechanistic or physiological pharmacokinetic models of the liver and intestine and / or clinical DDI studies with sensitivity index substrates. Additionally, the tendency of the compounds to activate nuclear receptors (e.g., PXR, CAR, or AhR) can be evaluated through in vitro cytochrome P450 hepatocyte induction studies, and the resulting data can be evaluated via a fold change approach, where the fold change in cytochrome P450 enzyme mRNA levels when incubated with the compounds presented herein or their pharmaceutically acceptable salts is calibrated based on cutoff values ​​determined from known positive and negative controls. For example, the compounds presented herein or their pharmaceutically acceptable salts are identified as inducers if: (1) they increase cytochrome P450 enzyme mRNA expression in a concentration-dependent manner; and (2) at the expected hepatic concentration of the drug, the fold change in cytochrome P450 mRNA expression relative to the mediator control is ≥2-fold. In addition, the evaluation of cytochrome P450 induction can be performed using relevant methods, which are based on the relative induction score (RIS) or I of a set of known inducers of the same cytochrome P450. max,u / EC 50 The calibration curves predict the magnitude of the clinical induction effect of the compounds provided herein or their pharmaceutically acceptable salts (e.g., the AUC ratio of the index substrate in the presence and absence of an inducer). If the predicted magnitude is greater than a predetermined cutoff value (e.g., an AUC ratio ≤ 0.8), the compounds provided herein or their pharmaceutically acceptable salts are considered to have in vivo induction potential.

[0446] In some implementations, the potency of the compounds provided herein or their pharmaceutically acceptable salts to inhibit hERG potassium channels can be tested. Cardiac potassium channels (hERG) are responsible for the rapid delayed rectified current (I0.05) in the ventricles. Kr ), and I Kr Inhibition of the cardiac action potential is the most common reason why non-cardiac drugs prolong the cardiac action potential. The increased action potential duration leads to QT interval prolongation, which is associated with dangerous ventricular arrhythmias (torsius ventricular tachycardia). Several methods exist for testing the inhibitory efficacy of hERG, including Fastpatch hERG and manual patch-clamp experiments.

[0447] In some embodiments, manual patch-clamp assays are used to test the potency of the compounds provided herein or their pharmaceutically acceptable salts in inhibiting hERG potassium channels. For example, in some embodiments, solutions or suspensions of the compounds provided herein or their pharmaceutically acceptable salts may be exposed to single cells at several concentrations (e.g., 0.3 µM, 1 µM, 3 µM, and 10 µM). The inhibitory effect of the compounds provided herein or their pharmaceutically acceptable salts on hERG potassium channels can be assessed in this system using electrical pulse patterns, plotted data, and calculated IC50 values ​​for the inhibition of hERG by the compounds provided herein or their pharmaceutically acceptable salts. 50 The value is used for measurement. An example scheme is as follows.

[0448] In this experiment, hERG potassium channels were used in the absence of endogenous I... Kr Human embryonic kidney cell line (HEK-293 (ATCC 293T, CRL-3216)) ™ See, for example, Brown, Arthur M. and David Rampe. Pharmaceutical News 7.4 (2000): 15-20; Weirich, Jörg, and H. Antoni, Basic Research in Cardiology 93 (1998): s125-s132, doi: 10.1007 / s003950050236; and Yap, Yee Guan and AJCamm. Clinical & Experimental Allergy 29 (1999): 174-181, doi: 10.1046 / j.1365-2222.1999.0290s3174.x.

[0449] All chemicals used in solution preparation were purchased from commercial suppliers (e.g., Sigma-Aldrich) and were of ACS reagent grade or higher purity. Stock solutions of the compounds described herein or their pharmaceutically acceptable salts, positive control compounds, and reference substances were prepared in dimethyl sulfoxide (DMSO) and stored frozen. Solutions of each compound described herein or its pharmaceutically acceptable salts, positive control compounds, and reference substances at concentrations thereof were freshly prepared daily by diluting the stock solutions to HEPES-buffered saline (HB-PS; 137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 10 mM glucose, pH 7.4). Since previous results have shown that ≤0.3% DMSO does not affect channel currents, all test and control solutions may contain 0.3% DMSO.

[0450] In some embodiments, a positive control compound may be included in the experiment. In some such embodiments, the positive control compound may be, for example, a solution of HB-PS containing terfenadine (Sigma-Aldrich) and 0.3% DMSO.

[0451] In some embodiments, a reference compound may be included in the experiment. In some such embodiments, the reference compound may be, for example, HB-PS containing E-4031 (Sigma-Aldrich) and a 0.3% DMSO solution.

[0452] If necessary, sonicate the test solution to promote dissolution. Record any visible precipitates observed during the preparation of the test formulation or exposure to the test system for reference.

[0453] The effects of the compounds presented herein, or their pharmaceutically acceptable salts, were initially evaluated at concentrations ranging from 1 µM to 10 µM. Subsequent concentrations were evaluated based on the inhibition observed at these concentrations.

[0454] HEK-293 cells were transfected with hERG cDNA. Stable transfectants were selected by co-expression of the G418 resistance gene incorporated into the expression plasmid. Selection pressure was maintained by including G418 in the culture medium. Cells were cultured in Dalberg Modified Eagle Medium / Hans' Nutrient Mix F-12 (DMEM / F-12) supplemented with 10% fetal bovine serum and appropriate concentrations of penicillin G sodium, streptomycin sulfate, and G418.

[0455] All experiments were conducted at near physiological temperatures (33℃-35℃). Each cell served as its own control.

[0456] The effects of the compounds provided herein or their pharmaceutically acceptable salts thereof will be evaluated at multiple (e.g., up to four) concentrations. Each concentration will be tested in at least three cell lines (n ≥ 3). Additional concentrations may be tested due to limitations imposed by the physiological and chemical effects (e.g., solubility or cytotoxicity) of the compounds provided herein or their pharmaceutically acceptable salts thereof.

[0457] The positive control compound was tested in at least two (2) cells (n≥2).

[0458] Cells were transferred to the recording chamber and superfused with a medium control solution. The pipette (intracellular) solution for whole-cell recording consisted of 130 mM potassium aspartate, 5 mM MgCl2, 5 mM EGTA, 4 mM ATP, and 10 mM HEPES (pH 7.2). Pipette solutions were prepared in batches, aliquoted, frozen, and thawed daily with fresh aliquots. Recording was performed at temperatures ranging from 33°C to 35°C using a combination of an online solution preheater, chamber heater, and feedback temperature controller. Temperature was measured in the recording chamber using a thermistor probe. Micropipettes for patch-clamp recording were prepared from glass capillaries using a P-97 micropipette puller (Sutter Instruments). A commercial patch-clamp amplifier (Molecular Devices) was used for the entire patch-clamp cell recording. The current recording was low-pass filtered before digitization.

[0459] Cells stably expressing hERG were held at -80 mV. The initiation and steady-state inhibition of hERG potassium currents induced by the compounds provided herein or their pharmaceutically acceptable salts were measured using a pulse pattern with a fixed amplitude (a pre-pulse of +20 mV for 1 second; repeated repolarization test ramps to -80 mV at 5-second intervals (at -0.5 V / sec)). Each recording ended with the application of an ultra-high concentration of a reference substance (e.g., 500 nM E-4031) to assess the contribution of the endogenous current. The remaining uninhibited current was digitally subtracted offline from the data to determine the potency of the compounds provided herein or their pharmaceutically acceptable salts for hERG inhibition. Peak currents were measured during the test ramp. Steady-state was maintained for at least 20 seconds before application of the compounds provided herein or their pharmaceutically acceptable salts, a positive control compound, or a reference substance. Peak tail currents were measured until a new steady state was reached. If steady state was not reached within 12 minutes, the response at 12 minutes was used instead of the steady-state value and labeled.

[0460] Data acquisition and analysis were performed using the commercial suite of pCLAMP (Molecular Devices) program. Steady state was defined by a finite, constant rate of change over time (linear time dependence). The percentage of current suppressed at each concentration was calculated using steady state before and after administration of each compound or its pharmaceutically acceptable salt provided herein.

[0461] In some embodiments, the Fastpatch hERG assay is used to test the potency of the compounds provided herein or their pharmaceutically acceptable salts to inhibit hERG potassium channels (e.g., encoded by the KCNH2 gene and expressed in HEK293 cells). For example, in some embodiments, a solution or suspension of the compounds provided herein or their pharmaceutically acceptable salts may be exposed to cells in an automated parallel patch-clamp system at several concentrations (e.g., 0.3 µM, 1 µM, 3 µM, and 10 µM). The inhibitory effect of the compounds provided herein or their pharmaceutically acceptable salts on hERG potassium channels can be assessed in this system using electrical pulse patterns, plotted data, and calculated IC50 values ​​for the inhibition of hERG by the compounds provided herein or their pharmaceutically acceptable salts. 50 The value is used for measurement. An example scheme is as follows.

[0462] Using QPATCH HT ® (Sophion Bioscience A / S, Denmark) An automated parallel patch-clamp system was used to evaluate the in vitro effects of the compounds described herein or their pharmaceutically acceptable salts at room temperature. The compounds described herein or their pharmaceutically acceptable salts were exposed to hERG at 0.3 µM, 1 µM, 3 µM, and 10 µM in at least five cells (n ≥ 5). The duration of exposure to each compound concentration was at least three minutes.

[0463] Prepare solutions or suspensions of the compounds described herein or their pharmaceutically acceptable salts daily. Various concentrations are prepared by diluting the stock solutions into appropriate HEPES-buffered saline solutions (HB-PS).

[0464] Previous results have shown that 0.3% DMSO does not affect the channel current. Therefore, all test and control solutions may contain up to 0.3% DMSO.

[0465] Each formulation of the compounds provided herein or their pharmaceutically acceptable salts may be sonicated, for example, at room temperature (e.g., Model 2510 / 5510, Branson Ultrasonics, Danbury, CT) to promote dissolution.

[0466] In some embodiments, a positive control may be included in the experiment. In some such embodiments, the positive control compound may be, for example, a 0.3% DMSO solution containing cisapride (Tocris Bioscience).

[0467] During the preparation of the recording phase, glass-lined 96-well compound plates were loaded with appropriate amounts of the compounds provided herein or their pharmaceutically acceptable salts and control solutions, and placed in a QPATCH system.® In the wells of (Sophion Bioscience A / S, Denmark).

[0468] HEK293 (ATCC 293T, CRL-3216) was stably transfected with appropriate ion channel cDNA. ™ Cells. In addition to cells that have already been cryopreserved, stable transfectants are maintained in a culture medium with appropriate selective pressure and antibiotics.

[0469] All experiments were conducted at room temperature. Each cell served as its own control.

[0470] via QPATCH ® The robotic pipetting system applied the medium to immature cells at 5-10 minute exposure intervals. Following medium application, various concentrations of the compound provided herein or its pharmaceutically acceptable salts (n-3, where n = cell number / concentration) were applied at intervals of at least three (3) minutes. ® Each solution exchange on the plate is performed multiple times, resulting in 100% replacement of the compounds in the QPlate.

[0471] Positive controls were administered in the same manner as the compounds provided herein or their pharmaceutically acceptable salts to verify sensitivity to ion channel blockade.

[0472] During the recording phase preparation, intracellular solutions (e.g., 137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 10 mM glucose, pH 7.4) are loaded into the intracellular compartment of the QPlate, and the cell suspension is pipetted into the extracellular compartment. After establishing the whole-cell configuration, the cells are processed using QPATCH. ® The system uses up to 48 parallel patch-clamp amplifiers to record membrane currents.

[0473] Valid whole-cell recordings meet the following criteria:

[0474] 1. Membrane resistance ≥ 200MΩ.

[0475] 2. Leakage current ≤ 25% of channel current or be subtracted.

[0476] The onset and blocking of hERG current were measured using a stimulation voltage pattern consisting of a 500 ms pre-pulse to -40 mV (leakage subtraction), a 2-second activation pulse to +40 mV, and a subsequent 2-second test pulse to -40 mV. The pulse pattern was repeated continuously at 10-second intervals from a hold potential of -80 mV. The peak tail current was measured during the -40 mV test pulse. The leakage current was calculated from the current amplitude induced by the -40 mV pre-pulse and subtracted from the total membrane current record.

[0477] Data acquisition and analysis were performed using standard software. Steady state was defined by a finite, constant rate of change over time (linear time dependence). Steady state before and after administration of the compound provided herein or its pharmaceutically acceptable salts was used to calculate the percentage of current inhibited at each concentration. If the current was blocked by ≥50%, the estimated IC was calculated using the following formula. 50 value:

[0478] Suppression % = {1-1 / [l+([test] / IC]} 50 ) N ]}*100

[0479] Wherein [test] refers to the concentration of the compound provided herein or its pharmaceutically acceptable salt, IC50. 50 This represents the concentration of the compound or its pharmaceutically acceptable salt provided in this paper at half-maximum inhibition, where N is the Hill coefficient, and inhibition% is the percentage of current inhibited at each test concentration. A nonlinear least-squares fit was solved using the Solver add-in of Excel (Microsoft, WA). This was achieved through QPATCH. ® The manual adjustment using the exponential compensation formula in the analysis software avoids overestimation of current suppression due to attenuation.

[0480] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are not hERG inhibitors. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are expressed at an IC50 concentration greater than 60 nM (e.g., greater than 100 nM, 300 nM, 500 nM, 1 µM, 3 µM, 5 µM, 10 µM, 20 µM, or 30 µM). 50 Inhibition of hERG. For example, the compounds provided herein or their pharmaceutically acceptable salts can inhibit hERG at an IC50 concentration greater than 500 nM (e.g., greater than 1 µM, 3 µM, 5 µM, 10 µM, 20 µM, or 30 µM). 50 Inhibition of hERG. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used at an IC50 concentration greater than 1 µM (e.g., greater than 3 µM, 5 µM, 10 µM, 20 µM, or 30 µM). 50Inhibition of hERG. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used at an IC50 concentration greater than 10 µM (e.g., greater than 20 µM or 30 µM). 50 Inhibition of hERG. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used at an IC50 concentration greater than 30 µM. 50 Inhibit hERG.

[0481] In some embodiments, the potential secondary pharmacology of the compounds provided herein or their pharmaceutically acceptable salts can be evaluated. For example, in some embodiments, solutions of the compounds provided herein or their pharmaceutically acceptable salts can be exposed at single or multiple concentrations to a group of primary cells, cell lines, or isolated tissues expressing known pharmacological receptors, enzymes, or transporters. The effects of the compounds provided herein or their pharmaceutically acceptable salts on secondary pharmacological targets of interest can be determined, with data initially plotted as percentages of inhibition. For secondary targets exceeding an inhibition threshold (typically ≥50%), IC50 is generated and calculated based on an 8-point concentration curve of the compounds provided herein or their pharmaceutically acceptable salts. 50 value.

[0482] An exemplary list of assays is included in Table 1 below. One or more of these assays can be used to evaluate the secondary pharmacological characteristics of the compounds provided herein. Exemplary protocols are described in Valentin, Jean-Pierre, and Tim Hammond. Journal of Pharmacological and Toxicological Methods 58.2 (2008): 77-87; doi: 10.1016 / j.vascn.2008.05.007; Wakefield, Ian D, et al. Fundamental & Clinical Pharmacology 16.3 (2002): 209-218, doi: 10.1046 / j.1472-8206.2002.00099.x; Whitebread, Steven, et al. Drug Discovery Today 10.21 (2005):1421-1433, doi: 10.1016 / S1359-6446(05)03632-9; and Lounkine, Eugen et al., Nature 486.7403 (2012): 361-367, doi: 10.1038 / nature11159.

[0483] Table 1.

[0484]

[0485]

[0486]

[0487] In some embodiments, the potential of the compounds provided herein or their pharmaceutically acceptable salts to induce phospholipid deposition can be evaluated. For example, in some embodiments, several concentrations of solutions or suspensions of the compounds provided herein or their pharmaceutically acceptable salts can be exposed to cells in a dye-based assay using a dye that binds to phospholipids. The effect of the compounds provided herein or their pharmaceutically acceptable salts on phospholipid accumulation can be determined, data can be plotted, and the IC50 of the compounds provided herein or their pharmaceutically acceptable salts on cell loss due to phospholipid deposition can be calculated. 50 Value. An example solution is as follows.

[0488] HepG2 medium is prepared by supplementing Dalberg Modified Eagle Medium (DMEM) low glucose medium with 1% 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), 10% fetal bovine serum (FBS), 1% non-essential amino acids (NEAA), and 1% penicillin-streptomycin mixture (PS).

[0489] Culture HepG2 cells (e.g., in a T-75 flask in a cell culture incubator set at 37°C, 5% CO2, and 95% relative humidity). Allow cells to reach 80%–90% confluence before isolation and division. Aspirate HepG2 medium from the HepG2 cells (e.g., from the T75 flask) and add 10 mL of phosphate-buffered saline (PBS), washing the cells twice. Aspirate the PBS, add 3–5 mL of trypsin-EDTA, and incubate the flask at 37°C for 5 minutes. Once cells are isolated, add 3 times the volume of HepG2 medium to the flask to neutralize the trypsin, and transfer the contents to a 50 mL vial. Centrifuge the vial containing cells (e.g., at 150 × g for 5 minutes at room temperature). Carefully aspirate the supernatant and resuspend the cell pellet in culture medium. Adjust the cell density to 6 × 10⁶ cells / year. 4 Cells / mL, and seed the cell suspension (e.g., 100 µL) into each well of a poly-D-lysine-coated 96-well plate (the stock solution of poly-D-lysine is 100 μg / mL, diluted to 50 μg / mL with phosphate buffer, and then added directly to 70 μL of blank 96-well plate. Incubate the plate overnight at 37°C. After incubation, discard the incubation solution and dry the plate for later use).

[0490] Prepare a medium (NBD-PE) containing 24 μg / mL of N-(7-nitrobenzo-2-oxa-1,3-diazol-4-yl)-1,2-bishexadecanoyl-sn-glycerol-3-phosphate ethanolamine, triethylammonium salt) and filter it (e.g., with a 0.2 µm filter) before use. Transfer a volume of NBD-PE medium (e.g., 120 µL) to each well of a poly-D-lysine-coated 96-well cell culture plate inoculated with HepG2 cells and incubate the plate at 37 °C for 24 hours under 95% humidity and 5% CO2 atmosphere.

[0491] After incubation, remove the cell culture plate from the incubator. Aspirate the working solution from the wells and fix the cells with 4% paraformaldehyde at room temperature for approximately 20 minutes. Then wash the wells twice with phosphate-buffered saline (e.g., 100 μL) and add Hoechst 33342 (e.g., 5 µM, 100 µL / well) to the plate. Incubate the plate at a humidified 37°C in a 5% CO2 atmosphere for 30 minutes. After incubation at 37°C for 30 minutes, remove the dye from the wells and wash the wells twice with phosphate-buffered saline (e.g., 100 μL each time). Add phosphate-buffered saline (e.g., 100 μL) to each well. Scan the plate using a high-content imaging system. Scan nine fields of view for each well and simultaneously record the fluorescence signals of NBD-PE and Hoechst 33342 based on different fluorescence channels. The instrument outputs the average fluorescence signal from the nine fields of view for each well. Perform measurements in duplicate. The fluorescence of NBD-PE was used for phospholipid deposition calculations, while the fluorescence of Hoechst 33342 was used for cell loss calculations.

[0492] Perform data analysis (e.g., using Microsoft Excel). The change in phospholipid deposition fold at a specific concentration of the test compound can be calculated using the following equation:

[0493] Change in multiple = (reading) 测试化合物 / reading 媒介物 )

[0494] The fold change values ​​were plotted against the concentrations of the compounds provided herein or their pharmaceutically acceptable salts, and the data were fitted to an sigmoid dose-response curve with a variable slope (e.g., using GraphPad Prism 8.0.2). EC50 values ​​of the compounds provided herein or their pharmaceutically acceptable salts... 50 The value can be calculated from the curve using the following equation:

[0495] Y = bottom + (top - bottom) / (1 + 10^(LogEC)) 50 - X)*Hill slope))

[0496] Where X is the logarithm of the concentration of the compound provided in this paper, the bottom is the smallest fold change observed with the compound provided in this paper, and the top is the largest fold change observed with the compound provided in this paper.

[0497] If a data point is an outlier / abnormal value caused by cell death, then that data point can be excluded.

[0498] Cell loss is calculated using the following equation:

[0499] Cell loss (mediator control) %) = (readings) 测试化合物 / reading 媒介物对照 )*100%

[0500] The percentage of cell loss, used as a mediator control, was plotted against the concentration of the test compound, and the data were fitted to an sigmoid dose-response curve with a variable slope (e.g., using GraphPad Prism 8.0.2). The IC50 values ​​for cell loss of the compounds provided herein or their pharmaceutically acceptable salts are shown. 50 The curve can be calculated using the following equation:

[0501] Y = 100 / (1+ 10^((LogIC 50 – X) × Hill slope))

[0502] Where X is the logarithm of the concentration of the compound provided in this paper.

[0503] In some cases, heterobifunctional degraders can induce the degradation of off-target proteins. Common off-target proteins that can be degraded by heterobifunctional degraders utilizing CRBN include GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α. This degradation is generally thought to be due to the E3 binding moiety of the heterobifunctional degrader promoting the formation of a ternary complex between the off-target protein and CRBN. GSPT1 is a translation termination factor, and CK1α is a kinase involved in many key cellular processes, including cell cycle progression and chromosome segregation; these are common essential genes, so unintended degradation of any one or both can lead to nonspecific cytotoxicity. IKZF proteins are zinc finger transcription factors involved in cell fate during hematopoiesis, and the degradation of these proteins is associated with hemotoxicity. See, for example, Moreau, Kevin et al., British Journal of Pharmacology 177.8 (2020): 1709-1718, doi: 10.1111 / bph.15014.

[0504] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can exhibit potent and selective induction of BCL6 protein degradation. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, can selectively target the BCL6 protein to degrade it relative to a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP (cathelicidin antimicrobial peptide), CCNA2 (cyclin-A2), FSP1 (ferroptosis inhibitor 1, also known as AIFM2), JCHAIN ​​(immunoglobulin J chain), NLRP7 (protein 7 containing NACHT, LRR, PYD domains), PTTG1 (securin), and / or TPX2 (target protein of Xklp2)). CAMP is an antimicrobial protein that is a component of the innate immune system and binds to bacterial lipopolysaccharide. CCNA2 controls the G1 / S and G2 / M transition phases of the cell cycle. FSP1 is a redox enzyme and an inhibitor of ferroptosis. JCHAIN ​​links two monomeric units of IgM or IgA; the J-linked dimer is the nucleating unit of the IgM pentamer, and the J-linked dimer of IgA induces dimers or larger polymers. NLRP7 inhibits CASP1 / cysteine-1-dependent IL1B secretion. PTTG1 is key to chromosome stability and negatively regulates TP53. TPX2 is essential for the normal assembly of the mitotic spindle.

[0505] As used herein, when referring to the compounds provided herein or their pharmaceutically acceptable salts, in a protein degradation assay, “selectively” or “selectively” indicates, relative to a comparison protein in the assay, at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) superior performance for the specific protein in the protein degradation assay.

[0506] In some embodiments, the compounds provided herein may exhibit potency against the BCL6 protein (e.g., nanomolar potency) and minimal activity against a second protein (e.g., single-digit micromolar potency, e.g., greater than 1 µM (e.g., greater than 3 µM, 5 µM, 10 µM, 20 µM, or 30 µM potency)). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, exhibit efficient degradation of the BCL6 protein and minimal potency in degrading a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as by Y). min DC50 and / or D max The values ​​are measured. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts may exhibit higher BCL6 protein degradation induction (e.g., as measured by Y) relative to the degradation induction of a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2). min DC 50 and / or D max (Measured by the value). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit at least 2, 3, 5, 10, 25, 50, or 100 times higher degradation induction of BCL6 protein relative to the second protein. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit up to 1000 times higher degradation induction of BCL6 protein relative to the second protein. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit about 2 to about 10 times higher degradation induction of BCL6 protein relative to the second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by Y). min DC 50 and / or D max(Values ​​measured). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit degradation induction of BCL6 protein about 10 to 100 times higher than that of the second protein. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit degradation induction of BCL6 protein about 100 to 1000 times higher than that of the second protein. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit degradation induction of BCL6 protein about 1000 to 10000 times higher than that of the second protein. In some embodiments, the second protein is selected from the group consisting of: GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and TPX2. In some embodiments, the second protein is selected from the group consisting of: GSPT1, IKZF1, IKZF2, IKZF3, and CK1α. In some embodiments, the second protein is selected from the group consisting of: C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and TPX2. In some embodiments, the second protein is C6orf132. In some embodiments, the second protein is CAMP. In some embodiments, the second protein is CCNA2. In some embodiments, the second protein is FSP1. In some embodiments, the second protein is JCHAIN. In some embodiments, the second protein is NLRP7. In some embodiments, the second protein is PTTG1. In some embodiments, the second protein is TPX2.

[0507] In some embodiments, the compounds provided herein can exhibit potency against the BCL6 protein, having similar activity to the second protein (i.e., activity against the BCL6 protein is less than 2-fold higher than activity against the second protein, and activity against the second protein is no more than 2-fold higher than activity against the BCL6 protein). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof can exhibit similar BCL6 protein degradation induction relative to the degradation of the second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as by Y...). min DC 50 and / or D maxThe values ​​measured herein (i.e., the degradation induction of BCL6 protein is less than 2-fold different from that of the second protein, and the activity against the second protein is no more than 2-fold higher than that against BCL6 protein). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit degradation induction of BCL6 protein less than 2-fold higher than that against the second protein. In some embodiments, the second protein is selected from the group consisting of: GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and TPX2. In some embodiments, the second protein is selected from the group consisting of: GSPT1, IKZF1, IKZF2, IKZF3, and CK1α. In some embodiments, the second protein is selected from the group consisting of: C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and TPX2. In some embodiments, the second protein is C6orf132. In some embodiments, the second protein is CAMP. In some embodiments, the second protein is CCNA2. In some embodiments, the second protein is FSP1. In some embodiments, the second protein is JCHAIN. In some embodiments, the second protein is NLRP7. In some embodiments, the second protein is PTTG1. In some embodiments, the second protein is TPX2.

[0508] In some embodiments, the compounds provided herein may exhibit potency against the BCL6 protein with minimal activity against a second protein (e.g., a reduction in protein abundance of <20%, as measured by proteomics assays, such as those described herein). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may exhibit efficient degradation of the BCL6 protein and minimal potency (e.g., as measured by abundance in proteomics assays) against a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG, and / or TPX2). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit higher BCL6 protein degradation induction (e.g., as measured by abundance in proteomics assays, such as those described herein) relative to the degradation induction of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold higher BCL6 protein degradation induction (e.g., as measured by abundance in proteomics assays, such as those described herein) relative to the degradation induction of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit degradation induction of BCL6 protein up to 1000 times higher than that of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in proteomics assays (e.g., as described herein). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit degradation induction of BCL6 protein about 2 to about 10 times higher than that of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in proteomics assays (e.g., as described herein).In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit degradation induction of BCL6 protein that is about 10-fold to about 100-fold higher than that of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in proteomics assays (e.g., as described herein). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit degradation induction of BCL6 protein that is about 100-fold to about 1000-fold higher than that of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in proteomics assays (e.g., as described herein). In some embodiments, the second protein is selected from the group consisting of: GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and TPX2. In some embodiments, the second protein is selected from the group consisting of: GSPT1, IKZF1, IKZF2, IKZF3, and CK1α. In some embodiments, the second protein is selected from the group consisting of: C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and TPX2. In some embodiments, the second protein is C6orf132. In some embodiments, the second protein is CAMP. In some embodiments, the second protein is CCNA2. In some embodiments, the second protein is FSP1. In some embodiments, the second protein is JCHAIN. In some embodiments, the second protein is NLRP7. In some embodiments, the second protein is PTTG1. In some implementations, the second protein is TPX2.

[0509] In some embodiments, the compounds provided herein may exhibit potency against the BCL6 protein with minimal activity against any other detectable protein (e.g., a reduction in protein abundance of <20%, as measured by proteomics assays, such as those described herein). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may exhibit efficient degradation of the BCL6 protein and have minimal potency in degrading any other detectable protein (e.g., as measured by abundance in proteomics assays, such as those described herein). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may exhibit higher BCL6 protein degradation induction relative to degradation induction against any other detectable protein (e.g., as measured by abundance in proteomics assays, such as those described herein). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit at least 2, 3, 5, 10, 25, 50, or 100 times higher degradation induction of BCL6 protein relative to any other detectable protein (e.g., as measured by abundance in a proteomics assay, such as those described herein). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit up to 1000 times higher degradation induction of BCL6 protein relative to any other detectable protein (e.g., as measured by abundance in a proteomics assay, such as those described herein). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit about 2 to about 10 times higher degradation induction of BCL6 protein relative to any other detectable protein (e.g., as measured by abundance in a proteomics assay, such as those described herein). In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts may exhibit degradation induction of BCL6 protein that is about 10 to about 100 times higher than that of any other detectable protein (e.g., as measured by abundance in proteomics assays, such as those described herein).

[0510] In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof can exhibit efficient degradation of BCL6 protein and minimal efficacy in degrading one or more other proteins, as measured by abundance in a proteomics assay. An exemplary proteomics experiment is as follows: OCI-Ly1 (DSMZ: ACC 722) cells were incubated for six hours with 100 nM of the compounds provided herein or pharmaceutically acceptable salts thereof or dimethyl sulfoxide (DMSO). The cells were then washed twice with phosphate-buffered saline and collected. The cells were lysed to extract total protein, and the protein was extracted according to EASYPEP. ™ Total protein was prepared for mass spectrometry analysis using the MS Sample Preparation Kit (Fisher Scientific) protocol. In short, the protein was reduced with dithiothreitol, alkylated with iodoacetamide, and digested with trypsin and LysC enzyme. Following the manufacturer's protocol, TMTPRO was used... ™ Peptides were labeled using 18plex reagent (Fisher Scientific). Labeled peptides from each sample were mixed in equal volumes and the peptide mixture was separated by alkaline reversed-phase chromatography. A total of 85 fractions were combined into 18 pooled fractions. The pooled fractions were dried by centrifugation and resuspended in 5% acetonitrile and 0.1% formic acid for mass spectrometry analysis. A Vanquish Neo chromatography system (Fisher Scientific) and an Orbitrap FUSION were used. ™ LUMOS ™ The Fisher Scientific mass spectrometer quantifies peptide abundance using tandem mass spectrometry. In short, two micrograms of total peptide are loaded onto a two-cm C8 capture column, followed by loading onto a 50-cm C18 column. Data-dependent acquisition is performed to obtain peptide sequence and abundance information. A PROTEOME DISCOVERER is used. ™ Peptide and protein abundances were determined using software and the Homo sapiens proteome database (TaxID 9606), and results were filtered to FDR < 0.01. Significance thresholds were set at p < 0.001 and fold change in abundance < 50%.

[0511] In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof can degrade the BCL6 protein and minimally degrade one or more other proteins, as measured by the abundance of a proteomic assay (e.g., a proteomic assay measuring peptides on a proteomic scale after exposing cells to the compounds provided herein or pharmaceutically acceptable salts thereof for a period of time). The measured abundance of peptides can be compared with control experiments, and proteins that increase or decrease after exposure to the compounds provided herein or pharmaceutically acceptable salts thereof can be identified. Exemplary embodiments are as follows.

[0512] Cells (e.g., OCI-Ly1 DSMZ: ACC 722) were incubated with a solution of the compound provided herein or its pharmaceutically acceptable salts at 100 nM or 500 nM for 6 h or 24 h. After incubation, the cells were washed twice with phosphate-buffered saline, precipitated, and rapidly frozen in liquid nitrogen. A precipitate for mass spectrometry analysis was prepared using the Accelerome TMT 16-plex kit (ThermoFisher #PIA50949) and Accelerome (Thermo Fisher). Briefly, cells were lysed with a lysis buffer containing a universal nuclease and a mixture of phosphatases and protease inhibitors (Thermo Fisher #78440). Protein extracts were digested with trypsin and LysC, reduced with dithiothreitol, and modified with iodoacetamide. Peptides were labeled with an isotopic TMTpro agent and pooled. The combined labeled peptides were separated by high-pH reversed-phase fractionation using a C18 column (Phenomenex #00F-4893-AN) on an Agilent 1260 Infinity II HPLC system. A total of 85 fractions were combined into 18 fractions. The combined fractions were concentrated by centrifugation and resuspended in 0.1% formic acid and 5% acetonitrile for analysis on an Orbitrap Ascend mass spectrometer (Thermo Fisher). Peptides were resolved using a 90-minute reversed-phase gradient and a 50 cm C18 column (Thermo Fisher #ES903). The SPS-MS3 analysis method with default settings was used (e.g., MS1 scan, orbitrap resolution 120,000, scan range 400 m / z–1600 m / z and RF lens 60%; MS2 scan, CID fragmentation, 30% collision energy, ion trap detector, Turbo scan rate and 45 ms injection time; MS3 scan, HCD fragmentation, 55% collision energy, orbitrap detector, 45,000 resolution, TurboTMT off and 200 ms injection time). Real-time searches were performed using the Homo sapiens proteome database (Uniprot 9606, downloaded 7 / 10 / 23), static modifications of “ureidomethyl” and “TMTpro16plex”, and the variable modification “Oxidation M”. Raw files were processed using ProteomeDiscoverer version 3.0 to identify and quantify proteins. Data was searched against the human proteome (above).Protein quantification values ​​were generated using the processing method “PWF_Tribrid_TMTpro_Quan_SPS_MS3_SequestFT_Percolator” and the consistency formula “CWF_Comprehensive_Enhanced Annotation_Reporter_Quan_MS3”. The Sequest HT nodes include dynamic modifications such as oxidation on Met, phosphorylation on Ser, Thr, and Tyr, and static modifications such as TMTpro on Lys and ureidomethyl groups on Cys.

[0513] As used herein, “determining BCL6 expression status” means assessing whether BCL6 is expressed, for example, at the mRNA or protein level. In some embodiments, the assessment includes BCL6 expression level (e.g., BCL6 expression above or below a threshold). BCL6 expression status can be assessed by a variety of methods (e.g., measuring protein levels, mRNA levels, or both) and can be assessed quantitatively or qualitatively, for example, using scales or thresholds accepted by, for example, regulatory agencies or pathologists. In some embodiments, the assessment includes reviewing the subject’s medical records. In some embodiments, BCL6 expression status is positive (e.g., a sample from the subject is positive for BCL6 expression). In some embodiments, BCL6 expression status is not positive for BCL6 expression (e.g., a sample from the subject is negative or indeterminate, for example, BCL6 expression is below a threshold or below the detection limit for a specific assay).

[0514] In some implementations, the BCL6 expression status of a sample from a subject can be determined. In some implementations, the BCL6 expression status can be determined by expression profiling (e.g., mRNA expression profiling) from a cancer sample or a blood sample. In some implementations, the BCL6 expression status can be determined by an mRNA-based assay, such as RNA sequencing (RNA-seq), reverse transcription polymerase chain reaction (RT-PCR), digital PCR (dPCR), or in situ hybridization (ISH). In some implementations, the BCL6 expression status can be determined by an IHC assay, using any suitable IHC method and reagents. For example, a pathologist or automated system (e.g., the BOND RX system (Leica), BOND-PRIME system (Leica), AutoStainer Link 48 system (Agilent), AutoStainer PLUS system (Agilent), Dako Omnis system (Agilent), BenchMark ULTRA system (Roche), or BenchMark ULTRA PLUS system (Roche)) can determine that a cancer sample (e.g., a biopsy sample) from a subject who has undergone IHC with an appropriate BCL6 antibody is positive for BCL6 expression. As another example, the IHC test can produce an IHC score of 0, 1, 2, or 3; in some such implementations, a positive BCL6 expression status can be indicated by a score of 1, 2, or 3 (e.g., 2 or 3) (e.g., as determined by a pathologist or automated system). As yet another example, IHC testing can produce a nuclear positivity percentage score from 0% to 100%; in some such embodiments, a positive BCL6 expression status can be indicated by a nuclear positivity percentage score greater than or equal to 1% (e.g., greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 15%, or greater than or equal to 20%). In some embodiments, a positive BCL6 expression status can be indicated by a nuclear positivity percentage score greater than or equal to 30% (e.g., greater than or equal to 35%, greater than or equal to 40%, or greater than or equal to 50%) (e.g., as determined by a pathologist or automated system). See, for example, Hans, Christine P. et al. Blood 103.1 (2004): 275-282, doi: 10.1182 / blood-2003-05-1545. In some such implementations, samples from subjects may have a nuclear positivity percentage score of 75% or higher (e.g., 80%, 90%, or 95%) (e.g., as determined by a pathologist or automated system).As another example, the IHC test can produce an H score from 0 to 300; in some such implementations, a positive BCL6 expression status can be indicated by an H score greater than or equal to 10 (e.g., greater than or equal to 30, greater than or equal to 50, greater than or equal to 60, greater than or equal to 75, greater than or equal to 100, greater than or equal to 150, or greater than or equal to 200). In some implementations, the H score is calculated as 3 × percentage of strongly stained nuclei + 2 × percentage of moderately stained nuclei + percentage of weakly stained nuclei.

[0515] Non-limiting examples of antibodies suitable for IHC assays of BCL6 expression include clones of PG-B6p (e.g., Dako / Agilent product number IR625), GI191E / A8 (e.g., Roche / Ventana product number 760-4241), LN22 (e.g., Lecia Biosystems product number PA0204), GI191E / A8 (e.g., Sigma / Cell Marque product number 227M-98), and EP278 (e.g., Sigma / Cell Marque product number 227R-27).

[0516] This document provides a method for treating cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the subject's cancer is positive for BCL6 expression. In some embodiments, the subject's cancer is negative for BCL6 expression. Therefore, this document also provides a method for treating cancer in a subject of need, the method comprising: (a) determining the BCL6 expression status of the cancer (e.g., by performing an assay or test, or by consulting the subject's medical records); and (b) administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof. This document also provides a method for treating cancer in a subject of need, the method comprising: (a) determining that the subject's cancer is positive for BCL6 expression (e.g., by an IHC test); and (b) administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof.

[0517] This article also provides a method for treating cancer in a subject of need, the method comprising: (a) determining the BCL6 expression status of the cancer; and (b) administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof. In some such embodiments, the subject's cancer is positive for BCL6 expression. In other such embodiments, the subject's cancer is not positive for BCL6 expression.

[0518] This article also provides a method for treating cancer, comprising administering to a subject identified as having cancer that is positive for BCL6 expression (e.g., a subject identified as having cancer that is positive for BCL6 expression by an IHC test) a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound provided herein or a pharmaceutically acceptable salt thereof.

[0519] This article also provides a method of treating cancer, comprising administering to a subject with cancer whose BCL6 expression status has been previously tested (e.g., a subject with cancer whose BCL6 expression has been previously tested by an IHC test) a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof. In some such embodiments, the subject's cancer is positive for BCL6 expression. In other such embodiments, the subject's cancer is not positive for BCL6 expression.

[0520] This article also provides a method of treating cancer, comprising administering a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound provided herein or a pharmaceutically acceptable salt thereof, to a subject having a record (e.g., a medical record) indicating that the subject’s cancer is positive for BCL6 expression (e.g., a subject previously identified by an IHC test as having cancer positive for BCL6 expression).

[0521] This article also provides a method of treating cancer, comprising administering a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof, to a subject having a record (e.g., a medical record) indicating that the subject's cancer has been previously tested for BCL6 expression. In some such embodiments, the subject's cancer is positive for BCL6 expression. In other such embodiments, the subject's cancer is not positive for BCL6 expression.

[0522] This article also provides a method for treating cancer, comprising administering to a subject who has been diagnosed with cancer that is positive for BCL6 expression (e.g., cancer that is positive for BCL6 expression by an IHC test) a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound provided herein or a pharmaceutically acceptable salt thereof.

[0523] This article also provides a method of treating cancer, comprising administering to a subject identified as having cancer previously tested for BCL6 expression (e.g., cancer previously tested for BCL6 expression by an IHC test) a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof. In some such embodiments, the subject's cancer is positive for BCL6 expression. In other such embodiments, the subject's cancer is not positive for BCL6 expression.

[0524] In some embodiments, this document provides a method for treating a subject's cancer, the method comprising measuring a sample (e.g., a tumor sample) obtained from the subject to determine whether the subject's cancer is positive for BCL6 expression, and administering to the subject suffering from cancer that is determined to be positive for BCL6 expression a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof.

[0525] In some embodiments, this document provides a method for treating a subject's cancer, the method comprising measuring a sample obtained from the subject (e.g., a tumor sample) to determine the BCL6 expression status of the cancer, and administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof. In some such embodiments, the subject's cancer is positive for BCL6 expression. In other such embodiments, the subject's cancer is not positive for BCL6 expression.

[0526] In some embodiments of any of these methods, the BCL6 expression status of cancer is determined (e.g., via biopsy or blood sample) after administering at least one dose (e.g., two, three, four, five or more doses) of the compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound provided herein or a pharmaceutically acceptable salt thereof, to a subject.

[0527] In some implementations, the subject is suspected of having BCL6-positive cancer, presenting with one or more symptoms of BCL6-expressing cancer, or having an elevated risk of developing BCL6-positive cancer. In some implementations, the subject has not received any treatment for the cancer. In some implementations, the subject has received first-line or multiple-line prior therapy for the cancer.

[0528] In some embodiments of any of these methods, the compounds provided herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the compounds provided herein or pharmaceutically acceptable salts thereof, are administered to the subject as a single therapy. Some embodiments of these methods also include administration of additional therapies or therapeutic agents to the subject.

[0529] In some embodiments, the cancer is large B-cell lymphoma (LBCL) (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL, or HBGCL-NOS). In some embodiments, the LBCL is positive for BCL6 expression, as determined by an IHC test (e.g., expressed as a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is DLBCL-NOS; in some such embodiments, the DLBCL-NOS is positive for BCL6 expression, as determined by an IHC test (e.g., expressed as a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is HGBCL-MYC / BCL-2 or HGBCL-NOS; in some such embodiments, as determined by IHC testing, HGBCL-MYC / BCL-2 or HGBCL-NOS is positive for BCL6 expression (e.g., expressed as a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is a primary immune-exempt site LBCL; in some such embodiments, as determined by IHC testing, the primary immune-exempt site LBCL is positive for BCL6 expression (e.g., expressed as a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is a primary mediastinal LBCL; in some such embodiments, as determined by IHC testing, the primary mediastinal LBCL is positive for BCL6 expression (e.g., expressed as a nuclear positivity percentage score greater than or equal to 30% in an IHC test).

[0530] In some implementations, the cancer is a transformed indolent B-cell lymphoma. In some implementations, as determined by an IHC test, the transformed indolent B-cell lymphoma is positive for BCL6 expression (e.g., represented by a nuclear positivity percentage score of ≥1% in an IHC test; e.g., a nuclear positivity percentage score of ≥30% in an IHC test).

[0531] In some implementations, cancer is FL. In some implementations, as determined by an IHC test, FL is positive for BCL6 expression (e.g., represented by a nuclear positivity percentage score of ≥1% in an IHC test; e.g., a nuclear positivity percentage score of ≥30% in an IHC test).

[0532] In some implementations, the cancer is BL. In some implementations, as determined by an IHC test, BL is positive for BCL6 expression (e.g., represented by a nuclear positivity percentage score of ≥1% in an IHC test; e.g., a nuclear positivity percentage score of ≥30% in an IHC test).

[0533] In some implementations, the cancer is NLPHL. In some implementations, as determined by an IHC test, NLPHL is positive for BCL6 expression (e.g., represented by a nuclear positivity percentage score of ≥1% in an IHC test; e.g., a nuclear positivity percentage score of ≥30% in an IHC test).

[0534] In some implementations, the cancer is peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)) or primary cutaneous T-cell lymphoproliferative or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disease, mycosis fungoides, Cezari syndrome, or primary cutaneous γ-δ) T-cell lymphoma. In some embodiments, PTCL or CTCL is positive for BCL6 expression, as determined by an IHC test (e.g., represented by a nuclear positivity percentage score greater than or equal to 1% in the IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in the IHC test). In some embodiments, the cancer is nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)). In some such embodiments, as determined by IHC testing, nodular T-follicular helper cell lymphomas (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma), or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)) are positive for BCL6 expression (e.g., represented by a nuclear positivity percentage score greater than or equal to 1% in an IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is follicular nodular T-follicular helper cell lymphoma. In some such implementations, as determined by an IHC test, follicular nodular T-follicular helper cell lymphoma is positive for BCL6 expression (e.g., represented by a nuclear positivity percentage score of ≥1% in an IHC test; e.g., a nuclear positivity percentage score of ≥30% in an IHC test).In some embodiments, the cancer is angioimmunoblastic nodular T-follicular helper cell lymphoma. In some such embodiments, as determined by IHC testing, the angioimmunoblastic nodular T-follicular helper cell lymphoma is positive for BCL6 expression (e.g., represented by a nuclear positivity percentage score greater than or equal to 1% in an IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma). In some such embodiments, as determined by IHC testing, the anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma) is positive for BCL6 expression (e.g., represented by a nuclear positivity percentage score greater than or equal to 1% in an IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is nodular T-follicular helper cell lymphoma (NOS). In some such embodiments, as determined by IHC testing, nodular T-follicular helper cell lymphoma (NOS) is positive for BCL6 expression (e.g., represented by a nuclear positivity percentage score greater than or equal to 1% in an IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is primary cutaneous T-cell lymphoproliferative disorder or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, Cezari syndrome, or primary cutaneous γ-δ T-cell lymphoma). In some such embodiments, as determined by IHC testing, primary cutaneous T-cell lymphoproliferative disorder or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, Cezari syndrome, or primary cutaneous γ-δ T-cell lymphoma) is positive for BCL6 expression (e.g., expressed as a nuclear positivity percentage score greater than or equal to 1% in an IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is mycosis fungoides. In some such embodiments, as determined by IHC testing, mycosis fungoides is positive for BCL6 expression (e.g., expressed as a nuclear positivity percentage score greater than or equal to 1% in an IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder.In some such embodiments, as determined by IHC testing, primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorders are positive for BCL6 expression (e.g., expressed as a nuclear positivity percentage score greater than or equal to 1% in an IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is mycosis fungoides. In some such embodiments, as determined by IHC testing, mycosis fungoides are positive for BCL6 expression (e.g., expressed as a nuclear positivity percentage score greater than or equal to 1% in an IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is primary cutaneous γ-δ T-cell lymphoma. In some such embodiments, as determined by IHC testing, primary cutaneous γ-δ T-cell lymphoma is positive for BCL6 expression (e.g., expressed as a nuclear positivity percentage score greater than or equal to 1% in an IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in an IHC test). In some embodiments, the cancer is Cézari syndrome. In some such embodiments, as determined by IHC testing, Cézari syndrome is positive for BCL6 expression (e.g., expressed as a nuclear positivity percentage score greater than or equal to 1% in an IHC test; e.g., a nuclear positivity percentage score greater than or equal to 30% in an IHC test).

[0535] In some cases, treatment of cancer or cancer models (e.g., PDX or CDX models) with the compounds provided herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compounds provided herein or pharmaceutically acceptable salts thereof, may result in regression of the cancer or cancer models (e.g., greater than or equal to 50% regression). In some cases, treatment of cancer or cancer models (e.g., PDX or CDX models) as a monotherapy with the compounds provided herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the compounds provided herein or pharmaceutically acceptable salts thereof, may result in regression of the cancer or cancer models (e.g., greater than or equal to 50% regression). In some such embodiments, the PDX model is positive for BCL6 expression, as determined by an IHC test (e.g., represented by a nuclear positivity percentage score of greater than or equal to 30% in an IHC test). In some embodiments, the PDX model is positive for MYC expression, as determined by an IHC test (e.g., represented by a nuclear positivity percentage score of greater than or equal to 30% in an IHC test). In some such implementations, the PDX model is positive for BCL6 expression (e.g., as determined by an IHC test, represented by a nuclear positivity percentage score of ≥30% in the IHC test) and positive for MYC expression (e.g., as determined by an IHC test, represented by a nuclear positivity percentage score of ≥30% in the IHC test) as determined by an IHC test.

[0536] This document provides for the use of the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of cancer (e.g., any cancer described herein). This document also provides for the use of the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of cancers that are positive for BCL6 expression (e.g., as determined by an IHC test).

[0537] This document provides for the use of the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicaments for the treatment of cancer (e.g., any cancers described herein). This document also provides for the use of the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicaments for the treatment of cancers that are positive for BCL6 expression (e.g., as determined by an IHC test).

[0538] This article provides for the use of the compounds provided herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating cancer (e.g., any cancers provided herein). This article also provides for the use of the compounds provided herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating cancers that are positive for BCL6 expression (e.g., as determined by an IHC test).

[0539] This document provides for the use of compounds provided herein, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines. This document also provides for the use of compounds provided herein, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines for treating cancers (e.g., any cancers provided herein). This document further provides for the use of compounds provided herein, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines for treating cancers that are positive for BCL6 expression (e.g., as determined by an IHC test).

[0540] This document provides for the use of compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment of cancer, such as any of the cancers provided herein. It also provides for the use of compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment of a subject with BCL6-positive cancer identified or diagnosed with BCL6-positive cancer, the treatment being performed by the following steps: testing a sample obtained from the subject (e.g., a tumor sample) (e.g., an IHC test) to determine whether the subject's cancer is BCL6-positive (e.g., as determined by an IHC test).

[0541] As used herein, cancer treatment may include treatment of the primary tumor (i.e., non-metastatic cancer) (e.g., as first-line, second-line, third-line, or subsequent therapy, including but not limited to recurrent / refractory cases), treatment of metastatic (or secondary) tumors, neoadjuvant therapy (e.g., prior to treatment with another therapy or treatment agent, such as surgery, radiation, chemotherapy, or first-line therapy), adjuvant therapy (e.g., after treatment with another therapy or treatment agent, such as surgery, radiation, chemotherapy, or first-line therapy), or maintenance therapy (e.g., treatment following a response to another therapy or treatment agent, such as surgery, radiation, chemotherapy, or first-line therapy).

[0542] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are used to treat a primary tumor. In some embodiments, the subject has not received any treatment for cancer. In some embodiments, the subject has received first-line or multiple-line therapy for cancer. In some embodiments, the subject has received chemotherapy, cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy) or both. In some embodiments, the subject has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R... 2 R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapies, or two or more of these. In some embodiments, the subject has received a regimen containing rituximab. In some embodiments, the subject has received a regimen containing oxtuzumab. In some embodiments, the subject has received a regimen containing motuzumab. In some embodiments, the subject has received a regimen containing icoretuzumab. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used to treat subjects who have received first-line or multiple-line systemic therapy for cancer. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used to treat subjects who have received second-line or multiple-line systemic therapy for cancer.

[0543] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are used to treat metastatic tumors. In some embodiments, the subject has not received treatment for metastatic tumors. In some embodiments, the subject has received first-line or multiple-line treatment for metastatic tumors. In some embodiments, the subject has received chemotherapy, cell-based therapies (e.g., adoptive cell therapies (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy) or both. In some embodiments, the subject has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R... 2 R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapies, or two or more of these. In some embodiments, the subject has received a regimen containing rituximab. In some embodiments, the subject has received a regimen containing oxtuzumab. In some embodiments, the subject has received a regimen containing motuzumab. In some embodiments, the subject has received a regimen containing icoretuzumab. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used to treat subjects who have received first-line or multiple-line systemic therapy for cancer. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used to treat subjects who have received second-line or multiple-line systemic therapy for cancer.

[0544] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are used as neoadjuvant therapy. In some embodiments, neoadjuvant therapy precedes surgery (e.g., surgical resection, such as partial or complete surgical resection). In some embodiments, neoadjuvant therapy precedes radiation therapy. In some embodiments, neoadjuvant therapy precedes chemotherapy.

[0545] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are adjunctive therapies. In some embodiments, the subject has received chemotherapy, cell-based therapies (e.g., adoptive cell therapies (e.g., CAR-T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy) or both. In some embodiments, the subject has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R 2R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapies, or two or more of these. In some embodiments, the subject has received a regimen containing rituximab. In some embodiments, the subject has received a regimen containing oxutuzumab. In some embodiments, the subject has received a regimen containing motuzumab. In some embodiments, the subject has received a regimen containing icoretuzumab. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used to treat subjects who have received first-line or multiple-line systemic therapy for cancer. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used to treat subjects who have received second-line or multiple-line systemic therapy for cancer. In some embodiments, adjuvant therapy follows surgery (e.g., surgical resection, such as partial or complete, total, or radical surgical resection). In some embodiments, adjuvant therapy follows radiation therapy. In some embodiments, adjuvant therapy follows chemotherapy.

[0546] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are maintenance therapy. In some embodiments, the subject has received chemotherapy, cell-based therapies (e.g., adoptive cell therapies (e.g., CAR-T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy), stem cell transplantation, or combinations thereof. In some embodiments, the subject has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R... 2 R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapies, or two or more thereof. In some embodiments, the subject has received a regimen containing rituximab. In some embodiments, the subject has received a regimen containing oxutuzumab. In some embodiments, the subject has received a regimen containing motuzumab. In some embodiments, the subject has received a regimen containing icoretuzumab. In some embodiments, the subject has received a stem cell transplant. In some embodiments, the subject has received a cell-based therapy (e.g., CAR T therapy). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used to treat subjects who have received first-line or multiple-line systemic therapy for cancer. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used to treat subjects who have received second-line or multiple-line systemic therapy for cancer.

[0547] As used herein, when referring to the compounds provided herein or their pharmaceutically acceptable salts, "monotherapy" means that the compounds provided herein or their pharmaceutically acceptable salts are the only therapeutic agent or therapy (e.g., an anticancer agent or therapy) administered to the subject during a treatment cycle (e.g., without the administration of other targeted therapies, anticancer agents, chemotherapy agents, or checkpoint inhibitors to the subject during a treatment cycle). As understood by those skilled in the art, monotherapy does not exclude the co-administration of drugs used to treat cancer or treatment-related side effects or general symptoms such as pain, rash, edema, photosensitivity, itching, skin discoloration, brittle hair, hair loss, brittle nails, nail breakage, nail discoloration, epidermal swelling, fatigue, weight loss, malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms (including nausea, diarrhea, and loss of appetite).

[0548] As used herein, "subject has received first-line or multiple-line therapy for cancer" means that the subject has previously received one or more therapeutic agents or therapies for cancer (e.g., anticancer agents or therapies) other than the compounds provided herein or their pharmaceutically acceptable salts during previous treatment cycles. In some embodiments, the subject is intolerant to the previously administered one or more therapeutic agents or therapies for cancer. In some embodiments, the subject is unresponsive to the previously administered one or more therapeutic agents or therapies for cancer. In some embodiments, the subject's response to the previously administered one or more therapeutic agents or therapies for cancer is inadequate. In some embodiments, the subject's response to the previously administered one or more therapeutic agents or therapies for cancer has ceased. In some implementations, non-response, inadequate response, or cessation of response can be determined by objective criteria (e.g., tumor volume, or by criteria such as RECIST 1.1, Lugano 2014 criteria (Cheson, Bruce D. et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JCO.2013.54.8800) or global response criteria (Olsen, Elise A. et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057)). In some implementations, non-response, inadequate response, or cessation of response can be determined by the subject's physician.

[0549] As used in this article, “the subject has not received any treatment for cancer” means that the subject has not previously received one or more treatments or therapies for cancer.

[0550] For any of the solid tumors described herein, the solid tumor can be a primary tumor or a metastatic (or secondary) tumor. As used herein, a "primary" tumor is one located at the site where the tumor began to grow (i.e., the site of origin). As used herein, a "metastatic" (or "secondary") tumor is one that has spread from the original tumor site to other parts of the body. In some embodiments, the metastatic or secondary tumor is the same type of cancer as the primary tumor. In some embodiments, the metastatic or secondary tumor is not genetically identical to the primary tumor.

[0551] In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal carcinoma of the breast), cancer of the central or peripheral nervous system (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligodendroastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple type I and II neuroendocrine tumors, parathyroid cancer, pituitary tumors, thyroid cancer (e.g., papillary thyroid carcinoma)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, bile duct cancer). Cancers including (e.g., cholangiocarcinoma), colorectal cancers (e.g., colonic adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancers (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, liver cancers (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), pancreatic cancers (e.g., pancreatic adenocarcinoma, islet cell carcinoma), small bowel cancer or stomach cancers (e.g., gastric adenocarcinoma, gastric signet ring cell carcinoma), and genitourinary cancers (e.g., bladder cancer (e.g., bladder urothelial carcinoma)). Kidney cancer (e.g., clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), testicular cancer (e.g., testicular germ cell tumor) or ureteral cancer), gynecological cancers (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, endometrioid carcinoma, uterine serous carcinoma, papillary serous uterine carcinoma, uterine body endometrial cancer) or vulvar cancer), head and neck cancers (e.g., ear cancer) For example, middle ear cancer, squamous cell carcinoma of the head and neck, nasal cavity cancer, oral cavity cancer, pharyngeal cancer (e.g., hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematologic malignancies (e.g., leukemia (e.g., acute lymphoblastic leukemia (ALL) (e.g., Philadelphia chromosome-positive ALL, Philadelphia chromosome-negative ALL), acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia (APL)), chronic myeloid leukemia (CML) or early T precursor lymphoblastic leukemia or myelodysplastic syndrome), lymphoma (e.g., Hodgkin's lymphoma) Lymphomas (e.g., nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) or typical Hodgkin lymphoma), non-Hodgkin lymphomas (e.g., B-cell lymphoproliferative and lymphomas (e.g., B-cell-predominant neoplastic lesions (e.g., IgG4-related diseases), progenitor B-cell tumors (e.g., B-lymphoblastic lymphoma), mature B-cell tumors (e.g., chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), marginal zone lymphoma, Burkitt lymphoma (BL), large B-cell lymphoma (e.g.,Nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), T-cell-rich / histiocytic large B-cell lymphoma, diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), ALK-positive large B-cell lymphoma, large B-cell lymphoma with IRF4 rearrangement, high-grade B-cell lymphoma with 11q abnormality, lymphomatoid granulomatosis, Epstein-Barr virus (Epstein-Barr virus) Large B-cell lymphoma positive for EBV (Epstein-Barr virus), diffuse large B-cell lymphoma associated with chronic inflammation, fibrin-associated large B-cell lymphoma, humoral overload large B-cell lymphoma, plasmablastic lymphoma, primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), primary cutaneous large B-cell lymphoma of the leg, intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL), mediastinal gray zone lymphoma or high-grade B-cell lymphoma (NOS), follicular lymphoma (FL), transformation of indolent B-cell lymphoma, mantle cell lymphoma (MCL) or plasma cell tumor (e.g., multiple myeloma), T-cell and NK-cell lymphoproliferative and lymphoma (e.g., T-cell predominant tumor-like lesions (e.g., autoimmune lymphoproliferative syndrome), precursor T-cell tumors (e.g., early T-precursor lymphoblasts). T-cell leukemia / lymphoma or T-lymphoblastic leukemia / lymphoma NOS), mature T-cell and NK-cell tumors (e.g., mature T-cell and NK-cell leukemias (e.g., T-prolymphocytic leukemia, T-large granular lymphocytic leukemia, NK-large granular lymphocytic leukemia, adult T-cell leukemia / lymphoma or aggressive NK-cell leukemia), primary cutaneous T-cell lymphoproliferative and lymphoma (cutaneous T-cell lymphoma (CTCL)). (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorders, primary cutaneous acral CD8-positive T-cell lymphoproliferative disorders, mycosis fungoides, Cezari syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disorders: lymphomatoid papulosis, primary cutaneous CD30-positive T-cell lymphoproliferative disorders: primary cutaneous anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous γ-δ T-cell lymphoma, primary cutaneous CD8-positive aggressive epidermal tropism-mediated cytotoxic T-cell lymphoma or primary cutaneous peripheral T-cell lymphoma NOS), peripheral T-cell lymphoma (PTCL) (e.g., intestinal T-cell and NK-cell lymphoproliferative and lymphoma (e.g.,Gastrointestinal indolent T-cell lymphoma, gastrointestinal indolent NK-cell lymphoproliferative disorder, enteropathy-associated T-cell lymphoma, monomorphic epithelial intestinal T-cell lymphoma or intestinal T-cell lymphoma (NOS), hepatocellular T-cell lymphoma, anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, or breast implant-associated anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma)). (AITL or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS), other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS) or EBV-positive T-cell and NK-cell lymphomas (e.g., EBV-positive nodular T-cell and NK-cell lymphoma or extranodal NK / T-cell lymphoma), Li-Fraumeni tumor (Li-Fraumeni) Tumors, mesenteric cancers (e.g., omental cancer, peritoneal cancer), pleural cancers, respiratory cancers (e.g., laryngeal cancer, lung cancer (e.g., squamous cell carcinoma, adenocarcinoma, mesothelioma, non-small cell lung cancer (NSCLC)), tracheal cancer), sarcomas (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcomas (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancers (e.g., melanoma), thymic cancers (e.g., thymoma), or combinations thereof.

[0552] In some implementations, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal carcinoma of the breast), cancer of the central or peripheral nervous system (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligodendroastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), thyroid cancer (e.g., papillary thyroid carcinoma)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., bile duct cancer, colorectal cancer (e.g., colonic adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal cancer). Cancers of the following types of organs include: adenocarcinoma, liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), or stomach cancer (e.g., gastric adenocarcinoma, gastric signet ring cell carcinoma); urogenital cancers (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., clear cell renal carcinoma, papillary renal carcinoma, chromophobe renal carcinoma), prostate cancer (e.g., prostate adenocarcinoma), or testicular cancer (e.g., testicular germ cell tumor); gynecological cancers (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian carcinoma, ovarian serous cystadenocarcinoma), or uterine cancer (e.g., uterine carcinosarcoma, endometrioid carcinoma, uterine serous carcinoma, uterine papillary cystadenocarcinoma). Hematologic malignancies include: uterine cancer (e.g., endometrial cancer), head and neck cancers (e.g., squamous cell carcinoma of the head and neck), hematologic malignancies (e.g., lymphomas such as Hodgkin lymphoma (e.g., nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)), non-Hodgkin lymphomas (e.g., B-cell lymphoproliferative and lymphomas such as mature B-cell tumors such as Burkitt lymphoma (BL), large B-cell lymphomas such as diffuse large B-cell lymphoma without specific indications (DLBCL-NOS), T-cell-rich / histiocytic large B-cell lymphoma, and diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., with MYC and / or B-cell lymphoma). CL2 rearranged HGBCL (HGBCL-MYC / BCL-2), primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL) or high-grade B-cell lymphoma NOS), follicular lymphoma (FL) or transformation of indolent B-cell lymphoma), T-cell and NK-cell lymphoproliferative and lymphoma (e.g., mature T-cell and NK-cell tumors (e.g., mature T-cell and NK-cell leukemias (e.g., adult T-cell leukemia / lymphoma), primary cutaneous T-cell lymphoproliferative and lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g.,Primary cutaneous CD4-positive small or medium-sized T-cell lymphoproliferative disorders, mycosis fungoides, Cézari syndrome; primary cutaneous CD30-positive T-cell lymphoproliferative disorders: lymphomatoid papulosis; primary cutaneous CD30-positive T-cell lymphoproliferative disorders: primary cutaneous anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma; primary cutaneous γ-δ T-cell lymphoma or primary cutaneous peripheral T-cell lymphoma (NOS), peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma) Follicular helper T-cell lymphoma (also known as follicular follicular helper T-cell lymphoma) or nodular T-follicular helper T-cell lymphoma (NOS, also known as follicular helper T-cell lymphoma NOS) or other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS), respiratory system cancers (e.g., lung cancer (e.g., squamous cell carcinoma of the lung, adenocarcinoma of the lung, mesothelioma, non-small cell lung cancer (NSCLC)), sarcomas (e.g., leiomyosarcoma, myxofibrosarcoma), skin cancers (e.g., melanoma), thymic carcinoma (e.g., thymoma), or combinations thereof.

[0553] In some implementations, the cancer is a hematologic malignancy (e.g., lymphoma (e.g., non-Hodgkin's lymphoma (e.g., B-cell lymphoproliferative and lymphoma (e.g., mature B-cell tumors (e.g., large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS) or primary mediastinal large B-cell lymphoma (primary mediastinal LBCL)), follicular lymphoma (FL) or transformation of indolent B-cell lymphoma)), T-cell and NK-cell lymphoproliferative and lymphoma (e.g., mature T-cell and NK-cell tumors (e.g., primary cutaneous T-cell lymphoproliferative and lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disease, mycosis fungoides)). Buergerian disease or Cezari syndrome) or peripheral T-cell lymphoma (PTCL) (e.g., nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)) or other peripheral T-cell lymphoma (e.g., peripheral T-cell lymphoma NOS)), breast cancer, gastrointestinal cancer, brain cancer (e.g., glioblastoma) or lung cancer (e.g., NSCLC).

[0554] In some implementations, the cancer is a mature B-cell tumor (e.g., chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Burkitt lymphoma (BL), large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), T-cell-rich / histiocytic large B-cell lymphoma, diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL), or high-grade B-cell lymphoma NOS (HBGCL-NOS), follicular lymphoma (FL), mantle cell lymphoma (MCL), or indolent). Transformation of B-cell lymphoma), peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)), primary cutaneous T-cell lymphoproliferative or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disease, mycosis fungoides, Cezari syndrome, or primary cutaneous γ-δ T-cell lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), diffuse histiocytic lymphoma (DHL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or early T-precursor lymphoblastic leukemia.In some implementations, the cancer is a mature B-cell tumor (e.g., BL, large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL or HBGCL-NOS), FL, MCL or transformation of indolent B-cell lymphoma), peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma)). Degenerative large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)), primary cutaneous T-cell lymphoproliferative or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disease, mycosis fungoides, Cezari syndrome or primary cutaneous γ-δ T-cell lymphoma) or ALL (e.g., B-ALL). In some implementations, the cancer is a mature B-cell tumor (e.g., large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL or HBGCL-NOS), FL or transformation of indolent B-cell lymphoma). In some implementations, the cancer is a mature B-cell tumor (e.g., large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL or HBGCL-NOS), FL, MCL or transformation of indolent B-cell lymphoma) or ALL (e.g., B-ALL).In some implementations, the cancer is peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS))).See, for example, Leeman-Neill and Bhagat, Expert Opinion on Therapeutic Targets 22.2 (2018): 143-152, doi:10.1080 / 14728222.2018.1420782; Mlynarczyk and Melnick. Immunological Reviews 288.1 (2019): 214-239, doi: 10.1111 / imr.12755; Hurtz, Christian et al., Journal of Experimental Medicine 208.11 (2011): 2163-2174, doi: 10.1084 / jem.20110304; Deb, Dhruba et al., Cancer Research 77.11 (2017): 3070-3081, doi: 10.1158 / 0008-5472.CAN-15-3052; Cardenas, Mariano G. et al., Clinical Cancer Research 23.4(2017): 885-893, doi: 10.1158 / 1078-0432.CCR-16-2071; Walker, Sarah R et al., Oncogene 34.9 (2015): 1073-1082, doi: 10.1038 / onc.2014.61; see, for example, Alaggio, Rita et al., Leukemia 36.7 (2022): 1720-1748, doi: 10.1038 / s41375-022-01620-2; Paik, Jin Ho et al., Human Pathology 131 (2023): 47-60, doi: 10.1016 / j.humpath.2022.12.003; and international publications WO 2021 / 080950, WO 2021 / 077010 and WO 2022 / 221673.

[0555] In some implementations, the cancer is non-Hodgkin lymphoma (e.g., mature B-cell tumors (e.g., chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Burkitt lymphoma (BL), large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL), or high-grade B-cell lymphoma NOS (HBGCL-NOS)), follicular lymphoma (FL), mantle cell lymphoma (MCL), or indolent B-cell lymphoma). Transformation of lymphoma), peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)) or primary cutaneous T-cell lymphoproliferative or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disease, mycosis fungoides, Cezari syndrome or primary cutaneous γ-δ) In some embodiments, the non-Hodgkin lymphoma is B-cell non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is CD20 positive. In some embodiments, the non-Hodgkin lymphoma is CD20 positive B-cell non-Hodgkin lymphoma. In some embodiments, the subject has not previously been treated for non-Hodgkin lymphoma. In some embodiments, the subject has previously received chemotherapy. In some embodiments, the subject has previously been treated with rituximab or oxetuzumab as monotherapy or in combination with other therapies or treatments. In some embodiments, the subject has previously been treated with rituximab as monotherapy or in combination with other therapies or treatments. In some embodiments, the subject has previously been treated with oxetuzumab as monotherapy or in combination with other therapies or treatments. In some embodiments, the subject has previously been treated with R-CHOP (RITUXAN). ® (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) or G-CHOP (GAZYVA)® (Ostuzumab), cyclophosphamide, daunorubicin, vincristine, and prednisone). In some cases, the subject had previously been treated with etoposide and R-CHOP (called R-EPOCH). In some cases, the subject had previously been treated with R-CHOP in combination with lenalidomide, venetoclax, ibrutinib, acalabrutinib, ostuzumab, polotuzumab, pembrolizumab, durvalumab, or motuzumab. In some implementations, the subject had previously been treated with cyclophosphamide, vincristine, and prednisone (CVP) with or without rituximab or ostuzumab. In some implementations, the subject had received first-line or multiple-line systemic therapy. In some implementations, the subject had received second-line or multiple-line systemic therapy. In some implementations, the subject has previously been treated with cell-based therapies (e.g., adoptive cell therapies (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (CAR-modified NK cells)) or antibody-armed cell therapy). In some implementations, the non-Hodgkin lymphoma is non-progressive (including stable disease) non-Hodgkin lymphoma. In some implementations, the non-Hodgkin lymphoma is relapsed or refractory non-Hodgkin lymphoma. In some implementations, the subject is a subject who has relapsed or is refractory to a rituximab-containing regimen. In some implementations, the subject is a subject who has relapsed or is refractory to an oxtuzumab-containing regimen. In some such implementations, treatment efficacy can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some implementations, the cancer is non-Hodgkin's lymphoma, and the compounds provided herein or their pharmaceutically acceptable salts are administered as a monotherapy.

[0556] In some implementations, the cancer is a large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL, or HBGCL-NOS). In some implementations, DLBCL (e.g., DLBCL-NOS) is characterized by BCL2 translocation, BCL6 translocation, CD79B mutation (e.g., H225Y, A205D, Y196del, Y196F, Y196D, Y207X, Y196N, A205fs, Y196S, Y196H, A205fs, T206fs, H194_E197delinsQ, E197G, K219T, E192fs, or Y196C), EZH2 mutation (e.g., Y646F, Y646N, A682G, or A692V mutation), MYC translocation, MYD88 mutation (e.g., L265P mutation), and NOTCH1 mutation (e.g., Q2394X, Q2501X, Q2...). 459X, Y2490X, G2427fs, Q2444X, P2514fs or P2517S), NOTCH2 mutations (e.g. Q2285K, S2136fs, Q2361X, P2288fs, L2415fs, G2410fs, Q2409X, S2388X, I2304fs, Q2364X, Q236 0fs, S2395X, E2261fs, M2267fs, Q2285fs, R2400X, P2303fs, Q2285fs, A2273fs, K2133fs, Q2389X, E2399X, E2290X, Q2325X, Y2340X, Y2392X or E2411fs), TP53 mutations (e.g.,R181C, E336A, R248W, P98fs, P152L, R280I, S149fs, P151H, G245D, Y236D, S127F, A 161T, D148fs, M246I, Y126C, H179R, A159P, C238G, L93fs, Y220C, R283fs, G244D, G2 45S, E171X, R209X, T155_R156dup, E271K, R306X, G105D, L93fs, G262V, W53X, G244 V, H214Y, R282W, R337C, Q331fs, R273G, R273C, C176Y, S215R, R213Q, I195T, G245R, I232T, R175H, Y126D, R273H, R196X, Y205C, C141Y, C229X, Y126N, P278S, P151S, Y2 36H, R282G, Y103X, V216M, G244S, G266E, V173A, V173fs, I254S, T125M, R342X, P152 fs, Y205D, V274L, L257P, C135Y, C176R, Y234N, R248Q, G244R, Y234H, R248G, M237I, R213X, E258D, V173M, L252_I254del, L252I, Y234C or C176F), 17p missing, 18q gain or combinations thereof. In some implementations, DLBCL (e.g., DLBCL-NOS) has BCL6 rearrangements, NOTCH2 mutations (e.g., Q2285K, S2136fs, Q2361X, P2288fs, L2415fs, G2410fs, Q2409X, S2388X, I2304fs, Q2364X, Q2360fs, S2395X, E2261fs, M2267fs, Q2285fs, R2400X, P2303fs, Q2285fs, A2273fs, K2133fs, Q2389X, E2399X, E2290X, Q2325X, Y2340X, Y2392X, E2411fs) or combinations thereof. In some embodiments, large B-cell lymphoma (e.g., DLBCL-NOS) is a large B-cell lymphoma originating from germinal center B-cell (GCB) cells. In some embodiments, large B-cell lymphoma (e.g., DLBCL-NOS) is a BN2 type large B-cell lymphoma (e.g., with BCL6 rearrangement and / or NOTCH2 mutation). In some embodiments, large B-cell lymphoma (e.g., DLBCL-NOS) is an EZB type large B-cell lymphoma (e.g.,(Having EZH2 mutations and / or BCL2 translocations). In some embodiments, large B-cell lymphoma (e.g., DLBCL-NOS) is C1 gene cluster large B-cell lymphoma (e.g., having BCL6 rearrangements and / or NOTCH2 mutations). For additional descriptions of these classifications, see, for example, Schmitz, Roland et al., New England Journal of Medicine 378.15 (2018): 1396-1407, doi: 10.1056 / NEJMoa1801445; Chapuy, Bjoern et al., Nature Medicine 24.5 (2018):679-690, doi: 10.1038 / s41591-018-0016-8.

[0557] In some embodiments, the cancer is FL. In some embodiments, the FL has a BCL2 translocation (e.g., t(14;18) translocation). In some embodiments, the FL has an EZH2 mutation (e.g., Y646F, Y646N, A682G, or A692V mutation). See, for example, Kridel, Robert, Laurie H. Sehn, and Randy D. Gascoyne. The Journal of Clinical Investigation 122.10 (2012): 3424-3431, doi: 10.1172 / JCI63186. In some embodiments, the cancer is FL, and the compounds provided herein or their pharmaceutically acceptable salts are administered as a monotherapy.

[0558] In some implementations, the cancer is B-ALL. In some implementations, B-ALL has MLL rearrangements (e.g., MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion), is pre-B cell receptor positive (pre-BCR+), has a Philadelphia chromosome, is Philadelphia chromosome-like, depends on Ras signaling, has BCL2 amplification, has JAK2 mutations (with or without high cytokine receptor-like factor 2 (CRLF2) expression), or a combination thereof. See, for example, Knight, Thomas, and Julie Anne Elizabeth Irving. Frontiers in Oncology 4(2014): 160, doi: 10.3389 / fonc.2014.00160; Geng, Huimin et al. Cancer Cell 27.3(2015): 409-425, doi: 10.1016 / j.ccell.2015.02.003; Jain, Nitin et al. Blood, 129.5(2017): 572-581, doi: 10.1182 / blood-2016-07-726588; and Hurtz, Christian et al. Genes & Development 33 (2019): 1265-1279, doi: 10.1101 / gad.327593.119. In some embodiments, the cancer is B-ALL, and the compound provided herein or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, the compound provided herein or a pharmaceutically acceptable salt thereof is used to treat a subject with B-ALL. In some embodiments, B-ALL is relapsed or refractory B-ALL following second- or multiple lines of systemic therapy.

[0559] In some implementations, the subject has previously been treated with another anticancer agent, chemotherapy agent, surgery, radiation, multikinase inhibitor, or a combination thereof.

[0560] In some implementations, the cancer is a large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL, or HBGCL-NOS). In some implementations, the subject has not previously been treated for large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL, or HBGCL-NOS). In some implementations, the subject has previously received chemotherapy. In some embodiments, the subject has previously been treated with rituximab or oxetuzumab as monotherapy or in combination with other therapies or treatments. In some embodiments, the subject has previously been treated with rituximab as monotherapy or in combination with other therapies or treatments. In some embodiments, the subject has previously been treated with oxetuzumab as monotherapy or in combination with other therapies or treatments. In some embodiments, the subject has previously been treated with lenalidomide in combination with rituximab or oxetuzumab. In some embodiments, the subject has previously been treated with cyclophosphamide, vincristine, and prednisone (CVP), optionally in combination with rituximab or oxetuzumab. In some embodiments, the subject has previously been treated with R-CHOP (RITUXAN). ® (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) or G-CHOP (GAZYVA) ®(Octuzumab), cyclophosphamide, daunorubicin, vincristine, and prednisone). In some cases, the subject has previously been treated with etoposide and R-CHOP (called R-EPOCH). In some cases, the subject has previously been treated with R-CHOP in combination with lenalidomide, venetoclax, ibrutinib, acalabrutinib, octuzumab, polotuzumab, pembrolizumab, durvalumab, or motuzumab. In some implementations, the subject has previously been treated with a regimen containing rituximab. In some implementations, the subject has previously been treated with a regimen containing octuzumab. In some implementations, the subject has previously been treated with a regimen containing motuzumab. In some implementations, the subject has previously been treated with a regimen containing icoretuzumab. In some implementations, the subject has received first-line or multiple-line systemic therapy. In some implementations, the subject has received second-line or multiple-line systemic therapy. In some implementations, the subject has previously been treated with cell-based therapies (e.g., adoptive cell therapies (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (CAR-modified NK cells)) or antibody-armed cell therapy). In some implementations, large B-cell lymphomas (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL, or HBGCL-NOS) are non-progressive (including stable disease) LBCLs. In some implementations, large B-cell lymphomas (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL, or HBGCL-NOS) are relapsed or refractory LBCLs. In some implementations, the subject is a subject who has relapsed or is refractory to a rituximab-containing regimen. In some implementations, the subject is a subject who has relapsed or is refractory to an oxutuzumab-containing regimen. In some such implementations, treatment efficacy can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof.In some implementations, the cancer is a large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL, or HBGCL-NOS), and the compound provided herein or a pharmaceutically acceptable salt thereof is administered as a single treatment. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used to treat subjects with large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL, or HBGCL-NOS). In some implementations, large B-cell lymphomas (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site LBCL, primary mediastinal LBCL, or HBGCL-NOS) are LBCLs that have relapsed or are refractory after second- or multiple lines of systemic therapy.

[0561] In some implementations, the cancer is FL. In some implementations, the subject has not previously received treatment for FL. In some implementations, the subject has previously received chemotherapy. In some implementations, the subject has previously been treated with rituximab or oxetuzumab as monotherapy or in combination with other therapies or treatments. In some implementations, the subject has previously been treated with rituximab as monotherapy or in combination with other therapies or treatments. In some implementations, the subject has previously been treated with oxetuzumab as monotherapy or in combination with other therapies or treatments. In some implementations, the subject has previously been treated with rituximab or oxetuzumab as monotherapy. In some implementations, the subject has previously been treated with bendamustine in combination with rituximab or oxetuzumab. In some implementations, the subject has previously been treated with lenalidomide in combination with rituximab or oxetuzumab (the combination of lenalidomide and rituximab is sometimes referred to as "R"). 2In some implementations, the subject has previously received cyclophosphamide, vincristine, and prednisone (CVP), optionally in combination with rituximab or oxotuzumab. In some implementations, the subject has previously received R-CHOP or G-CHOP. In some implementations, the subject has received first-line or multiple lines of systemic therapy. In some implementations, the subject has received second-line or multiple lines of systemic therapy. In some implementations, the subject has previously received cell-based therapies (e.g., adoptive cell therapies (e.g., CAR)). Treatment may include T-therapy, cytokine-induced killer (CIK) cells, natural killer (CAR-modified NK cells), or antibody-armed cell therapy. In some embodiments, non-Hodgkin lymphoma is non-progressive (including stable disease) FL. In some embodiments, FL is relapsed or refractory FL. In some embodiments, the subject is a subject who has relapsed or is refractory to a regimen containing rituximab. In some embodiments, the subject is a subject who has relapsed or is refractory to a regimen containing oxtuzumab. In some such embodiments, treatment efficacy may be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, the cancer is FL, and the compound provided herein or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, the compound provided herein or a pharmaceutically acceptable salt thereof is used to treat a subject with FL. In some embodiments, FL is relapsed or refractory FL after second- or multiple-line systemic therapy.

[0562] In some implementations, the cancer is BL. In some implementations, the subject has not previously received treatment for BL. In some implementations, the subject has previously received chemotherapy. In some implementations, the subject has previously been treated with rituximab or oxetuzumab as monotherapy or in combination with other therapies or treatments. In some implementations, the subject has previously been treated with rituximab as monotherapy or in combination with other therapies or treatments. In some implementations, the subject has previously been treated with oxetuzumab as monotherapy or in combination with other therapies or treatments. In some implementations, the subject has previously been treated with rituximab or oxetuzumab as monotherapy. In some implementations, the subject has previously been treated with bendamustine in combination with rituximab or oxetuzumab. In some implementations, the subject has previously been treated with R-CHOP or G-CHOP. In some implementations, the subject has previously been treated with rituximab, cyclophosphamide, vincristine, doxorubicin, and methotrexate (R-CODOX-M). In some implementations, the subject has previously been treated with rituximab, ifosfamide, etoposide, and cytarabine (R-IVAC). In some implementations, the subject has previously been treated with rituximab in combination with dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH-R). In some implementations, the subject has received first-line or multiple lines of systemic therapy. In some implementations, the subject has received second-line or multiple lines of systemic therapy. In some implementations, the subject has previously been treated with cell-based therapies (e.g., adoptive cell therapies (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (CAR-modified NK cells)) or antibody-armed cell therapy). In some implementations, the BL is non-progressive (including stable disease) BL. In some implementations, the BL is relapsed or refractory BL. In some implementations, the subject is a subject who has relapsed or is refractory to a rituximab-containing regimen. In some embodiments, the subject is a subject who has relapsed or is refractory to a regimen containing oxutuzumab. In some such embodiments, treatment efficacy can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, the cancer is BL, and the compound provided herein or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, the compound provided herein or a pharmaceutically acceptable salt thereof is used to treat a subject with BL. In some embodiments, the BL is BL that has relapsed or is refractory to second- or multiple-line systemic therapy.

[0563] In some implementations, the cancer is peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)) or primary cutaneous T-cell lymphoproliferative or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disease, mycosis fungoides, Cezari syndrome, or primary cutaneous γ-δ) (T-cell lymphoma). In some implementations, the subject has not previously been treated for PTCL or CTCL. In some implementations, the subject has previously received chemotherapy. In some implementations, the subject has previously been treated with rituximab or oxetuzumab as monotherapy or in combination with other therapies or treatments. In some implementations, the subject has previously been treated with rituximab as monotherapy or in combination with other therapies or treatments. In some implementations, the subject has previously been treated with oxetuzumab as monotherapy or in combination with other therapies or treatments. In some implementations, the subject has previously been treated with rituximab or oxetuzumab as monotherapy. In some implementations, the subject has previously been treated with bendamustine in combination with rituximab or oxetuzumab. In some implementations, the subject has previously been treated with lenalidomide in combination with rituximab or oxetuzumab (the combination with rituximab is sometimes referred to as "R"). 2In some embodiments, the subject has previously been treated with cyclophosphamide, vincristine, and prednisone (CVP), optionally in combination with rituximab or oxotuzumab (R-CVP or G-CVP, respectively). In some embodiments, the subject has previously been treated with R-CHOP or G-CHOP. In some embodiments, the subject has received first-line or multiple lines of systemic therapy. In some embodiments, the subject has received second-line or multiple lines of systemic therapy. In some embodiments, the subject has previously received cell-based therapies (e.g., adoptive cell therapies (e.g., CAR)). Treatment may include T-cell therapy, cytokine-induced killer (CIK) cells, natural killer (CAR-modified NK) cells, or antibody-armed cell therapy. In some implementations, PTCL or CTCL is non-progressive (including stable disease) PTCL or CTCL. In some implementations, PTCL or CTCL is relapsed or refractory PTCL or CTCL. In some implementations, the subject is a subject who has relapsed or is refractory to a rituximab-containing regimen. In some implementations, the subject is a subject who has relapsed or is refractory to an oxtuzumab-containing regimen. In some such implementations, treatment efficacy can be assessed by... Progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof, are measured. In some embodiments, the cancer is PTCL or CTCL, and the compound provided herein or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, the compound provided herein or a pharmaceutically acceptable salt thereof is used to treat a subject with PTCL or CTCL. In some embodiments, PTCL or CTCL is relapsed or refractory PTCL or CTCL after second- or multiple-line systemic therapy.

[0564] In some embodiments, the cancer is B-ALL. In some embodiments, the B-ALL is Philadelphia chromosome-positive B-ALL. In some embodiments, the B-ALL is Philadelphia chromosome-negative B-ALL. In some embodiments, the subject has previously received chemotherapy. In some embodiments, the subject has previously received at least one cycle of induction, consolidation, intensification, and optional maintenance therapy. In some cases, induction therapy may include anthracyclines, vincristine, corticosteroids, and cyclophosphamide. In some embodiments, the anthracycline is doxorubicin. In some embodiments, the corticosteroid is dexamethasone. In some cases, the combination of doxorubicin, vincristine, dexamethasone, and cyclophosphamide is referred to as CVAD. In some embodiments, induction therapy may also include a tyrosine kinase inhibitor (e.g., a BCR-ABL inhibitor for subjects with the fusion). In some embodiments, induction therapy may also include asparaginase (e.g., for pediatric subjects). In some cases, consolidation therapy may include methotrexate, cytarabine, vincristine, 6-mercaptopurine, 6-thioguanine, cyclophosphamide, and etoposide. In some embodiments, consolidation therapy may also include a tyrosine kinase inhibitor (e.g., a BCR-ABL inhibitor for subjects with the fusion). In some embodiments, consolidation therapy may also include asparaginase (e.g., for pediatric subjects). In some cases, intensification therapy may include anthracyclines, vincristine, corticosteroids, and cyclophosphamide. In some embodiments, intensification therapy may also include a tyrosine kinase inhibitor (e.g., a BCR-ABL inhibitor for subjects with the fusion). In some embodiments, intensification therapy may also include asparaginase (e.g., for pediatric subjects). Typically, pediatric and young adult regimens include higher cumulative doses of asparaginase and vincristine compared to adult regimens, but may have lower cumulative doses of anthracyclines and cyclophosphamide. During any of these cycling phases, anti-CD20 immunotherapy (e.g., rituximab) may be added to subjects expressing the CD20 protein on their cells. See, for example, Muffly, Lori, and Emily Curran. Hematology 2014, the American Society of Hematology Education Program Book 2019.1 (2019): 17-23, doi: 10.1182 / hematology.2019000009. In some implementations, the subject has received first-line or multiple lines of systemic therapy. In some implementations, the subject has received second-line or multiple lines of systemic therapy. In some implementations, B-ALL is relapsed or refractory B-ALL.In some such embodiments, treatment efficacy can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, the cancer is B-ALL, and the compound provided herein or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, the compound provided herein or a pharmaceutically acceptable salt thereof is used to treat a subject with B-ALL. In some embodiments, B-ALL is relapsed or refractory B-ALL after second- or multiple lines of systemic therapy.

[0565] This article also provides a method for treating a subject with cancer, wherein the method includes:

[0566] Administer a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof as a monotherapy or in combination with a first anticancer agent to a subject who has been given one or more doses of a first anticancer agent for a period of time.

[0567] This article also provides a method for treating a subject with cancer, wherein the method includes:

[0568] (a) administering one or more doses of a first anticancer agent to the subject for a period of time; and

[0569] (b) Following (a), administer to the subject a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof as a monotherapy or in combination with a first anticancer agent.

[0570] This article also provides a method for treating a subject with cancer, wherein the method includes:

[0571] (a) administering one or more doses of a first anticancer agent to the subject for a period of time; and

[0572] (b) Following (a), administer to the subject a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof as a monotherapy or in combination with a second anticancer agent.

[0573] In some embodiments of any of the methods for treating cancer provided herein, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject qd (once daily). In some embodiments of any of the methods for treating cancer provided herein, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject bid (twice daily). In some embodiments of any of the methods for treating cancer provided herein, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject tid (three times daily). In some embodiments of any of the methods for treating cancer provided herein, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject qid (four times daily). In some embodiments of any of the methods for treating cancer provided herein, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject qod (every other day). In some embodiments of any of the methods for treating cancer provided herein, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject q.week (once weekly). In some embodiments of any of the methods for treating cancer provided herein, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject biw (twice weekly). In some embodiments of any of the methods for treating cancer provided herein, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject tiw (three times weekly).

[0574] BCL6 activity is also associated with autoimmunity. See, for example, Li, Qing et al., *European Journal of Immunology* 50.4 (2020): 525-536, doi: 10.1002 / eji.201948299; Pearce, Andrew C. et al., *Journal of Biological Chemistry* 297.2 (2021): 100928, doi: 10.1016 / j.jbc.2021.100928; Venkatadri, Rajkumar et al., *European Journal of Immunology* 52.5 (2022): 825-834, doi: 10.1002 / eji.202149324; Patel, Preeyam S. et al., *Science Advances* 8.25 (2022): eabo1782, doi: 10.1126 / sciadv.abo1782; Ding, Shu, YuRao, and Qianjin Lu. Cellular & Molecular Immunology 19 (2022): 863-865, doi:10.1038 / s41423-022-00882-1. Therefore, this article also provides a method for treating or preventing an autoimmune disease or condition in a subject of need, comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof.

[0575] This document provides for the use of the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment or prevention of autoimmune diseases or conditions (e.g., any autoimmune diseases or conditions described herein).

[0576] This article provides for the use of the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines for the treatment or prevention of autoimmune diseases or conditions (e.g., any autoimmune diseases or conditions provided herein).

[0577] This article provides for the use of the compounds described herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment or prevention of autoimmune diseases or conditions (e.g., any autoimmune diseases or conditions described herein).

[0578] This article provides for compounds or pharmaceutically acceptable salts thereof provided herein, or pharmaceutical compositions thereof, used as medicines for the treatment or prevention of autoimmune diseases or conditions (e.g., any autoimmune diseases or conditions provided herein).

[0579] This article provides information on the use of compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment or prevention of autoimmune diseases or conditions (e.g., any autoimmune diseases or conditions provided herein).

[0580] In some implementations, autoimmune diseases or conditions include acquired hemophilia, Addison's disease, ankylosing spondylitis, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA vasculitis), antisynthetic enzyme syndrome, atherosclerosis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune sclerosing cholangitis, autoimmune thyroiditis, autoimmune uveitis, Crohn's disease, dermatomyositis, diffuse scleroderma, Goodpasture's syndrome, graft-versus-host disease (GVHD) (e.g., chronic graft-versus-host disease (cGVHD)), Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and Hughes' syndrome. Autoimmune diseases include: IgG4-related diseases, immune thrombocytopenic purpura (ITP), inflammatory bowel disease, localized scleroderma, multiple sclerosis, myasthenia gravis (MG), neuromyelitis optica spectrum disorders (NMOSD) (e.g., neuromyelitis optica (NMO)), bullous pemphigoid, pemphigus, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, seronegative spondyloarthritis, Sjögren's syndrome, systemic lupus erythematosus, thrombocytopenic purpura, type 1 diabetes mellitus, ulcerative colitis, leukoplakia, or combinations thereof. In some embodiments, the autoimmune disease or symptom is rheumatoid arthritis, systemic lupus erythematosus, or combinations thereof. In some embodiments, the autoimmune disease or symptom is ANCA vasculitis, GVHD (e.g., cGVHD), myasthenia gravis, NMO, or combinations thereof. In some embodiments, the autoimmune disease or condition is ANCA vasculitis, antisynthetic enzyme syndrome, arthritis (e.g., rheumatoid arthritis or inflammatory arthritis), GVHD (e.g., cGVHD), IgG4-RD, lupus (e.g., systemic lupus erythematosus), ITP, MG (e.g., muscle-specific tyrosine kinase (MuSK) positive MG), MS, NMOSD (e.g., NMO), pemphigus (e.g., pemphigus vulgaris), Sjögren's syndrome, or a combination thereof.In some implementations, the autoimmune disease or condition is arthritis (e.g., rheumatoid arthritis or inflammatory arthritis), GVHD (e.g., cGVHD), IgG4-RD, lupus (e.g., systemic lupus erythematosus), MG (e.g., muscle-specific tyrosine kinase (MuSK) positive MG), MS, NMOSD (e.g., NMO), pemphigus (e.g., pemphigus vulgaris), Sjögren's syndrome, or a combination thereof. See, for example, Pearce, Andrew C. et al., Journal of Biological Chemistry 297.2 (2021): 100928, doi: 10.1016 / j.jbc.2021.100928; Ding, Shu, Yu Rao, and Qianjin Lu, Cellular & Molecular Immunology (2022): 863–865; doi: 10.1038 / s41423-022-00882-1; Lee, Dennis SW, Olga L. Rojas, and Jennifer L. Gommerman, Nature Reviews Drug Discovery 20.3 (2021): 179-199, doi:10.1038 / s41573-020-00092-2; and international publication WO 2020 / 014599; WO 2021 / 074620.

[0581] In some embodiments of any of the methods provided herein for the treatment or prevention of autoimmune diseases or conditions, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject once daily (qd). In some embodiments of any of the methods provided herein for the treatment or prevention of autoimmune diseases or conditions, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject twice daily (bid). In some embodiments of any of the methods provided herein for the treatment or prevention of autoimmune diseases or conditions, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject three times daily (tid). In some embodiments of any of the methods provided herein for the treatment or prevention of autoimmune diseases or conditions, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject four times daily (qid). In some embodiments of any of the methods provided herein for the treatment or prevention of autoimmune diseases or conditions, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject every other day (qod). In some embodiments of any of the methods provided herein for the treatment or prevention of autoimmune diseases or conditions, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to a subject once weekly (q.week). In some embodiments of any of the methods provided herein for the treatment or prevention of autoimmune diseases or conditions, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to the subject biw (twice a week). In some embodiments of any of the methods provided herein for the treatment or prevention of autoimmune diseases or conditions, the compound provided herein or a pharmaceutically acceptable salt thereof is administered to the subject tiw (three times a week).

[0582] This article also provides a method for treating lymphoproliferative disorders in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof.

[0583] This document provides for the use of the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of lymphoproliferative disorders (e.g., any lymphoproliferative disorders described herein).

[0584] This article provides for the use of the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines for the treatment of lymphoproliferative disorders (e.g., any lymphoproliferative disorders provided herein).

[0585] This article provides for the use of the compounds described herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of lymphoproliferative disorders (e.g., any lymphoproliferative disorders described herein).

[0586] This article provides for compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, which are used as medicines for treating lymphoproliferative disorders (e.g., any lymphoproliferative disorders provided herein).

[0587] This article provides information on the use of compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment of lymphoproliferative disorders (e.g., any lymphoproliferative disorders provided herein).

[0588] In some implementations, lymphoproliferative disorder is EBV-associated lymphoproliferative disorder.

[0589] A method for modulating (e.g., reducing) the activity of the BCL6 protein in cells is also provided, the method comprising contacting the cells with a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is ex vivo. In some embodiments, the contact is in vivo, wherein the method comprises administering to a subject an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer as described herein.

[0590] As used herein, the term “contact” means bringing indicated portions together in an in vitro, in vivo, or ex vivo system. For example, “contacting” cells with a compound provided herein includes applying the compound provided herein to cells in vitro or in vivo, including, for example, introducing the compound provided herein into a sample containing cells (e.g., grown in a culture or derived from a subject), organoids, or organisms (e.g., animals (e.g., tumor-bearing animals) or humans).

[0591] A method for regulating (e.g., reducing) BCL6 protein levels in cells is also provided, the method comprising contacting the cells with a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the BCL6 protein level is reduced by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) compared to cells not contacted with the compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, wherein the method comprises administering an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof to a subject having cells containing BCL6 protein. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer as described herein.

[0592] A method for inducing BCL6 protein ubiquitination in cells is also provided, the method comprising contacting the cells with a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, wherein the method comprises administering an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof to a subject having cells containing BCL6 protein. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer as described herein.

[0593] A method is also provided for forming a ternary complex in cells comprising BCL6 protein, a compound provided herein or a pharmaceutically acceptable salt thereof, and CRBN protein or a fragment thereof, the method comprising contacting the cells with the compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, wherein the method comprises administering an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof to a subject having cells containing BCL6 protein. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer as described herein.

[0594] This article also provides a method for inducing the degradation of BCL6 protein in mammalian cells, the method comprising contacting mammalian cells with an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof.

[0595] This article also provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound provided herein as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0596] This document further provides a method for increasing cell death in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound provided herein as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. This document also provides a method for increasing tumor cell death in a subject, the method comprising administering to the subject an effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof that increases tumor cell death.

[0597] When used as a medicine, the compounds provided herein or their pharmaceutically acceptable salts may be administered in the form of pharmaceutical compositions as described herein.

[0598] combination

[0599] In any of the indications described herein, the compounds provided herein or their pharmaceutically acceptable salts may be used as monotherapy. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts may be administered prior to the administration of additional therapeutic agents or additional therapies. For example, one or more doses of the compounds provided herein or their pharmaceutically acceptable salts may be administered to a subject in need over a period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of the compounds provided herein or their pharmaceutically acceptable salts may reduce the size of the tumor (e.g., tumor burden) prior to at least partial resection of the tumor.

[0600] In some embodiments, one or more doses of the compound provided herein or a pharmaceutically acceptable salt thereof may be administered to a subject in need over a period of time in one or more rounds of radiotherapy. In some embodiments, treatment with one or more doses of the compound provided herein or a pharmaceutically acceptable salt thereof to reduce tumor size (e.g., tumor burden) may be administered prior to one or more rounds of radiotherapy.

[0601] In some embodiments of any of the methods described herein, the compound provided herein or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of at least one other therapeutic agent (e.g., a chemotherapeutic agent).

[0602] Other non-limiting examples of therapeutic agents include: RAS pathway targeted therapeutic agents (e.g., Ras / RAF / MEK / PI3K pathway inhibitors (e.g., Ras inhibitors, KRas targeted therapeutic agents, SOS1 inhibitors, SOS1 / Ras protein-protein interaction inhibitors, SHP2 inhibitors, PI3K-AKT-mTOR pathway inhibitors)), kinase targeted therapeutic agents (e.g., MEK inhibitors, ERK inhibitors, Raf inhibitors (e.g., BRaf inhibitors), PI3K inhibitors, AKT inhibitors, BTK inhibitors, mTOR inhibitors, CDK4 / 5 inhibitors, CDK4 inhibitors). / 6 inhibitors, MET inhibitors, JAK inhibitors (e.g., JAK2 inhibitors), FAK inhibitors, ErbB family inhibitors (e.g., EGFR inhibitors, Her2 inhibitors, Src inhibitors), menin inhibitors, mTORC1 inhibitors, YAP inhibitors, proteasome inhibitors, farnesyltransferase inhibitors, HSP90 inhibitors, PTEN inhibitors, inhibitors of polycomb inhibitory complex 2 (PRC2) (e.g., EZH1 / 2 or EZH2 inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., BCL-2 inhibitors, BCL-X inhibitors). L Inhibitors), XPO1 inhibitors, steroids, chemotherapy agents, angiogenesis-targeted therapies, immune-targeting agents (including immunomodulatory imide drugs (sometimes called "IMiD" or "CELMoD")), immunotherapies (e.g., anti-PD1, anti-PD-L1, anti-CD19, anti-CD20, anti-CD22, anti-CD3, CD30, anti-CD79B, or CD47 therapies), including antibodies (e.g., single-target antibodies targeting one or more of PD1, PD-L1, CD19, CD20, CD22, CD3, CD30, CD79B, or CD47), Bispecific antibodies (including bispecific T-cell adaptors (BiTE)) or antibody-drug conjugates (ADCs) incorporating one or more of PD1, PD-L1, CD19, CD20, CD22, CD3, CD30, CD79B or CD47, or their antigen-binding fragments, PD-1 inhibitors or PD-L1 inhibitors, cell-based therapeutics (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy), and radiotherapy.

[0603] As used herein, a biosimilar antibody is an antibody or antigen-binding fragment that has the same primary amino acid sequence as a reference antibody and optionally may have detectable differences in post-translational modifications (e.g., glycosylation and / or phosphorylation) compared to the reference antibody (e.g., a different glycoform).

[0604] In some implementations, additional therapeutic agents are PI3K inhibitors, Abl inhibitors (e.g., BCR-Abl inhibitors), BTK inhibitors, JAK inhibitors (e.g., JAK2 inhibitors), BRaf inhibitors, MEK inhibitors, menin inhibitors, BCL-2 inhibitors, and BCL-X inhibitors. L Inhibitors, MCL-1 inhibitors, XPO1 inhibitors, inhibitors of polycomb inhibitory complex 2 (e.g., EZH1 / 2 or EZH2 inhibitors), immunomodulatory imide drugs, steroids, anti-CD19 therapy, anti-CD20 therapy, anti-CD3 therapy, chemotherapy, or combinations thereof.

[0605] Unbound by any particular theory, it is believed that targeting BCL6 can lead to the induction of genes it normally suppresses, such as BCL2. In some implementations, additional therapeutic agents are BCL-2 inhibitors (e.g., foselutoclax (UBX-1325), lacutoclax, lisaftoclax, navitoclax, obatoclax, pelcitoclax, venetoc, sonrotoclax (BGB-11417), surzetoclax, oblimersen (e.g., oblimersen), beclanorsen, AZD-0466, ICP-248, TQB-3909, UBX-1967, ZN-d5, or combinations thereof).

[0606] In some implementations, PI3K inhibitors are alpelisib (BYL719), amdizalisib, apitolisib (GDC-0980), bimilisib, buparlisib (BKM120), and copanlisib (ALIQOPA). ™BAY80-6946 (e.g., cupanniside dihydrochloride or cupanniside dihydrochloride hydrate), dactolisib (NVP-BEZ235, BEZ-235), dezapelisib, dordaviprone, duvelisib (e.g., duvelisib hydrate), eganelisib, fimepinostat, gedatolisib (PF-05212384, PKI-587), idelalisib, inavolisib, lenilisib Niolisib (e.g., niolisib phosphate), linperlisib, omipalisib (GSK2126458, GSK458), parsaclisib, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), paxalisib, rigosertib, risovalisib, seletalisib, serabelisib (TAK-117, MLN1117, INK) 1117), Sonolisib (PX-866), Taselisib (GDC-0032, RG7604), Umbralisib (e.g., Umbralisib tosylate), Voxtalisib (XL756, SAR245409), Wortmannin, Zandelisib, AMG 511, AMG319, ASN003, AZD8835, BGT-226 (NVP-BGT226), CH5132799, CUDC-907, GDC-0077, GDC-0084 (RG7666), GS-9820, GSK1059615, GSK2636771, KIN-193 (AZD-6428), LY2023414, LY294002, PF-04691502, PI-103, PKI-402, PQR309, SAR260301, SF1126, SHC-014748-M, TQ-B-3525, VS-5584 (SB2343), WX-037, XL-765, ZSTK474 or combinations thereof.In some implementations, the PI3K inhibitors are apelelisib, amdizalisib, appitolizib, bimiralisib, bupanisib, cupanisib (e.g., cupanisib dihydrochloride or cupanisib dihydrochloride hydrate), datolizib, dezapelisib, dordaviprone, duvelisib (e.g., duvelisib hydrate), eganelisib, fimepinostat, gidalisib, idelalisib, and inalisib. Navolisib), leniolisib (e.g., leniolisib phosphate), linperlisib, parsaclisib, paxalisib, risovalisib, seletalisib, seletalisib, sonolisib, tenalisib, umbralisib (e.g., umbralisib tosylate), zandelisib, PF-04691502, SHC-014748-M, TQ-B-3525, or combinations thereof.

[0607] In some implementations, the Abl inhibitor (e.g., a BCR-Abl inhibitor) is aciminib (e.g., aciminib hydrochloride), bafetinib, bosutinib (e.g., bosutinib monohydrate), danusertib, dasatinib (e.g., dasatinib monohydrate), flumatinib (e.g., flumatinib mesylate), imatinib (e.g., imatinib mesylate), nilotinib (e.g., ... Examples include nilotinib monochloride hydrate, olverembatinib (e.g., olverembatinib mesylate), ponatinib (e.g., ponatinib hydrochloride), radotinib (e.g., radotinib dihydrochloride), risvodetinib (IkT-148009), ruserontinib, vamotinib, vandetanib, AN-019, AT-9283, NPB-001-056, or combinations thereof.

[0608] In some embodiments, the cancer is B-ALL, and the additional therapy or treatment is an Abl inhibitor. In some embodiments, the cancer is Philadelphia chromosome-positive B-ALL, and the additional therapy or treatment is an Abl inhibitor. In some embodiments, the cancer is Philadelphia chromosome-like B-ALL, and the additional therapy or treatment is an Abl inhibitor. In some embodiments, the Abl inhibitor is selected from the group consisting of imatinib, dasatinib, ponatinib, or combinations thereof.

[0609] In some implementations, the BTK inhibitors are abivertinib, acalabrutinib, atuzabrutinib, branebrutinib, dasatinib (e.g., dasatinib monohydrate), edralbrutinib (SHR-1459), elsubrutinib, evobrutinib, fenebrutinib, ibrutinib, luxeptinib, nemtabrutinib, olafertinib, orelabrutinib, and pitubrutinib. Pirtobrutinib, remibrutinib, rilzabrutinib, spebrutinib, sunvozertinib, tirabrutinib (e.g., tirabrutinib hydrochloride), tolebrutinib, vecabrutinib, zanubrutinib, AC-0058 (AC-0058TA), BMS-986142, CT-1530, DTRMWXHS-12, LY-3337641 (HM-71224), M-7583, TAS-5315, or combinations thereof. In some implementations, the BTK inhibitor is avitinib, acalabrutinib, aturubrutinib, brumbutinib, dasatinib (e.g., dasatinib monohydrate), edabrutinib, elsutinib, evobrutinib, fenrerutinib, ibrutinib, nemetabutinib, orelabrutinib, pitubrutinib, remibrutinib, rizabrutinib, locbrutinib, sipebrutinib, suvortinib, telarabrutinib (e.g., telarabrutinib hydrochloride), torebrutinib, zanubrutinib, AC-0058, BIIB-091, BMS-986142, DTRMWXHS-12, LY-3337641, TAS-5315, TL-925, or combinations thereof.

[0610] In some embodiments, the cancer is B-ALL, and the additional therapy or treatment agent is a BTK inhibitor. In some embodiments, the cancer is pre-BCR+ B-ALL, and the additional therapy or treatment agent is a BTK inhibitor. In some embodiments, the cancer is Ras signaling-dependent B-ALL, and the additional therapy or treatment agent is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or acalabrutinib.

[0611] In some implementations, JAK inhibitors are abrocitinib, baricitinib, brepocitinib, decernotinib, delgocitinib, deuruxolitinib, elsutinib, fedratinib (e.g., fedratinib dihydrochloride monohydrate), filgotinib (e.g., filgotinib maleate), gandotinib, gusacitinib, ilginatinib, itacitinib, ivarmacitinib, izencitinib, jaktinib, molotinib, nezulcitinib, and pacritinib. Nib (e.g., paffininib citrate), peficitinib (e.g., peficitinib hydrobromide), povorcitinib (INCB-54707), ropsacitinib, ruxolitinib (e.g., ruxolitinib phosphate), socitinib, tasocitinib (e.g., tofacitinib citrate), tengotinib (tinengotinib), upadacitinib (e.g., upadacitinib hydrate), zasocitinib, AGA-201, ATI-1777, ATI-501, ESK-001, GLPG-3667, INCB-52793, LNK-01001, LNK-01003, R-348, TD-8236, TLL-018, TQ-05105, VTX-958, or combinations thereof.In some implementations, the JAK inhibitors are abuxitinib, baricitinib, brecitinib, decetinib, digotinib, deuterated ruxolitinib, fendatinib (e.g., fendatinib dihydrochloride monohydrate), fenogertinib (e.g., fenogertinib maleate), tucatinib, golidocitinib, gousartinib, erginatinib, itatinib, imaxitinib, isentinib, jaktinib, lepzacitinib (ATI-1777), londamocitinib, molotinib, nezucitinib, pacitinib (e.g., pacitinib citrate), piracetinib (e.g., piracetinib hydrobromide), povaxitinib (INCB-54707), and litharge. ritlecitinib (e.g., ritlecitinib tosylate), tasoxitinib, roxatinib, ruxolitinib (e.g., ruxolitinib phosphate), soxitinib, tofacitinib (e.g., tofacitinib citrate), tengotinib, utpatinib (e.g., utpatinib hydrate), zanoxitinib, AGA-201, ATI-501, CPL-409116, ESK-001, GLPG-3667, LNK-01001, LNK-01003, KL-130008, NS-229, R-348, TD-8236, TDM-180935, TLL-018, TQ-05105, VC-005, VTX-958, VVN-461, or combinations thereof.

[0612] In some implementations, the JAK2 inhibitor is adelatinib, baricitinib, brecitinib, deuterated ruxotinib, feidatinib (e.g., feidatinib dihydrochloride monohydrate), feigortinib (e.g., feigortinib maleate), tucatinib, gousatinib, iginatinib, isentinib, jaktinib, molotinib (e.g., molotinib dihydrochloride), nezucitinib, paktinib (e.g., paktinib citrate), piracetinib (e.g., piracetinib hydrobromide), roxatinib, ruxoritinib (e.g., ruxoritinib phosphate), tasoxitinib (e.g., tofacitinib citrate), AT-9283, CPL-409116, KL-130008, TQ-05105, or a combination thereof.

[0613] In some implementations, the cancer is B-ALL, and the additional therapy or treatment agent is a JAK inhibitor. In some implementations, the cancer is JAK2 (e.g., JAK2...). R683G or JAK2 I682F The cancer is a mutant B-ALL, and the additional therapy or treatment is a JAK inhibitor. In some implementations, the cancer is JAK2 with high CRLF2 expression (e.g., JAK2).R683G or JAK2 I682F Mutant B-ALL, and the additional treatment or therapeutic agent is a JAK inhibitor (e.g., a JAK2 inhibitor) and a BCL-2 inhibitor (e.g., venetoclax).

[0614] In some implementations, BRaf inhibitors are avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), and encorafenib (e.g., BRAFTOVI). ™ LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF) ® The BRaf inhibitors are: RO5185426, ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, PLX-4720, or combinations thereof. In some embodiments, the BRaf inhibitor is avotometinib, dabrafenib (e.g., dabrafenib mesylate), cannefenib, naponafenib, sorafenib (e.g., sorafenib tosylate), vemurafenib, C17071479-F, CHIR-265, FORE-8394, HLX-208, or combinations thereof.

[0615] In some embodiments, the MEK inhibitor is avotometinib, bimetinib, cobimetinib (e.g., cobimetinib fumarate), mirdametinib, nedometinib, pimasertib, refametinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide, GSK-1120212), tunlametinib, zapnometinib, FCN-159, NFX-179, TAK-733, or combinations thereof. In some embodiments, the MEK inhibitor is a MEK-Raf protein-protein interaction stabilizer, such as NST-628 or avotometinib (VS6766).

[0616] In some implementations, the menin inhibitor is revumenib (e.g., revumenib fumarate), icovamenib (BMF-219), ziftomenib, DS-1594, DSP-5336, HMPL-506, JNJ-6617, or a combination thereof.

[0617] In some implementations, the cancer is B-ALL, and the additional therapy or treatment agent is a menin inhibitor. In some implementations, the cancer is MLL rearrangement (e.g., MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion) B-ALL, and the additional therapy or treatment agent is a menin inhibitor.

[0618] In some embodiments, the BCL-2 inhibitor is foskra (UBX-1325), levotrac, lissatoprac, navitoc, obacara, persitoc, venetoc, sotoprac (BGB-11417), suzekra, olimosen (e.g., olimosenna), belanoxen, AZD-0466, ICP-248, TQB-3909, UBX-1967, ZN-d5, or combinations thereof. In some embodiments, the BCL-2 inhibitor is foskra (UBX-1325), lissatoprac, navitoc, obacara, persitoc, venetoc, sotoprac, olimosen (e.g., olimosenna), belanoxen, or combinations thereof.

[0619] In some embodiments, the cancer is B-ALL, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some embodiments, the cancer is MLL rearrangement-related (e.g., MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion) B-ALL, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some embodiments, the cancer is BCL2-amplified B-ALL, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is venetoc.

[0620] In some implementations, the cancer is a transformation of diffuse large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL), or high-grade B-cell lymphoma NOS (HBGCL-NOS)), follicular lymphoma (FL), mantle cell lymphoma (MCL), or indolent B-cell lymphoma, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some embodiments, the cancer is a large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL), or high-grade B-cell lymphoma NOS (HBGCL-NOS)), and the additional therapy or treatment agent is a BCL-2 inhibitor. In some embodiments, the cancer is a transformation of indolent B-cell lymphoma, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some embodiments, the cancer is DLBCL-NOS, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some implementations, the BCL-2 inhibitor is venetoclax.

[0621] In some implementations, the cancer is FL, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some implementations, the BCL-2 inhibitor is venetoc.

[0622] In some implementations, the cancer is MCL, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some implementations, the BCL-2 inhibitor is venetoc.

[0623] In some implementations, the cancer is T-ALL, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some implementations, the BCL-2 inhibitor is venetoclax.

[0624] In some implementations, BCL-X LThe inhibitors are lissatopella, navittox, obacillus, percitopella, mirzotamab clezutoclax, ABBV-155, APG-1252-12A, AZD-0466, DT-2216, PA-15227, UBX-1325, UBX-1967, XZ-739, 753-B, or combinations thereof. In some embodiments, BCL-X... L Inhibitors are rixatoclax, navittoclax, octaclax, or combinations thereof.

[0625] In some implementations, the MCL-1 inhibitor or degrader is omacetaxine (e.g., omacetaxine succinate), murizatoclax, tapotoclax, ABBV-467, GS-9716, S-64315, or a combination thereof.

[0626] In some embodiments, the XPO1 inhibitor is eltanexor, felezonexor, selinexor, verdinexor, BIIB-100, JS-110, or a combination thereof. In some embodiments, the XPO1 inhibitor is selinexor.

[0627] In some embodiments, the PRC2 inhibitor is lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, SHR-2554, XNW-5004, or combinations thereof. In some embodiments, the PRC2 inhibitor is an EZH1 / 2 inhibitor. In some embodiments, the EZH1 / 2 inhibitor is valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), HH-2853, HM-97662, or combinations thereof. In some embodiments, the PRC2 inhibitor is an EZH2 inhibitor. In some implementations, the EZH2 inhibitor is lilametosat, movastatin, tazestat (e.g., tazestat hydrobromide), EBI-2511, SHR-2554, XNW-5004, or a combination thereof. Non-limiting examples of EZH2 and / or EZH1 / 2 inhibitors are described in international publications WO 2011 / 140325, WO 2012 / 005805, WO 2012 / 050532, WO 2012 / 118812, WO 2012 / 142513, WO 2012 / 142504, WO 2013 / 049770, WO 2013 / 039988, WO 2013 / 067300, WO 2015 / 141616, WO 2017 / 084494, WO 2018 / 210296, WO 2018 / 210302, WO 2019 / 091450, WO 2019 / 204490, WO 2019 / 226491, WO 2020 / 063863, WO 2020 / 171606, WO 2020 / 228591, WO 2021 / 016414, WO 2021 / 063332, WO 2021 / 063340, WO 2021 / 180235, and WO 2022 / 035303.

[0628] In some implementations, the cancer is a transformation of diffuse large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL), or high-grade B-cell lymphoma NOS (HBGCL-NOS)), follicular lymphoma (FL), mantle cell lymphoma (MCL), or indolent B-cell lymphoma, and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some implementations, the cancer is a large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS), diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL), or high-grade B-cell lymphoma NOS (HBGCL-NOS)), and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is HBGCL-NOS, and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is primary mediastinal large B-cell lymphoma, and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor).In some embodiments, the cancer is follicular lymphoma (FL), and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is mantle cell lymphoma (MCL), and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is a transformation of indolent B-cell lymphoma, and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor).

[0629] In some implementations, the cancer is BL, and the additional therapy or treatment is an inhibitor of PRC2 (e.g., an EZH1 / 2 or EZH2 inhibitor).

[0630] In some implementations, the cancer is NLPHL, and the additional therapy or treatment is an inhibitor of PRC2 (e.g., an EZH1 / 2 or EZH2 inhibitor).

[0631] In some embodiments, the cancer is B-ALL (e.g., Philadelphia chromosome-positive B-ALL, Philadelphia chromosome-negative B-ALL, or B-ALL with MLL rearrangements (e.g., MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion)), and the additional therapy or treatment is a PRC2 inhibitor. In some embodiments, the cancer is FL, and the additional therapy or treatment is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is MCL, and the additional therapy or treatment is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor).

[0632] In some implementations, the cancer is peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)) or primary cutaneous T-cell lymphoproliferative or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disease, mycosis fungoides, Cezari syndrome, or primary cutaneous γ-δ) In some implementations, the cancer is peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS))), and the additional therapy or treatment agent is an inhibitor of PRC2 (e.g., EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor).In some embodiments, the cancer is nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)), and the additional therapy or therapeutic agent is a PRC2 inhibitor (e.g., EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma), and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is nodular T-follicular helper cell lymphoma (NOS) (also known as follicular helper T-cell lymphoma NOS), and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is primary cutaneous T-cell lymphoproliferative disorder or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, Cezari syndrome, or primary cutaneous γ-δ T-cell lymphoma), and the additional therapy or treatment agent is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some implementations, the cancer is mycosis fungoides, and the additional therapy or treatment is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some implementations, the cancer is Cezari syndrome, and the additional therapy or treatment is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor).

[0633] An exemplary wild-type human EZH2 sequence is shown below. This is one of several isotypes of EZH2, and it should be understood that residue numbering can be changed based on a reference isotype.

[0634] SEQ ID NO: 1 (UniParc ID UPI000006D77C):

[0635] MGQTGKKSEKGPVCWRKRVKSEYMRLRQLKRFRRADEVKSMFSSNRQKILERTEILNQEWKQRRIQPVHILTSVSSLRGTRECSVTSDLDFPTQVIPLKTLNAVASVPIMYSWSPLQQNFMVEDETVLHNIPYMGDEVLDQDGTFIEELIKNYDGKVHGDRECGFINDEIFVELVNALGQYNDDDDD DDGDDPEEREEKQKDLEDHRDDKESRPPRKFPSDKIFEAISSMFPDKGTAEELKEKYKELTEQQLPGALPPECTPNIDGPNAKSVQREQSLHSFHTLFCRRCFKYDCFLHRKCNYSFHATPNTYKRKNTETALDNKPCGPQCYQHLEGAKEFAAALTAERIKTPPKRPGGRRRGRLPNNSSRPSTPTI NVLESKDTSDREAGTETGGENNDKEEEEKKDETSSSSEANSRCQTPIKMKPNIEPPENVEWSGAEASMFRVLIGTYYDNFCAIARLIGTKTCRQVYEFRVKESSIIAPAPAEDVDTPPRKKKRKHRLWAAHCRKIQLKKDGSSNHVYNYQPCDHPRQPCDSSCPCVIAQNFCEKFCQCSSECQNRFP GCRCKAQCNTKQCPCYLAVRECDPDLCLTCGAADHWDSKNVSCKNCSIQRGSKKHLLLAPSDVAGWGIFIKDPVQKNEFISEYCGEIISQDEADRRGKVYDKYMCSFLFNLNNDFVVDATRKGNKIRFANHSVNPNCYAKVMMVNGDHRIGIFAKRAIQTGEELFFDYRYSQADALKYVGIEREMEIP

[0636] In some implementations, the steroid is dexamethasone, prednisone, or a combination thereof.

[0637] In some implementations, the immunomodulatory imide is avadomide, lenalidomide, iberdomide, pomalidomide, thalidomide, CC-99282, or a combination thereof.

[0638] In some implementations, additional therapies or treatments include lenalidomide and rituximab or oxotuzumab.

[0639] In some implementations, the anti-CD19 therapy is blinatumomab (e.g., BLINCYTO). ® (Blintolimab or its biosimilars), coltuximab ravtansine, inebiizumab (e.g., inebiizumab-cdon or its biosimilars), loncastuximab tesirine (e.g., loncastuximab-lpyl or its biosimilars), obexelimab, tafasitamab (e.g., tafasitamab-cxix or its biosimilars), dDT-2219, LY-3541860, their biosimilars, or combinations thereof. In some embodiments, the anti-CD19 therapy is a bispecific antibody or its antigen-binding fragment (e.g., BLINCYTO). ® (Blinc...

Claims

1. A compound of formula (Ic): Formula (Ic) Or its pharmaceutically acceptable salt, wherein: m3 is 1; X 3 It is C 1-3 Alkylene; R 1 It is H; R 2a It is H; R 5 Choose from the following groups: -OH, -NH2, -R 5A -OR 5A and -NR 5A R f ,in: R 5A Choose from the following groups: Optionally by 1 to 3 R c Replacement C 1-6 Alkyl; and -(C 0-3 (alkylene)-R b1 Wherein C 0-3 Alkylene is optionally surrounded by 1 to 2 R c replace; X a Choose from the following groups: N and CR Xa ; R 6 and R Xa Independently select from the following groups: H, halogenated group, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy groups, CN, and -C≡CH; m4 and m5 are independently 0, 1 or 2; Each R a4 and R a5 Choose independently from the following groups: -F, CN, C 1-3 Alkyl groups, OH groups, and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl; L A1 It is CH -2 or CHR L , Where R L Choose from the following groups: -F, -OH, and optionally surrounded by 1 to 3 R groups. c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 -F atoms) 1-3 alkyl); c1 is 0, 1, or 2; R Ya It is arbitrarily selected by 1 to 3 Rs c Replacement C 1-6 alkyl; Each R Yb Choose independently from the following groups: -F and C, which may be replaced by 1 to 3 -F groups. 1-3 alkyl; X is CH; Each R b1 Choose independently from the following groups: C 3-6 Cycloalkyl and 4 to 8-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. g replace; Each R c Independently select from the following groups: halogenated, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e C(=O)C 1-6 Alkyl, C(=O)OC 1-6 Alkyl, C(=O)N(R) f 2. S(O) 0-2 (C 1-6 Alkyl groups and S(O) 0-2 (C- 1-6 (halogenated alkyl); Each R d and R e Independently select from the following groups: H, C (=O)C 1-6 Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Haloalkyl, C(=O)N(R) f 2. S(O) 1-2 (C 1-6 Alkyl groups), S(O) 1-2 (C- 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f )2 and optionally by 1 to 3 R h Replacement C 1-6 alkyl; Each R f Independently select from the following groups: H and optionally selected by 1 to 3 Rs. h Replacement C 1-6 alkyl; Each R g Independently select from the following groups: R h , Oxide group, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and Each R h Independently select from the following groups: halogenated, cyano, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl) and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

2. The compound according to claim 1, wherein the compound is not compound numbered R242, R242a, R242b, R212 or R167 as depicted in Table R1, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein one or more of (1)-(3) are applicable: (1) m4 is 1 or 2, where each R a4 Independently, C is optionally replaced by 1 to 3 Fs. 1-3 alkyl; (2) m5 is 1 or 2; and / or (3) c1 is 1 or 2.

4. The compound according to any one of claims 1 to 3, wherein m4 is 0; and m5 is 0.

5. The compound according to any one of claims 1 to 3, wherein m4 is 1 or 2, wherein each R a4 Independently, C is optionally replaced by 1 to 3 Fs. 1-3 Alkyl group; and m5 is 0.

6. The compound according to any one of claims 1 to 5, wherein L A1 It is CH2.

7. The compound according to any one of claims 1 to 4, wherein Part of it is .

8. The compound according to any one of claims 1 to 3 or 5 to 6, wherein... Part of it is (For example, ).

9. The compound according to any one of claims 1 to 8, wherein c1 is 0.

10. The compound according to any one of claims 1 to 8, wherein c1 is 1 or 2.

11. The compound according to any one of claims 1 to 8 or 10, wherein Some selections are made from the following groups: , and .

12. The compound according to any one of claims 1 to 11, wherein R Ya It is a methyl group.

13. The compound according to any one of claims 1 to 12, wherein each R Yb Yes -F.

14. The compound according to any one of claims 1 to 13, wherein R 5 Yes -NR 5A R f .

15. The compound according to any one of claims 1 to 14, wherein R 5 It is -NH(Me).

16. The compound according to any one of claims 1 to 15, wherein –(X) 3 ) m3 -R 1 It is isopropyl.

17. The compound according to any one of claims 1 to 16, wherein R 6 It is -Cl.

18. The compound according to any one of claims 1 to 17, wherein X a It is N.

19. The compound according to any one of claims 1 to 13, wherein R 5 It is -NH(Me); R 6 It is -Cl; and X a It is N.

20. The compound according to claim 1, wherein the compound of formula (Ic) is selected from the group consisting of compounds numbered 109, 119, 120, 126, 126a, 126b, 127, 127a, 127b, 128, 129, 129a, 129b, 130, 130a, 130b, 133, 134, 138, 138a, 138b, 139, 139a, 139b, 140, 140a and 140b, or pharmaceutically acceptable salts thereof.

21. The compound according to claim 1, wherein the compound of formula (Ic) is selected from the group consisting of: 2-[[6-[[5-chloro-2-[(3S,4S)-4-[[4-[3-(2,6-dioxo-3-piperidinyl)-5-fluoro-1-methyl-indazol-6-yl]-1-piperidinyl]methyl]-3-methyl-1-piperidinyl]pyrimidin-4-yl]amino]-1-isopropyl-2-oxo-1,8-naphthidin-3-yl]oxy]-N-methylacetamide; 2-((6-((5-chloro-2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydro-1,8-naphthidin-3-yl)oxy)-N-methylacetamide; and 2-((6-((5-chloro-2-(4-((4-(3-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)amino)-1-isopropyl-2-oxo-1,2-dihydro-1,8-naphthidin-3-yl)oxy)-N-methylacetamide, or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. A method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 22.

24. The method of claim 23, wherein the cancer is a hematologic cancer, breast cancer, gastrointestinal cancer, brain cancer, lung cancer, or a combination thereof.

25. The method of claim 24, wherein the cancer is a hematologic cancer (e.g., lymphoma (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL))), non-Hodgkin lymphoma (e.g., B-cell lymphoproliferative and lymphoma (e.g., mature B-cell tumors (e.g., Burkitt lymphoma (BL)), large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), T-cell-rich / histiocytic large B-cell lymphoma, diffuse large B-cell lymphoma / high-grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2))), primary immune-exempt site large B-cell lymphoma (primary immune-exempt site LBCL), primary mediastinal lymphoma). Large B-cell lymphoma (primary mediastinal LBCL) or high-grade B-cell lymphoma NOS), follicular lymphoma (FL) or transformation of indolent B-cell lymphoma), T-cell and NK-cell lymphoproliferative and lymphoma (e.g., mature T-cell and NK-cell tumors, e.g., mature T-cell and NK-cell leukemias, e.g., adult T-cell leukemia / lymphoma), primary cutaneous T-cell lymphoproliferative and lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disease, mycosis fungoides, Cezari syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disease: lymphomatoid papulosis, primary cutaneous CD30-positive T-cell lymphoproliferative disease: primary cutaneous anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous γ-δ T-cell lymphoma or primary cutaneous peripheral T-cell lymphoma NOS), peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma), nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular follicular helper T-cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma) or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)) or other peripheral T-cell lymphoma (e.g., peripheral T-cell lymphoma NOS)).

26. The method of claim 25, wherein the hematologic cancer is selected from the group consisting of: lymphoma (e.g., non-Hodgkin lymphoma (e.g., B-cell lymphoproliferative and lymphoma (e.g., mature B-cell tumors (e.g., large B-cell lymphoma (e.g., nonspecific diffuse large B-cell lymphoma (DLBCL-NOS) or primary mediastinal large B-cell lymphoma (primary mediastinal LBCL)), follicular lymphoma (FL) or transformation of indolent B-cell lymphoma)), T-cell and NK-cell lymphoproliferative and lymphoma (e.g., mature T-cell and NK-cell tumors (e.g., primary cutaneous T-cell lymphoproliferative and lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary Cutaneous CD4-positive small or medium T-cell lymphoproliferative disorders or mycosis fungoides or Cezari syndrome) or peripheral T-cell lymphoma (PTCL) (e.g., nodular T-follicular helper cell lymphoma (e.g., angioimmunoblastic nodular T-follicular helper cell lymphoma (also known as angioimmunoblastic T-cell lymphoma (AITL) or angioimmunoblastic follicular helper T-cell lymphoma), follicular nodular T-follicular helper cell lymphoma (also known as follicular helper T-cell lymphoma or nodular T-follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma NOS)) or other peripheral T-cell lymphoma (e.g., peripheral T-cell lymphoma NOS)).

27. The method of claim 25, wherein the hematologic cancer is FL.

28. The method of claim 25, wherein the hematologic cancer is DLBCL.

29. The method according to any one of claims 23 to 28, wherein the cancer is positive for BCL6 expression (e.g., as determined by an IHC test).

30. The method according to any one of claims 23 to 29, wherein the therapeutically effective amount of the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 22 is administered to the subject as a single therapy.

31. The method according to any one of claims 23 to 29, wherein the method comprises administering an additional therapy or treatment agent to the subject.

32. The method of claim 31, wherein the additional therapy or therapeutic agent is a PI3K inhibitor, an Abl inhibitor (e.g., a BCR-Abl inhibitor), a BTK inhibitor, a JAK inhibitor, a BRaf inhibitor, a MEK inhibitor, a BCL-2 inhibitor, or a Bcl-X inhibitor. L Inhibitors, XPO1 inhibitors, inhibitors of polycomb inhibitory complex 2 (PRC2), immunomodulatory imide drugs, anti-CD19 therapy, anti-CD20 therapy, anti-CD3 therapy, chemotherapy, or combinations thereof.

33. The method of claim 32, wherein the additional therapy or therapeutic agent is an inhibitor of PRC2 (e.g., an EZH1 / 2 or EZH2 inhibitor).

34. A method for treating or preventing autoimmune symptoms in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 22.

35. A method for treating a subject with lymphoproliferative disorder, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 22.

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