Quinolone BCL6 difunctional degradation agent

Abstract

The present disclosure provides a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), or (I-a-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (I-b) (e.g., Formula (I-b-1) or (I-b-2)), or Formula (II), 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 the same and methods of use and manufacture thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. provisional application serial numbers 63 / 501,082 filed May 9, 2023; 63 / 497,063 filed April 19, 2023; 63 / 444,778 filed February 10, 2023; 63 / 444,801 filed February 10, 2023; 63 / 420 filed October 28, 2022; 421, 63 / 420,411 filed October 28, 2022, 63 / 395,638 filed August 5, 2022, 63 / 395,630 filed August 5, 2022, 63 / 351,715 filed June 13, 2022, 63 / 351,697 filed June 13, 2022, each of which is incorporated herein by reference in its entirety.

[0003] Description of the electronically submitted text file

[0004] This application contains a sequence listing submitted electronically in XML format. The sequence listing XML is incorporated herein by reference. The XML file, created on May 26, 2023, is named TLS-043WO_SL.xml and is 2,663 bytes in size. Technical Field

[0005] The present disclosure provides compounds of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II), or pharmaceutically acceptable salts thereof, that induce BCL6 protein degradation. These compounds can be used, for example, to treat cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the same and methods of use and manufacture thereof. Background Art

[0006] The B-cell lymphoma 6 (BCL6) protein is a transcriptional repressor involved in the formation and maintenance of germinal centers (GCs) within lymphoid follicles. It controls the function of GCs and coordinates the activity of signaling mediators in the maturation of GC B cells. There are more than 1,000 known or putative BCL6 target genes, including MYC, BCL2, genes related to DNA damage response (e.g., ATR, TP53), and cell cycle checkpoint control (e.g., CDKN1A, CDKN1B). BCL6 is expressed in dark zone cells of GC, where somatic hypermutation is allowed to occur to produce high-affinity B cell receptors. Overexpression or loss of control of BCL6 (e.g., through translocation) can allow the maintenance of the hypermutation-promoting function and abolish the anti-tumor function of BCL6. Summary of the Invention

[0007] Provided herein are compounds having formula (I):

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein:

[0010] R 1 Selected from the group consisting of: H, halo, cyano, and R b1 ;

[0011] m3 is 0, 1, 2, or 3;

[0012] Each X 3 Independently selected from the group consisting of: -O-, -NR f -, -C(=O)- and optionally 1-3 R c Substituted C 1-3 alkylene;

[0013] The condition is N-(X 3 ) m3 -R 1 The portion does not contain any OO, NO, NN, O-halogenated or N-halogenated bonds;

[0014] Each R 2 are independently selected from the group consisting of: H, halo, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -OH, and -NR d R e ;

[0015] R 3 Selected from the group consisting of:

[0016] -A 1 -C(R4 R 4 )-A 2 and -CH=CH-A 2 ,in:

[0017] A 1 is -O- or -S-;

[0018] Each R 4 Independently selected from the group consisting of: H, C 1-6 Alkyl and C 1-6 haloalkyl; or

[0019] The R 4 The pairs together with their respective attached carbon atoms form C 3-6 Cycloalkyl ring or 4-8 membered heterocyclyl ring, wherein the C 3-6 The cycloalkyl ring or the 4-8 membered heterocyclyl ring is optionally substituted by 1-3 R g replace;

[0020] A 2 Selected from the group consisting of: -C(O)OH, -C(O)NH2, -C(O)R 3A 、-C(O)OR 3A 、-C(O)NR 3A R f 、-S(O) 1-2 (C 1-6 alkyl), -P(O)-(C 1-6 -C(=NH)NH2, wherein:

[0021] R 3A Selected from the group consisting of: C 1-6 Alkyl, C 3-6 Alkenyl, C 3-6 Alkynyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: R a and-(C 0-3 Alkylene)-R b1 ;

[0022] X a and X c are independently selected from the group consisting of: N, CH, and CF, provided that X a and X c One or two of them are N;

[0023] X b Selected from the group consisting of: N and CR x1 ;

[0024] R6 and R x1 Each independently selected from the group consisting of: H, halo, C 1-2 Alkyl, C 1-2 Halogenated alkyl, C 1-2 alkoxy, CN, and -C≡CH;

[0025] L is -(L A ) n1 -, where L A and n1 is defined according to (AA) or (BB):

[0026] (AA)

[0027] n1 is an integer from 1 to 15; and

[0028] Each L A Independently selected from the group consisting of: L A1 , L A3 , and L A4 , the condition is 1-3 occurrences of L A It's L A4 ;

[0029] (BB)

[0030] n1 is an integer from 0 to 20; and

[0031] Each L A Independently selected from the group consisting of: L A1 and L A3 ;

[0032] Each L A1 Independently selected from the group consisting of: -CH2-, -CHR L -, and -C(R L )2-;

[0033] Each L A3 Independently selected from the group consisting of: -N(R d )-、-N(R b )-、-O-、-S(O) 0-2 -, and C(=O);

[0034] Each L A4 Independently selected from the group consisting of:

[0035] (a)C 3-15 Cycloalkylene or 3-15 membered heterocyclylene, each of which is optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and R b ;as well as

[0036] (b)C 6-15 arylene or 5-15 membered heteroarylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: R a and R b ;

[0037] Provided that L does not contain any NO, OO, NN, NS(O)0 or OS(O) 0-2 key;

[0038] Each R L independently selected from the group consisting of: halo, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e 、C(=O)N(R f )2、S(O) 0-2 (C 1-6 Alkyl), S(O) 0-2 (C 1-6 Halogenated alkyl), S(O) 1-2 N(R f )2. -R b , and optionally 1-6 R c Substituted C 1-6 alkyl;

[0039] Ring C is selected from the group consisting of: c1 is 0, 1, 2, or 3;

[0040] Each R Y Independently selected from the group consisting of: R a and R b ;

[0041] R aN is H or optionally 1-3 R c Substituted C 1-6 alkyl;

[0042] Y 1 and Y 2 are independently N, CH, or CR Y ;

[0043] yy represents the point of attachment to L;

[0044] X is CH, C, or N;

[0045] Is a single bond or a double bond;

[0046] L CSelected from the group consisting of: a bond, -CH2-, -CHR a -、-C(R a )2-、-C(=O)-、-N(R d )-, and the condition is that when X is N, L C is not O; and

[0047] There is a further proviso that when ring C is attached to -L via the ring nitrogen C -, X is CH, and L C It is a key;

[0048] Each R a Independently selected from the group consisting of:

[0049] (a) halogenated;

[0050] (b) cyano;

[0051] (c) -OH;

[0052] (d) oxo;

[0053] (e) optionally 1-6 R c Substituted C 1-6 alkoxy;

[0054] (f)-NR d R e ;

[0055] (g) optionally 1-6 R c Substituted C(=O)C 1-6 alkyl;

[0056] (h) C(=O)OH;

[0057] (i) C(=O)OC 1-6 alkyl;

[0058] (j)C(=O)OC 1-6 alkyl halide;

[0059] (k)C(=O)N(R f )2;

[0060] (l)S(O) 0-2 (C 1-6 alkyl);

[0061] (m)S(O) 0-2 (C 1-6 haloalkyl);

[0062] (n)S(O) 1-2 N(R f )2; and

[0063] (o)C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R c replace;

[0064] Each R b Independently selected from the group consisting of:-(L b ) b -R b1 and -R b1 ,in:

[0065] Each b is independently 1, 2, or 3;

[0066] Each -L b are independently selected from the group consisting of: -O-, -N(H)-, -N(C 1-3 Alkyl)-, -S(O) 0-2 -, C(=O), and C 1-3 an alkylene group; and

[0067] Each R b1 Independently selected from the group consisting of: C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R g replace;

[0068] Each R c independently selected from the group consisting of: halo, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e 、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)OH, C(=O)N(R f )2、S(O) 0-2 (C 1-6 Alkyl), S(O) 0-2 (C 1-6 haloalkyl), and S(O) 1-2 N(R f )2;

[0069] Each R d and R e independently selected from the group consisting of: H, C(=O)C 1-6 Alkyl, C(=O)C1-6 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), S(O) 1-2 (C 1-6 Halogenated alkyl), S(O) 1-2 N(R f )2, and optionally 1-3 R h Substituted C 1-6 alkyl;

[0070] Each R f independently selected from the group consisting of: H and optionally 1-3 R h Substituted C 1-6 alkyl;

[0071] Each R g Independently selected from the group consisting of: R h , oxo, C 1-3 Alkyl, and C 1-3 haloalkyl; and

[0072] Each R h are independently selected from the group consisting of: halo, cyano, -OH, -(C 0-3 Alkylene)-C 1-6 Alkoxy, -(C 0-3 Alkylene)-C 1-6 Halogenated alkoxy, -(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.

[0073] Also provided herein are pharmaceutical compositions comprising a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0074] Provided herein are methods for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0075] Also provided herein are BCL6 proteins that non-covalently bind to a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or a pharmaceutically acceptable salt thereof.

[0076] Also provided herein are ternary complexes comprising a BCL6 protein, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or a pharmaceutically acceptable salt thereof, and a CRBN protein or a portion thereof.

[0077] For ease of understanding the disclosure set forth herein, a plurality of other terms are provided. Typically, the nomenclature used herein and the laboratory procedures in the 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 those of ordinary skill in the art of this disclosure. Each patent, application, disclosed application and other publications mentioned throughout the specification and the accompanying appendix are incorporated herein by reference in their entirety. If there is a conflict in this disclosure with any content incorporated by reference, then this disclosure shall prevail.

[0078] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION

[0079] The present disclosure provides compounds of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II), or pharmaceutically acceptable salts thereof, that induce degradation of BCL6 protein. These compounds can be used, for example, to treat cancer. The present disclosure also provides compositions containing the compounds provided herein and methods of using and making the same.

[0080] Under antigen attack, germinal centers (GC) are formed in lymphoid follicles, and B cells in the GC dark zone undergo rapid proliferation and somatic hypermutation, and their immunoglobulin variable genes all produce high-affinity B cell receptors, as well as other genes (including BCL6). BCL6 is generally considered to be the "master regulator" of GC reaction. In some cancers, BCL6 may mutate, translocate, and / or BCL6 expression may be upregulated. See, for example, Leeman-Neill and Bhagat, Expert Opinion on Therapeutic Targets [Expert Opinion on Therapeutic Targets] 22.2 (2018): 143-152; Mlynarczyk and Melnick. Immunological Reviews [Immunology Review] 288.1 (2019): 214-239.

[0081] The BCL6 protein has multiple domains, including the BTB domain, the RD2 domain, and the 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 corepressors of BCL6 (such as SMRT, NCOR, and BCOR). See, for example, Cardenas, Mariano G. et al. Clinical Cancer Research [Clinical Cancer Research] 23.4 (2017): 885-893.

[0082] Compounds that induce target protein degradation are sometimes referred to as heterobifunctional compounds, PROTACs, or degraders. Such compounds typically include a portion that binds to the target protein and a portion that binds to an ubiquitin E3 ligase (sometimes referred to as an E3 ligase or simply E3), and these two portions are optionally separated by a linker. In order to induce degradation, heterobifunctional compounds are thought to induce the formation of a ternary complex between the target protein, the compound, and the E3 ligase. After the ternary complex is formed, the target protein is ubiquitinated, and the ubiquitinated target protein is degraded by the proteasome. Several E3 ligases have been used as partner E3 ligases for heterobifunctional degraders. Cerebellum protein (cereblon, CRBN) E3 ligase (also referred to herein as CRBN protein) is used herein.

[0083] Degradation approaches to the target protein may have potential advantages over, for example, small molecule inhibition of the target protein. One potential advantage is that the duration of action of heterobifunctional compounds is generally based on the rate of resynthesis of the target protein. Another potential advantage is that many heterobifunctional compounds are believed to be released from the ubiquitinated target protein-E3 ligase complex and available for formation of additional ternary complexes; this is sometimes referred to as the "catalytic" turnover of the heterobifunctional compound. In some cases, degradation of the target protein may also be more advantageous than small molecule inhibition because degradation may impair the scaffold function of the target protein, while small molecules may not. It is also generally accepted that a high affinity for the target protein is not always required for the formation of the ternary complex.

[0084] Heterobifunctional compounds are further described, for example, in International Publication Nos. WO 2021 / 077010 and WO 2022 / 221673; McCull, William et al., ACS Chemical Biology 13.11 (2018): 3131-3141; Chamberlain and Hamann, Nature Chemical Biology 15.10 (2019): 937-944; Li and Song, Journal of Hematology & Oncology 13 (2020): 1-14; Wu et al., Nature Structural & Molecular Biology 27.7 (2020): 605-614; Dong et al., Journal of Medicinal Chemistry 64.15 (2021): 10606-10620; Yang et al., Targeted Oncology 16.1(2021):1-12.

[0085] Compound Examples

[0086] Provided herein are compounds having formula (I):

[0087]

[0088] or a pharmaceutically acceptable salt thereof, wherein:

[0089] R 1 Selected from the group consisting of: H, halo, cyano, and R b1 ;

[0090] m3 is 0, 1, 2, or 3;

[0091] Each X 3 Independently selected from the group consisting of: -O-, -NR f -, -C(=O)- and optionally 1-3 R c Substituted C 1-3 alkylene;

[0092] The condition is N-(X 3 ) m3 -R 1 The portion does not contain any OO, NO, NN, O-halogenated or N-halogenated bonds;

[0093] Each R 2 are independently selected from the group consisting of: H, halo, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -OH, and -NR d R e ;

[0094] R 3 Selected from the group consisting of:

[0095] -A 1 -C(R 4 R 4 )-A 2 and -CH=CH-A 2 ,in:

[0096] A 1 is -O- or -S-;

[0097] Each R 4 Independently selected from the group consisting of: H, C 1-6 Alkyl and C 1-6 haloalkyl; or

[0098] The R 4The pairs together with their respective attached carbon atoms form C 3-6 Cycloalkyl ring or 4-8 membered heterocyclyl ring, wherein the C 3-6 The cycloalkyl ring or the 4-8 membered heterocyclyl ring is optionally substituted by 1-3 R g replace;

[0099] A 2 Selected from the group consisting of: -C(O)OH, -C(O)NH2, -C(O)R 3A 、-C(O)OR 3A 、-C(O)NR 3A R f 、-S(O) 1-2 (C 1-6 alkyl), -P(O)-(C 1-6 -C(=NH)NH2, wherein:

[0100] R 3A Selected from the group consisting of: C 1-6 Alkyl, C 3-6 Alkenyl, C 3-6 Alkynyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: R a and-(C 0-3 Alkylene)-R b1 ;

[0101] X a and X c are independently selected from the group consisting of: N, CH, and CF, provided that X a and X c One or two of them are N;

[0102] X b Selected from the group consisting of: N and CR x1 ;

[0103] R 6 and R x1 Each independently selected from the group consisting of: H, halo, C 1-2 Alkyl, C 1-2 Halogenated alkyl, C 1-2 alkoxy, CN, and -C≡CH;

[0104] L is -(L A ) n1 -, where L A and n1 is defined according to (AA) or (BB):

[0105] (AA)

[0106] n1 is an integer from 1 to 15; and

[0107] Each L A Independently selected from the group consisting of: L A1 , L A3 , and L A4 , the condition is 1-3 occurrences of L A It's L A4 ;

[0108] (BB)

[0109] n1 is an integer from 0 to 20; and

[0110] Each L A Independently selected from the group consisting of: L A1 and L A3 ;

[0111] Each L A1 Independently selected from the group consisting of: -CH2-, -CHR L -, and -C(R L )2-;

[0112] Each L A3 Independently selected from the group consisting of: -N(R d )-、-N(R b )-、-O-、-S(O) 0-2 -, and C(=O);

[0113] Each L A4 Independently selected from the group consisting of:

[0114] (a)C 3-15 Cycloalkylene or 3-15 membered heterocyclylene, each of which is optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and R b ;as well as

[0115] (b)C 6-15 arylene or 5-15 membered heteroarylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: R a and R b ;

[0116] Provided that L does not contain any NO, OO, NN, NS(O)0 or OS(O) 0-2 key;

[0117] Each R L independently selected from the group consisting of: halo, cyano, -OH, -C1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e 、C(=O)N(R f )2、S(O) 0-2 (C 1-6 Alkyl), S(O) 0-2 (C 1-6 Halogenated alkyl), S(O) 1-2 N(R f )2. -R b , and optionally 1-6 R c Substituted C 1-6 alkyl;

[0118] Ring C is selected from the group consisting of:

[0119] c1 is 0, 1, 2, or 3;

[0120] Each R Y Independently selected from the group consisting of: R a and R b ;

[0121] R aN is H or optionally 1-3 R c Substituted C 1-6 alkyl;

[0122] Y 1 and Y 2 are independently N, CH, or CR Y ;

[0123] yy represents the point of attachment to L;

[0124] X is CH, C, or N;

[0125] Is a single bond or a double bond;

[0126] L C Selected from the group consisting of: a bond, -CH2-, -CHR a -、-C(R a )2-、-C(=O)-、-N(R d )-, and O, provided that when X is N, L C is not O; and

[0127] There is a further proviso that when ring C is attached to -L via the ring nitrogen C -, X is CH, and L C It is a key;

[0128] Each R a Independently selected from the group consisting of:

[0129] (a) halogenated;

[0130] (b) cyano;

[0131] (c) -OH;

[0132] (d) oxo;

[0133] (e) optionally 1-6 R c Substituted C 1-6 alkoxy;

[0134] (f)-NR d R e ;

[0135] (g) optionally 1-6 R c Substituted C(=O)C 1-6 alkyl;

[0136] (h) C(=O)OH;

[0137] (i) C(=O)OC 1-6 alkyl;

[0138] (j)C(=O)OC 1-6 alkyl halide;

[0139] (k)C(=O)N(R f )2;

[0140] (l)S(O) 0-2 (C 1-6 alkyl);

[0141] (m)S(O) 0-2 (C 1-6 haloalkyl);

[0142] (n)S(O) 1-2 N(R f )2; and

[0143] (o)C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R c replace;

[0144] Each R b Independently selected from the group consisting of:-(L b ) b -R b1 and -R b1 ,in:

[0145] Each b is independently 1, 2, or 3;

[0146] Each -L b are independently selected from the group consisting of: -O-, -N(H)-, -N(C 1-3 Alkyl)-, -S(O) 0-2 -, C(=O), and C 1-3 an alkylene group; and

[0147] Each R b1 Independently selected from the group consisting of: C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R g replace;

[0148] Each R c independently selected from the group consisting of: halo, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e 、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)OH, C(=O)N(R f )2、S(O) 0-2 (C 1-6 Alkyl), S(O) 0-2 (C 1-6 haloalkyl), and S(O) 1-2 N(R f )2;

[0149] Each R d and R e independently selected from the group consisting of: 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), S(O) 1-2 (C 1-6 Halogenated alkyl), S(O) 1-2 N(R f )2, and optionally 1-3 R h Substituted C1-6 alkyl;

[0150] Each R f independently selected from the group consisting of: H and optionally 1-3 R h Substituted C 1-6 alkyl;

[0151] Each R g Independently selected from the group consisting of: R h , oxo, C 1-3 Alkyl, and C 1-3 haloalkyl; and

[0152] Each R h are independently selected from the group consisting of: halo, cyano, -OH, -(C 0-3 Alkylene)-C 1-6 Alkoxy, -(C 0-3 Alkylene)-C 1-6 Halogenated alkoxy, -(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.

[0153] In some embodiments, with the proviso that when X is N, Ring C is

[0154] In some embodiments, R 3 Yes-A 1 -C(R 4 R 4 )-A 2 .

[0155] In some embodiments, A 1 Yes -O-.

[0156] In some embodiments, each R 4 It’s H.

[0157] In some embodiments, A 2 Is -C(O)NH2 or -C(O)NR 3A R f In some embodiments, R 3A is optionally replaced by 1-6 R c Substituted C 1-3 Alkyl. For example, A 2 It can be -C(O)NH2, -C(O)NHMe or -C(O)NMe2. For example, A 2 It may be -C(O)NHMe.

[0158] In some embodiments, R 3 yes

[0159] In some embodiments, X a It is N; X c is N; and X b It's CR x1 (e.g., CH).

[0160] In some embodiments, X a is CH; X c is N; and X b It's CR x1 (e.g., CH).

[0161] In some embodiments, R 6 It is -Cl or -F.

[0162] In some embodiments, each R 2 It’s H.

[0163] In some embodiments, an R 2 Selected from the group consisting of: halo, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, and C 1-3 haloalkoxy; and each remaining R 2 It’s H.

[0164] In some embodiments, m3 is 0.

[0165] In some embodiments, m3 is 1; and X 3 It is C 1-3 Alkylene.

[0166] In some embodiments, R 1 It’s H.

[0167] In some embodiments, m3 is 1; X 3 is methylene, ethylene or isopropylene; and R 1 It’s H.

[0168] In some embodiments, R 3 Yes-A 1 -C(R 4 R 4 )-A 2 , where A 1 is O; each R 4 is H; and A 2 Is -C(O)NH2 or -C(O)NR 3A Rf , where R 3A is optionally replaced by 1-6 R c Substituted C 1-3 Alkyl; each R 2 It is H; X a is N or CH; X c It is N; X b is CH; and R 6 In some embodiments, m3 is 1; X 3 is methylene, ethylene or isopropylene; and R 1 is H. In some embodiments, X a is N. In some embodiments, A 2 It is C(O)NHMe.

[0169] In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, c1 is 0. In some embodiments, c1 is 1; and R Y is halo (e.g., -F). In some embodiments, R aN It is C 1-3 Alkyl (eg, methyl).

[0170] In some embodiments, Ring C is In some embodiments, c1 is 0. In some embodiments, c1 is 1; and R Y is halo (e.g., -F). In some embodiments, R aN It is C 1-3 Alkyl (eg, methyl).

[0171] In some embodiments, c1 is 0. In some embodiments, c1 is 1; and R Y is halo (eg, -F).

[0172] In some embodiments, X is CH.

[0173] In some embodiments, L C It is a key.

[0174] In some embodiments, The portion is selected from the group consisting of:

[0175] In some embodiments, The portion is selected from the group consisting of:

[0176] In some embodiments, Partly Where: m3 is 1; X 3 It is C 1-3 Alkylene; R 1 It is H; X a is CH or N; X c It is N; R 6 is -F or -Cl; and The portion is selected from the group consisting of: In some embodiments, -(X 3 ) m3 -R 1 is methyl, ethyl, or isopropyl. In some embodiments, X a In some embodiments, X a It's N.

[0177] In some embodiments, L is -(L A ) n1 -, where L A and n1 are defined according to (AA).

[0178] In some embodiments, n1 is an integer from 1 to 5.

[0179] In some embodiments, n1 is an integer from 2 to 4 (eg, 2 or 3).

[0180] In some embodiments, L is selected from the group consisting of:

[0181] -L A4 -L A1 -L A4 - bb ;

[0182] -L A4 -L A4 - bb ;

[0183] -L A4 -L A3 -L A4 - bb ;and

[0184] -L A4 -L A1 -L A4 -L A3 - bb ,

[0185] where bb represents the point of attachment to ring C.

[0186] In some embodiments, each L A4Independently C 3-10 Cycloalkylene or 4-12 membered heterocyclylene, each of which is optionally substituted by 1-6 R a In some embodiments, each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0187] In some embodiments, each L A4 are independently optionally substituted by 1-3 R a In some embodiments, each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0188] In some embodiments, each L A4 are independently optionally substituted by 1-3 R a In some embodiments, each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0189] In some embodiments, an L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and another L A4 is optionally replaced by 1-3 R a Substituted bicyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene. In some embodiments, each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0190] In some embodiments, an L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and another L A4 is optionally replaced by 1-3 R a Substituted bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene. In some embodiments, each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0191] In some embodiments, an L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and another L A4 is optionally replaced by 1-3 R a The substituted bicyclic bridged 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene group. In some embodiments, each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0192] In some embodiments, each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0193] In some embodiments, L is -L A4 -L A1 -L A4 - bb In some embodiments, L A1It is -CH2-, -CHMe-, or -CMe2-.

[0194] In some embodiments, L is -L A4 -L A3 -L A4 - bb In some embodiments, L A3 It is -C(=O) or -O-.

[0195] In some embodiments, L is -L A4 -L A1 -L A4 -L A3 - bb , and L A3 It is C(=O).

[0196] In some embodiments, L is selected from the group consisting of:

[0197] -L A4 -L A3 - bb ;

[0198] -L A4 -L A1 - bb ;and

[0199] -L A4 -L A1 -L A3 - bb ,

[0200] where bb represents the point of attachment to ring C.

[0201] In some embodiments, L is -L A4 -L A3 - bb In some embodiments, L A3 Is -NH- or -N(C 1-3 In some embodiments, L A4 is optionally replaced by 1-6 R a In some embodiments, L A4 is optionally replaced by 1-3 R a In some embodiments, L A4 is optionally replaced by 1-3 R a Substituted bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene. In some embodiments, L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, LA4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0202] In some embodiments, L is selected from the group consisting of: the portions depicted in Table L:

[0203] Table L

[0204]

[0205]

[0206]

[0207]

[0208] where bb represents the point of attachment to ring C.

[0209] In some embodiments, L is selected from the group consisting of: the portion depicted in Table L1-a:

[0210] Table L1-a

[0211]

[0212]

[0213] where bb represents the point of attachment to ring C.

[0214] In some embodiments, L is selected from the group consisting of: the portion depicted in Table L2-a:

[0215] Table L2-a

[0216]

[0217] where bb represents the point of attachment to ring C.

[0218] In some embodiments, the compound of formula (I) is a compound of formula (I-aa):

[0219]

[0220] or a pharmaceutically acceptable salt thereof, wherein:

[0221] X a is N or CH;

[0222] R 6 is -F or -Cl;

[0223] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0224] Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y Selected from halo (eg, -F) and C optionally substituted with 1-3 F 1-3 The group consists of alkyl groups, and R aN It is C 1-3 alkyl;

[0225] L is selected from the group consisting of:

[0226] -L A4 -L A1 -L A4 - bb ;

[0227] -L A4 -OL A4 - bb ;

[0228] -L A4 -C(=O)-L A4 - bb ;and

[0229] -L A4 -L A1 -L A4 -C(=O)- bb ,

[0230] where bb represents the point of attachment to ring C;

[0231] L A1 is CH2, CHMe, or CMe2; and

[0232] Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein:

[0233] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0234] In some embodiments of Formula (I-aa), each L A4 are independently optionally substituted by 1-3 R aa substituted monocyclic 4-6 membered nitrogen-containing heterocyclic group,

[0235] Each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0236] In some embodiments of Formula (I-aa), one L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and

[0237] Another L A4 is optionally replaced by 1-3 R a a substituted bicyclic spirocyclic 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group,

[0238] Each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0239] In some embodiments of Formula (I-aa), one L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and

[0240] Another L A4 is optionally replaced by 1-3 R a a substituted bicyclic bridged 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene group,

[0241] Each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0242] In some embodiments of Formula (I-aa), L is -L A4 -L A1 -L A4 - bb ; and L A1 It is CH2 or CHMe.

[0243] In some embodiments of Formula (I-aa), L is selected from the group consisting of the moieties depicted in Table L1-a.

[0244] In some embodiments of Formula (I-aa), L is selected from the group consisting of the moieties depicted in Table LIa, wherein bb represents the point of attachment to Ring C.

[0245] Table LIa

[0246]

[0247]

[0248] In some embodiments, the compound of formula (I-aa) is a compound of formula (I-aa-1):

[0249]

[0250] or a pharmaceutically acceptable salt thereof, wherein:

[0251] X a is N or CH;

[0252] R 6 is -F or -Cl;

[0253] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0254] Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y Selected from halo (eg, -F) and C optionally substituted with 1-3 F 1-3 The group consists of alkyl groups, and R aN It is C 1-3 alkyl;

[0255] L A1 is CH2, CHMe, or CMe2; and

[0256] Each L A4 are independently optionally substituted by 1-3 R a A substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group, wherein:

[0257] Each L A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms, and

[0258] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0259] In some embodiments of Formula (I-aa-1), -L A4 -L A1 -L A4 - a moiety selected from the group consisting of the moieties depicted in Table LIa-1, wherein bb represents the point of attachment to ring C.

[0260] Table LIa-1

[0261]

[0262] In some embodiments, the compound of formula (I-aa) is a compound of formula (I-aa-2):

[0263]

[0264] or a pharmaceutically acceptable salt thereof, wherein:

[0265] X a is N or CH;

[0266] R 6 is -F or -Cl;

[0267] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0268] Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y Selected from halo (eg, -F) and C optionally substituted with 1-3 F 1-3 The group consists of alkyl groups, and R aN It is C 1-3 alkyl;

[0269] L A1 is CH2, CHMe, or CMe2;

[0270] Z 1 and Z 2 Independently selected from the group consisting of: CH, CR a4 , and N;

[0271] Z 3 and Z 4 Independently selected from the group consisting of: CH, CR a5 , and N,

[0272] The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When N is Z 3 Is CH or CR a5 ;

[0273] m4 and m5 are independently selected from the group consisting of: 0, 1, and 2; and

[0274] Each R a4 and R a5Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0275] In some embodiments of Formula (I-aa-2), Z 1 is N. In some embodiments of Formula (I-aa-2), Z 1 is N; and Z 2 Is CH or CR a4 In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 Is CH or CR a4 ; and Z 3 It's N.

[0276] In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 Is CH or CR a4 ; Z 3 is N; and Z 4 Is CH or CR a5 .

[0277] In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CH; and m4 and m5 are both 0. In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CH; one of m4 and m5 is 1; and the other of m4 and m5 is 0. In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CH; one of m4 and m5 is 1; the other of m4 and m5 is 0; and R a4 or R a5 When present, Z is methyl. 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CH; m4 is 1; and m5 is 0. In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z4 is CH; m4 is 1; m5 is 0; and R a4 It's methyl.

[0278] In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 It is CH; Z 3 is N; and Z 4 It's CR a5 (e.g., CF). In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CF; and m4 and m5 are both 0.

[0279] In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 Is CH or CR a4 ; Z 3 is N; and Z 4 is N. In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is N; and m4 and m5 are both 0. In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is N; one of m4 and m5 is 1; and the other of m4 and m5 is 0. In some embodiments of Formula (I-aa-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is N; one of m4 and m5 is 1; the other of m4 and m5 is 0; and R a4 or R a5 When present, Z is methyl. 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is N; m4 is 1; m5 is 0. In some embodiments, R a4 It's methyl.

[0280] In some embodiments of Formula (I-aa-2), The moiety is selected from the group consisting of the moieties depicted in Table LIa-2, wherein bb represents the point of attachment to ring C.

[0281] Table LIa-2

[0282]

[0283]

[0284] In some embodiments, the compound of formula (I-aa) is a compound of formula (I-aa-3):

[0285]

[0286] or a pharmaceutically acceptable salt thereof, wherein:

[0287] X a is N or CH;

[0288] R 6 is -F or -Cl;

[0289] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0290] Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y Selected from halo (eg, -F) and C optionally substituted with 1-3 F 1-3 The group consists of alkyl groups, and R aN It is C 1-3 alkyl;

[0291] L A1 is CH2, CHMe, or CMe2; and

[0292] One L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and

[0293] Another L A4 is optionally replaced by 1-3 R a Substituted bicyclic 6-12 membered nitrogen-containing heterocyclylene group, wherein:

[0294] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0295] In some embodiments of Formula (I-aa-3), each L A4Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0296] In some embodiments of Formula (I-aa-3), one L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and another L A4 is optionally replaced by 1-3 R a In some embodiments, each L is a substituted bicyclic spirocyclic 6-12 (e.g., 7, 9, or 11) membered nitrogen-containing heterocyclyl. A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0297] In some embodiments of Formula (I-aa-3), one L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and another L A4 is optionally replaced by 1-3 R a In some embodiments, each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0298] In some embodiments of Formula (I-aa-3), one L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and another L A4 is optionally replaced by 1-3 R a In some embodiments, each L is a substituted bicyclic fused 6-12 (eg, 6) membered nitrogen-containing heterocyclyl. A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0299] In some embodiments of Formula (I-aa-3), -L A4 -L A1 -L A4 - a moiety selected from the group consisting of the moieties depicted in Table LIa-3, wherein bb represents the point of attachment to ring C.

[0300] Table LIa-3

[0301]

[0302] In some embodiments, the compound of formula (I-aa) is a compound of formula (I-aa-4):

[0303]

[0304] or a pharmaceutically acceptable salt thereof, wherein:

[0305] X a is N or CH;

[0306] R 6 is -F or -Cl;

[0307] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0308] Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y Selected from halo (eg, -F) and C optionally substituted with 1-3 F 1-3 The group consists of alkyl groups, and R aN It is C 1-3 alkyl; and

[0309] Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein:

[0310] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0311] In some embodiments of Formula (I-aa-4), each L A4 are independently optionally substituted by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclic group, wherein each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. For example, each L A4 and may be independently selected from the group consisting of piperazinylene and piperidinylene.

[0312] In some embodiments of Formula (I-aa-4), -L A4 -C(=O)-L A4 - a moiety selected from the group consisting of the moieties depicted in Table LIa-4, wherein bb represents the point of attachment to ring C.

[0313] Table LIa-4

[0314]

[0315] In some embodiments, the compound is a compound having Formula (Ia):

[0316]

[0317] or a pharmaceutically acceptable salt thereof, wherein:

[0318] X a is N or CH;

[0319] R 6 is -F or -Cl;

[0320] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0321] Ring C is selected from the group consisting of:

[0322] L is selected from the group consisting of:

[0323] -L A4 -L A1 -L A4 - bb ;

[0324] -L A4 -OL A4 - bb ;

[0325] -L A4 -C(=O)-L A4 - bb ;and

[0326] -L A4 -L A1 -L A4 -C(=O)- bb ,

[0327] where bb represents the point of attachment to ring C;

[0328] L A1 is CH2, CHMe, or CMe2; and

[0329] Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein:

[0330] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0331] In some embodiments of Formula (Ia), each L A4 are independently optionally substituted by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclic group,

[0332] Each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0333] In some embodiments of Formula (Ia), one L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and

[0334] Another L A4 is optionally replaced by 1-3 R a a substituted bicyclic spirocyclic 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group,

[0335] Each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0336] In some embodiments of Formula (Ia), one L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and

[0337] Another L A4 is optionally replaced by 1-3 R a a substituted bicyclic bridged 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene group,

[0338] Each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0339] In some embodiments of Formula (Ia), L is -L A4 -L A1 -L A4 - bb ; and L A1 It is CH2 or CHMe.

[0340] In some embodiments of Formula (Ia), L is selected from the group consisting of the moieties depicted in Table L1-a.

[0341] In some embodiments of Formula (Ia), L is selected from the group consisting of the moieties depicted in Table LIa (supra), wherein bb represents the point of attachment to Ring C.

[0342] In some embodiments, the compound of formula (Ia) is a compound of formula (Ia-1):

[0343]

[0344] or a pharmaceutically acceptable salt thereof, wherein:

[0345] X a is N or CH;

[0346] R 6 is -F or -Cl;

[0347] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0348] Ring C is selected from the group consisting of:

[0349] L A1 is CH2, CHMe, or CMe2; and

[0350] Each L A4 are independently optionally substituted by 1-3 R a A substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group, wherein:

[0351] Each L A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms, and

[0352] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0353] In some embodiments of Formula (Ia-1), -L A4 -L A1 -L A4 - a moiety selected from the group consisting of the moieties depicted in Table LIa-1 (supra), wherein bb represents the point of attachment to ring C.

[0354] In some embodiments, the compound of formula (Ia) is a compound of formula (Ia-2):

[0355]

[0356] or a pharmaceutically acceptable salt thereof, wherein:

[0357] X ais N or CH;

[0358] R 6 is -F or -Cl;

[0359] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0360] Ring C is selected from the group consisting of:

[0361] L A1 is CH2, CHMe, or CMe2;

[0362] Z 1 and Z 2 Independently selected from the group consisting of: CH, CR a4 , and N;

[0363] Z 3 and Z 4 Independently selected from the group consisting of: CH, CR a5 , and N,

[0364] The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When N is Z 3 Is CH or CR a5 ;

[0365] m4 and m5 are independently selected from the group consisting of: 0, 1, and 2; and

[0366] Each R a4 and R a5 Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0367] In some embodiments of Formula (Ia-2), Z 1 is N. In some embodiments of Formula (Ia-2), Z 1 is N; and Z 2 Is CH or CR a4 In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 Is CH or CR a4 ; and Z 3 It's N.

[0368] In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 Is CH or CR a4 ; Z 3 is N; and Z 4 Is CH or CR a5 .

[0369] In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CH; and m4 and m5 are both 0. In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CH; one of m4 and m5 is 1; and the other of m4 and m5 is 0. In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CH; one of m4 and m5 is 1; the other of m4 and m5 is 0; and R a4 or R a5 When present, Z is methyl. 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CH; m4 is 1; and m5 is 0. In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CH; m4 is 1; m5 is 0; and R a4 It's methyl.

[0370] In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 is N; and Z 4 It's CR a5 (e.g., CF). In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is CF; and m4 and m5 are both 0.

[0371] In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 Is CH or CR a4 ; Z 3 is N; and Z 4 is N. In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is N; and m4 and m5 are both 0. In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is N; one of m4 and m5 is 1; and the other of m4 and m5 is 0. In some embodiments of Formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is N; one of m4 and m5 is 1; the other of m4 and m5 is 0; and R a4 or R a5 When present, Z is methyl. 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 is N; m4 is 1; m5 is 0. In some embodiments, R a4 It's methyl.

[0372] In some embodiments of Formula (Ia-2), The moiety is selected from the group consisting of the moieties depicted in Table LIa-2 (supra), wherein bb represents the point of attachment to ring C.

[0373] In some embodiments, the compound of formula (Ia) is a compound of formula (Ia-3):

[0374]

[0375] or a pharmaceutically acceptable salt thereof, wherein:

[0376] X a is N or CH;

[0377] R 6 is -F or -Cl;

[0378] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1It is H;

[0379] Ring C is selected from the group consisting of:

[0380] L A1 is CH2, CHMe, or CMe2; and

[0381] One L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and

[0382] Another L A4 is optionally replaced by 1-3 R a Substituted bicyclic 6-12 membered nitrogen-containing heterocyclylene group, wherein:

[0383] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0384] In some embodiments of Formula (Ia-3), each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0385] In some embodiments of Formula (Ia-3), one L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and another L A4 is optionally replaced by 1-3 R a In some embodiments, each L is a substituted bicyclic spirocyclic 6-12 (e.g., 7, 9, or 11) membered nitrogen-containing heterocyclyl. A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0386] In some embodiments of Formula (Ia-3), one L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and another L A4 is optionally replaced by 1-3 R a In some embodiments, each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0387] In some embodiments of Formula (Ia-3), one L A4 is optionally replaced by 1-3 Ra a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and another L A4 is optionally replaced by 1-3 R a In some embodiments, each L is a substituted bicyclic fused 6-12 (eg, 6) membered nitrogen-containing heterocyclyl. A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0388] In some embodiments of Formula (Ia-3), -L A4 -L A1 -L A4 - a moiety selected from the group consisting of the moieties depicted in Table LIa-3 (supra), wherein bb represents the point of attachment to ring C.

[0389] In some embodiments, the compound of formula (Ia) is a compound of formula (Ia-4):

[0390]

[0391] or a pharmaceutically acceptable salt thereof, wherein:

[0392] X a is N or CH;

[0393] R 6 is -F or -Cl;

[0394] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0395] Ring C is selected from the group consisting of:

[0396] and

[0397] Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein:

[0398] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0399] In some embodiments of Formula (Ia-4), each L A4 are independently optionally substituted by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclic group, wherein each LA4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. For example, each L A4 and may be independently selected from the group consisting of piperazinylene and piperidinylene.

[0400] In some embodiments of Formula (Ia-4), -L A4 -C(=O)-L A4 - a moiety selected from the group consisting of the moieties depicted in Table LIa-4 (supra), wherein bb represents the point of attachment to ring C.

[0401] In some embodiments, the compound of formula (I) is a compound of formula (I-bb):

[0402]

[0403] or a pharmaceutically acceptable salt thereof, wherein:

[0404] X a is N or CH;

[0405] R 6 is -F or -Cl;

[0406] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0407] Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y Selected from halo (eg, -F) and C optionally substituted with 1-3 F 1-3 The group consists of alkyl groups, and R aN It is C 1-3 alkyl;

[0408] L is -L A4 -L A3 - bb or -L A4 -L A1 -L A3 - bb , where bb represents the point of attachment to ring C; and

[0409] L A4 is optionally replaced by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein:

[0410] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0411] In some embodiments of Formula (I-bb), L is -L A4 -L A3 - bb , and L A3 It is -NH-.

[0412] In some embodiments of Formula (I-bb), L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclic group,

[0413] Among them L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0414] In some embodiments of Formula (I-bb), L A4 is optionally replaced by 1-3 R a a substituted bicyclic spirocyclic 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group,

[0415] Among them L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0416] In some embodiments of Formula (I-bb), L is selected from the group consisting of the moieties depicted in Table L2-a.

[0417] In some embodiments of Formula (I-bb), L is selected from the group consisting of the moieties depicted in Table LIb, wherein bb represents the point of attachment to Ring C.

[0418] Table LIb

[0419]

[0420] In some embodiments, the compound of formula (I-bb) is a compound of formula (I-bb-1):

[0421]

[0422] or a pharmaceutically acceptable salt thereof, wherein:

[0423] X a is N or CH;

[0424] R 6 is -F or -Cl;

[0425] m3 is 1, X 3 It is C 1-3 Alkylene, and R1 It is H;

[0426] Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y Selected from halo (eg, -F) and C optionally substituted with 1-3 F 1-3 The group consists of alkyl groups, and R aN It is C 1-3 alkyl;

[0427] L A4 is optionally replaced by 1-3 R a A substituted 6-12 membered nitrogen-containing heterocyclylene group, wherein:

[0428] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl; and

[0429] L A3 It is -NH-, -N(C 1-3 alkyl)-, or -O-.

[0430] In some embodiments of Formula (I-bb-1), L A4 is optionally replaced by 1-3 R a Substituted bicyclic spirocyclic 6-12 (eg, 8-10 (eg, 9)) membered nitrogen-containing heterocyclylene group, wherein L A4 Contains 1-2 (e.g., 1) ring nitrogen atoms and no additional ring heteroatoms.

[0431] In some embodiments of Formula (I-bb-1), -L A4 -L A3 - selected from the group consisting of the moieties depicted in Table LIb-1, wherein bb represents the point of attachment to ring C.

[0432] Table LIb-1

[0433]

[0434] In some embodiments, the compound of formula (I-bb) is a compound of formula (I-bb-2):

[0435]

[0436] or a pharmaceutically acceptable salt thereof, wherein:

[0437] X a is N or CH;

[0438] R 6 is -F or -Cl;

[0439] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0440] Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y Selected from halo (eg, -F) and C optionally substituted with 1-3 F 1-3 The group consists of alkyl groups, and R aN It is C 1-3 alkyl;

[0441] L A3 It is -NH-, -N(C 1-3 alkyl)-, or -O-;

[0442] m4 is selected from the group consisting of: 0, 1, and 2; and

[0443] Each R a4 Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0444] In some embodiments of Formula (I-bb-2), m4 is 0 or 1; and R a4 When present, it is methyl.

[0445] In some embodiments, the compound is a compound having Formula (Ib):

[0446]

[0447] or a pharmaceutically acceptable salt thereof, wherein:

[0448] X a is N or CH;

[0449] R 6 is -F or -Cl;

[0450] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0451] Ring C is selected from the group consisting of:

[0452] L is -L A4 -L A3 -bb or -L A4 -L A1 -L A3 - bb , where bb represents the point of attachment to ring C; and

[0453] L A4 is optionally replaced by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein:

[0454] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0455] In some embodiments of Formula (Ib), L is -L A4 -L A3 - bb , and L A3 It is -NH-.

[0456] In some embodiments of Formula (Ib), L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclic group,

[0457] Among them L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0458] In some embodiments of Formula (Ib), L A4 is optionally replaced by 1-3 R a a substituted bicyclic spirocyclic 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group,

[0459] Among them L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

[0460] In some embodiments of Formula (Ib), L is selected from the group consisting of the moieties depicted in Table L2-a.

[0461] In some embodiments of Formula (Ib), L is selected from the group consisting of the moieties depicted in Table LIb (supra), wherein bb represents the point of attachment to Ring C.

[0462] In some embodiments, the compound of formula (Ib) is a compound of formula (Ib-1):

[0463]

[0464] or a pharmaceutically acceptable salt thereof, wherein:

[0465] X a is N or CH;

[0466] R 6 is -F or -Cl;

[0467] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0468] Ring C is selected from the group consisting of:

[0469] L A4 is optionally replaced by 1-3 R a A substituted 6-12 membered nitrogen-containing heterocyclylene group, wherein:

[0470] L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl; and

[0471] L A3 It is -NH-, -N(C 1-3 alkyl)-, or -O-.

[0472] In some embodiments of Formula (Ib-1), L A4 is optionally replaced by 1-3 R a Substituted bicyclic spirocyclic 6-12 (eg, 8-10 (eg, 9)) membered nitrogen-containing heterocyclylene group, wherein L A4 Contains 1-2 (e.g., 1) ring nitrogen atoms and no additional ring heteroatoms.

[0473] In some embodiments of Formula (Ib-1), -L A4 -L A3 - selected from the group consisting of the moieties depicted in Table LIb-1 (supra), wherein bb represents the point of attachment to ring C.

[0474] In some embodiments, the compound of formula (Ib) is a compound of formula (Ib-2):

[0475]

[0476] or a pharmaceutically acceptable salt thereof, wherein:

[0477] X a is N or CH;

[0478] R 6 is -F or -Cl;

[0479] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0480] Ring C is selected from the group consisting of:

[0481] L A3 It is -NH-, -N(C 1-3 alkyl)-, or -O-;

[0482] m4 is selected from the group consisting of: 0, 1, and 2; and

[0483] Each R a4 Independently selected from the group consisting of: -F, CN, C 1-3 Alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

[0484] In some embodiments of Formula (Ib-2), m4 is 0 or 1; and R a4 When present, it is methyl.

[0485] In some embodiments of Formula (I-aa) (e.g., (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)) or (I-bb) (e.g., Formula (I-bb-1)), X a It's N.

[0486] In some embodiments of Formula (I-aa) (e.g., (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)) or (I-bb) (e.g., Formula (I-bb-1)), X a It is CH.

[0487] In some embodiments of Formula (Ia) (e.g., (Ia-1), (Ia-2), (Ia-3), or (Ia-4)) or (Ib) (e.g., Formula (Ib-1)), X a It's N.

[0488] In some embodiments of Formula (Ia) (e.g., (Ia-1), (Ia-2), (Ia-3), or (Ia-4)) or (Ib) (e.g., Formula (Ib-1)), X a It is CH.

[0489] In some embodiments, the compound is selected from the group consisting of a compound in Table C1 or a pharmaceutically acceptable salt thereof.

[0490] Table C1

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517] In certain compounds of Table C1, one or more stereogenic centers are represented by "V3000 Enhanced Stereochemistry Notation" (see: support.collaborativedrug.com / hc / en-us / articles / 360020872171-Advanced-Stereochemistry-Registration-Atropisomers-Mixtures-Unknowns-and-Non-Tetrahedral-Chi rality, accessed December 23, 2022, and Accelrys Chemical Representation Guide, Accelrys Software Inc., 2014, each of which is incorporated herein by reference in its entirety). Using this stereochemical notation, certain stereogenic centers are represented 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 have the following meanings:

[0518] (1) When a stereogenic center (e.g., a stereogenic carbon) is represented in a structural formula by a "flat" bond (i.e., no chemical bond at the stereogenic center is represented by a wedge or dash), each of the stereogenic centers can independently adopt the (R)- or (S)-configuration. For example, the structure represents (S)-(1-methylpyrrolidin-2-yl)methanol, (R)-(1-methylpyrrolidin-2-yl)methanol, or a mixture thereof. As another non-limiting example, the structure Representative: (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.

[0519] When one or more stereogenic centers are represented by a wedge and a dash, the following symbols are used:

[0520] (2) When a stereogenic center is indicated by "abs" or by a stereochemical symbol not enhanced (e.g., "abs," "&x," or "orx"), the stereogenic center has the absolute configuration shown in the structural formula. For example, Both refer to (S)-(1-methylpyrrolidin-2-yl)methanol.

[0521] (3) When a stereogenic center is represented by "orx" in a structural formula, the stereogenic center has been resolved, but the configuration of the stereogenic center has not yet been determined. For example, the structure refers to stereoisomers selected from the group consisting of (S)-(1-methylpyrrolidin-2-yl)methanol and (R)-(1-methylpyrrolidin-2-yl)methanol.

[0522] (4) When two or more stereogenic centers are indicated by "orx" in a structural formula, each of these stereogenic centers has been resolved, but the configuration at the stereogenic center has not been determined. In particular:

[0523] a. For any pair of stereogenic centers represented by "orx" in a structural formula, when the numerical portion of the symbol is different (for example, two stereogenic centers are represented by "or1" and "or2", respectively), each stereogenic center is independently defined according to definition (3) (see above). For example, the structure refers to a stereoisomer selected from the group consisting of:

[0524] b. For any pair of stereogenic centers represented by "orx" in a structural formula, when the numerical portion of the symbol is the same (for example, two stereogenic centers are each represented by "or1"), the structural formula refers to a stereoisomer having the relative stereochemistry at these stereogenic centers, as shown in the structural formula, but the absolute configuration of these stereogenic centers has not been determined. For example, the structural Refers to one of the following two "cis (syn)" stereoisomers: As another example, the structure Refers to one of the following "anti" stereoisomers:

[0525] (5) When two or more stereogenic centers are represented by "&x" in a structural formula, the structural formula refers to a mixture of stereoisomers having different configurations at the stereogenic centers. In particular:

[0526] a. For any pair of stereogenic centers represented by "&x" in a structural formula, when the numerical parts of the symbols are different (for example, two stereogenic centers are represented by "&1" and "&2", respectively), the structural formula refers to a mixture of stereoisomers of these two stereogenic centers, wherein the configuration at each stereogenic center can vary independently of each other. For example, the structure Refers to a mixture of four stereoisomers:

[0527] b. For any pair of stereogenic centers represented by "&x" in a structural formula, when the numerical portion of the symbol is the same (for example, two stereogenic centers are each represented by "&1"), the structural formula refers to a mixture of stereoisomers of these two or more stereogenic centers, wherein the relative configurations are as shown in the structural formula. For example, the structural Refers to a mixture of the following "cis (syn)" stereoisomers: and As another example, the structure Refers to the following mixture of "anti" stereoisomers:

[0528] Exemplary compounds of Formula (I-aa) (e.g., Formula (Ia)) include Compounds 101, 102, 103, 104, 107, 108, 281, 287, 288, 298, 305, 305a, 305b, 306, 306a, 306b, 307, 307a, 307b, 308, 308a, 308b, 309, 309a, 309b, 310, 311, 316, 320, 321, 322, 323, 324, 325, 327, 328, 332, 333, 334, 336, 336a, 337, 340, 345, and 346 (as shown in Table C1) or a pharmaceutically acceptable salt thereof.

[0529] Exemplary compounds of Formula (I-aa-1) (e.g., Formula (Ia-1)) include Compounds 101, 102, 107, 108, 281, 288, 305, 305a, 305b, 306, 306a, 306b, 307, 307a, 307b, 308, 308a, 308b, 309, 309a, 309b, 310, 320, 332, 333, 334, 336, 336a, 337, 340, and 346 (as shown in Table C1) or a pharmaceutically acceptable salt thereof.

[0530] Exemplary compounds of formula (I-aa-2) (e.g., formula (Ia-2)) include compounds: 101, 102, 107, 108, 281, 288, 307, 307a, 307b, 308, 308a, 308b, 309, 309a, 309b, 333, 334, 336, 336a, 337, 340, and 346 (as shown in Table C1) or a pharmaceutically acceptable salt thereof.

[0531] Exemplary compounds having Formula (I-aa-3) (eg, Formula (Ia-3)) include Compounds: 103, 104, 298, 311, and 325 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0532] Exemplary compounds having Formula (I-aa-4) (eg, Formula (Ia-4)) include Compounds: 327, 328, and 345 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0533] Exemplary compounds of Formula (I-bb) (e.g., Formula (Ib)) include Compounds 261, 261a, 261b, 266, 266a, 266b, 279, 279a, 279b, 280, 280a, 280b, 299, 299a, 300, 300a, 300b, 301, 301a, 301b, 302, 302a, 302b, 312, 312a, 313, 313a, 317, 317a, 338, 339, 341, 342, 343, and 344.

[0534] Exemplary compounds of formula (I-bb-1) (e.g., formula (Ib-1)) include compounds: 280, 280a, 280b, 338, 339, 341, 342, 343, and 344 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0535] Exemplary compounds having Formula (I-bb-2) (eg, Formula (Ib-2)) include Compounds: 341 and 342 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0536] In some embodiments, the compound is selected from the group consisting of a compound in Table C2 or a pharmaceutically acceptable salt thereof.

[0537] Table C2

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552] Examples of some compounds of formula (I) are synthesized using methods involving the splitting of stereoisomeric mixtures (e.g., SFC separation of stereoisomers). In Table C1, the split stereoisomer centers in these compounds are marked with "or1" and / or "or2" enhanced stereochemical symbols. In some cases, stereoisomer splitting is performed in the last step of synthesis, thereby providing a single stereoisomer of a compound of formula (I). Alternatively, in some other cases, splitting is performed on an intermediate or starting material, wherein each constituent stereoisomer of the intermediate or starting material can be subjected to subsequent steps of synthesis alone to provide the corresponding compound of formula (I) as a single stereoisomer. The splitting method and the association between the splitting intermediate and the compound of formula (I) are disclosed in the examples herein and in Example 28, 39, or 83. One of ordinary skill in the art will appreciate that, under any method of stereoisomer splitting, stereoisomers having (R)- and (S)-configurations at the split stereoisomer center are provided. See Table C3, wherein the compounds of Table C1 are provided in diastereomeric form when their stereoisomers contain or1 and / or or2 stereochemical symbols, followed by the corresponding stereoisomers having (R)- and (S)-configurations.

[0553] Table C3

[0554]

[0555]

[0556] Exemplary compounds having formula (I) also include those compounds shown in: Table C1 of U.S. Provisional Application Serial No. 63 / 420,411, filed on October 28, 2022; Table C1 of U.S. Provisional Application Serial No. 63 / 444,778, filed on February 10, 2023; Table C1 of U.S. Provisional Application Serial No. 63 / 497,063, filed on April 19, 2023; and Table C1 of U.S. Provisional Application Serial No. 63 / 501,082, filed on May 9, 2023; or pharmaceutically acceptable salts thereof, wherein each Table C1 is incorporated herein by reference in its entirety.

[0557] Also provided herein are compounds having formula (II):

[0558]

[0559] or a pharmaceutically acceptable salt thereof, wherein:

[0560] The TBM is selected from the group consisting of: (T1), (T2), and (T3):

[0561]

[0562] X 1 and X 2 Independently selected from the group consisting of: N and CR 2 ;

[0563] Each R 2 are independently selected from the group consisting of: H, halo, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -OH, and -NR d R e ;

[0564] m3 is 0, 1, 2, or 3;

[0565] Each X 3 Independently selected from the group consisting of: -O-, -NR f -, -C(=O)- and optionally 1-3 R c Substituted C 1-3 alkylene;

[0566] R 1 Selected from the group consisting of: H, halo, cyano, and R b1 ;

[0567] The condition is N-(X 3 ) m3 -R 1The portion does not contain any OO, NO, or N-halogenated bonds;

[0568] R 3 Selected from the group consisting of:

[0569] -A 1 -C(R 4 R 4 )-A 2 ;and

[0570] -CH=CH-A 2 ,in:

[0571] A 1 is -O- or -S-;

[0572] Each R 4 Independently selected from the group consisting of: H, C 1-6 Alkyl and C 1-6 haloalkyl; or

[0573] The R 4 The pairs together with their respective attached carbon atoms form C 3-6 Cycloalkyl ring or 4-8 membered heterocyclyl ring, wherein the C 3-6 The cycloalkyl ring or the 4-8 membered heterocyclyl ring is optionally substituted by 1-3 R g replace;

[0574] A 2 Selected from the group consisting of: -C(O)OH, -C(O)NH2, -C(O)R 3A 、-C(O)OR 3A 、-C(O)NR 3A R f 、-S(O) 1-2 (C 1-6 alkyl), -P(O)-(C 1-6 -C(=NH)NH2, wherein:

[0575] R 3A Selected from the group consisting of: C 1-6 Alkyl, C 3-6 Alkenyl, C 3-6 Alkynyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: R a and-(C 0-3 Alkylene)-R b1 ;

[0576] X a and X care independently selected from the group consisting of: N, CH, and CF, provided that X a and X c One or two of them are N;

[0577] X b Selected from the group consisting of: N and CR x1 ;

[0578] R 6 and R x1 Each independently selected from the group consisting of: H, halo, C 1-2 Alkyl, C 1-2 Halogenated alkyl, C 1-2 alkoxy, CN, and -C≡CH;

[0579] R 5 Selected from the group consisting of:

[0580] a)H;

[0581] b) halogenated;

[0582] c) cyano;

[0583] d) NO2;

[0584] e)C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R c replace;

[0585] f) optionally 1-6 R c Substituted C 1-6 alkoxy; and

[0586] g)-L 51 -R 51 ;

[0587] L 51 Selected from the group consisting of: bond, O, S(O) 0-2 ,C(O),C(O)O*,OC(O)*,C(O)N(R f )*、N(R f )C(O)*、N(R f )C(O)N(R f )、N(R f )C(O)O*、OC(O)N(R f )*、S(O)2N(R f )*、N(R f )SO2*, and -N(R d )-(C 0-2Alkylene)-*, where * represents 51 Attachment point, and -N(R d )-(C 0-2 Alkylene)-*C 0-2 The alkylene moiety is optionally substituted with 1-3 substituents independently selected from the group consisting of: C 1-3 Alkyl and halo;

[0588] R 51 Selected from the group consisting of:

[0589] a)H;

[0590] b)C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R c and further optionally substituted by R b1 Replacement; and

[0591] c)C 3-10 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl, or 5-15 membered heteroaryl, each of which is optionally independently selected from R a and R b and further optionally substituted with -C(O)N(R f )(CH2CH2O) 1-4 -R a replace;

[0592] L is -(L A ) n1 -, where L A and n1 is defined according to (AA) or (BB):

[0593] (AA)

[0594] n1 is an integer from 1 to 15; and

[0595] Each L A Independently selected from the group consisting of: L A1 , L A3 , and L A4 , the condition is 1-3 occurrences of L A It's L A4 ;

[0596] (BB)

[0597] n1 is an integer from 0 to 20; and

[0598] Each L AIndependently selected from the group consisting of: L A1 and L A3 ;

[0599] Each L A1 Independently selected from the group consisting of: -CH2-, -CHR L -, and -C(R L )2-;

[0600] Each L A3 Independently selected from the group consisting of: -N(R d )-、-N(R b )-、-O-、-S(O) 0-2 -, and C(=O);

[0601] Each L A4 Independently selected from the group consisting of:

[0602] (a)C 3-15 Cycloalkylene or 3-15 membered heterocyclylene, each of which is optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and R b ;as well as

[0603] (b)C 6-15 arylene or 5-15 membered heteroarylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: R a and R b ;

[0604] Provided that L does not contain any NO, NN, NS(O)0, or OS(O) 0-2 key;

[0605] Each R L independently selected from the group consisting of: halo, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e 、C(=O)N(R f )2、S(O) 0-2 (C 1-6 Alkyl), S(O) 0-2 (C 1-6 Halogenated alkyl), S(O) 1-2 N(R f )2. -R b , and optionally 1-6 R c Substituted C 1-6 alkyl;

[0606] Ring C is selected from the group consisting of: c1 is 0, 1, 2, or 3;

[0607] Each R Y Independently selected from the group consisting of: R a and R b ;

[0608] R aN is H or optionally 1-3 R c Substituted C 1-6 alkyl;

[0609] Y 1 and Y 2 are independently N, CH, or CR Y ;

[0610] yy represents the point of attachment to L;

[0611] X is CH, C, or N;

[0612] Is a single bond or a double bond;

[0613] L C Selected from the group consisting of: a bond, -CH2-, -CHR a -、-C(R a )2-、-C(=O)-、-N(R d )-, and the condition is that when X is N, L C is not O; and

[0614] There is a further proviso that when ring C is attached to -L via the ring nitrogen c -, X is CH, and L C It is a key;

[0615] Each R a Independently selected from the group consisting of:

[0616] (a) halogenated;

[0617] (b) cyano;

[0618] (c) -OH;

[0619] (d) oxo;

[0620] (e) optionally 1-6 R c Substituted C 1-6 alkoxy;

[0621] (f)-NR d R e ;

[0622] (g) optionally 1-6 R c Substituted C(=O)C 1-6 alkyl;

[0623] (h) C(=O)OH;

[0624] (i) C(=O)OC 1-6 alkyl;

[0625] (j)C(=O)OC 1-6 alkyl halide;

[0626] (k)C(=O)N(R f )2;

[0627] (l)S(O) 0-2 (C 1-6 alkyl);

[0628] (m)S(O) 0-2 (C 1-6 haloalkyl);

[0629] (n)S(O) 1-2 N(R f )2; and

[0630] (o)C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R c replace;

[0631] Each R b Independently selected from the group consisting of:-(L b ) b -R b1 and -R b1 ,in:

[0632] Each b is independently 1, 2, or 3;

[0633] Each -L b are independently selected from the group consisting of: -O-, -N(H)-, -N(C 1-3 Alkyl)-, -S(O) 0-2 -, C(=O), and C 1-3 an alkylene group; and

[0634] Each R b1 Independently selected from the group consisting of: C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R g replace;

[0635] Each R c independently selected from the group consisting of: halo, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e 、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)OH, C(=O)N(R f )2、S(O) 0-2 (C 1-6 Alkyl), S(O) 0-2 (C 1-6 haloalkyl), and S(O) 1-2 N(R f )2;

[0636] Each R d and R e independently selected from the group consisting of: 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), S(O) 1-2 (C 1-6 Halogenated alkyl), S(O) 1-2 N(R f )2, and optionally 1-3 R h Substituted C 1-6 alkyl;

[0637] Each R f independently selected from the group consisting of: H and optionally 1-3 R h Substituted C 1-6 alkyl;

[0638] Each R g Independently selected from the group consisting of: R h , oxo, C 1-3 Alkyl, and C 1-3 haloalkyl; and

[0639] Each R h are independently selected from the group consisting of: halo, cyano, -OH, -(C 0-3 Alkylene)-C1-6 Alkoxy, -(C 0-3 Alkylene)-C 1-6 Halogenated alkoxy, -(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,

[0640] The condition is when TBM is (T1), where X 1 and X 2 Independently selected from CR 2 ; and when X is N, ring C is

[0641] In formula (II), L, ring C, L C , and X may be as defined herein for formula (I).

[0642] Exemplary compounds having formula (II) include those shown in: Table C1 of U.S. Provisional Application Serial No. 63 / 351,715, filed on June 13, 2022; Table C1 of U.S. Provisional Application Serial No. 63 / 351,697, filed on June 13, 2022; Table C1 of U.S. Provisional Application Serial No. 63 / 395,630, filed on August 5, 2022; Table C1 of U.S. Provisional Application Serial No. 63 / 395,638, filed on August 5, 2022; Table C1 of U.S. Provisional Application Serial No. 63 / 420,421, filed on October 28, 2022; and Table C1 of U.S. Provisional Application Serial No. 63 / 444,801, filed on February 10, 2023; or pharmaceutically acceptable salts thereof, wherein each Table C1 is incorporated herein by reference in its entirety.

[0643] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, reduces cell viability in a cell line expressing a BCL6 protein, wherein EC 50 Less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compound reduces cell viability in a cell line expressing a BCL6 protein, wherein EC 50Less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compound can reduce cell viability in a cell line expressing a BCL6 protein, wherein EC 50 From about 0.1 nM to about 100 nM, from about 0.1 nM to about 50 nM, from about 1 nM to about 50 nM, from about 1 nM to about 20 nM, or from about 0.1 nM to about 1 nM.

[0644] In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, induces degradation of a BCL6 protein in a cell line expressing a BCL6 protein, wherein the DCs 50 Less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, induces degradation of BCL6 protein in a cell line expressing BCL6 protein, wherein DC 50 Less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compound can induce degradation of BCL6 protein in a cell line expressing BCL6 protein, wherein DC 50 From about 0.1 nM to about 100 nM, from about 0.1 nM to about 50 nM, from about 1 nM to about 50 nM, from about 1 nM to about 20 nM, or from about 0.1 nM to about 1 nM.

[0645] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, induces degradation of a BCL6 protein in a cell line expressing a BCL6 protein, wherein Y min In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, induces degradation of a BCL6 protein in a cell line expressing a BCL6 protein, wherein Y min In some embodiments, the compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, induces degradation of BCL6 protein in a cell line expressing the BCL6 protein, wherein Y min Less than 30% (e.g., less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%). For example, the compound can induce degradation of BCL6 protein in a cell line expressing BCL6 protein, wherein Y min From about 1% to about 70% (eg, from about 5% to about 50% or from about 10% to about 30%).

[0646] Also provided herein is a BCL6 protein that non-covalently binds to a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof.

[0647] Also provided herein is a ternary complex comprising a BCL6 protein, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)) or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II), or a pharmaceutically acceptable salt thereof, and a CRBN protein or a portion thereof.

[0648] Chemical definition

[0649] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0650] The term "oxo" refers to a divalent double-bonded oxygen atom (ie, "=0"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.

[0651] The term "alkyl" refers to a saturated acyclic hydrocarbon group which may be straight or branched and contains the indicated number of carbon atoms. 1-10 Indicates that the group may have from 1 to 10 (inclusive) carbon atoms therein. The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, n-hexyl. As used in this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0652] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halo (eg, -CF3, -CHF2, or -CH2F).

[0653] The term "alkoxy" refers to an -O-alkyl group (eg, -OCH3).

[0654] The term "alkylene" refers to a divalent alkyl group (e.g., -CH2-). Similarly, terms such as "cycloalkylene" and "heterocyclylene" refer to divalent cycloalkyl and heterocyclyl groups, respectively. For the avoidance of doubt, in "cycloalkylene" and "heterocyclylene", both groups may be located on the same ring carbon atom (e.g., geminal diradicals, such as ) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., adjacent ring carbon and / or nitrogen atoms)) (e.g., ).

[0655] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2-6 Indicates that the group can have from 2 to 6 (inclusive) carbon atoms in it. An alkenyl group can be unsubstituted or substituted with one or more substituents.

[0656] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2-6 Indicates that the group can have from 2 to 6 (inclusive) carbon atoms in it. An alkynyl group can be unsubstituted or substituted with one or more substituents.

[0657] The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic or polycyclic group, wherein at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0658] 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 or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. As used in this context, the term "saturated" means that there are only single bonds 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 can have any degree of unsaturation, provided that there are one or more double bonds in the cycloalkyl group, none of the rings in the ring system is aromatic, and the partially unsaturated cycloalkyl group is not fully saturated as a whole. Examples of partially unsaturated cycloalkyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Cycloalkyl groups can include multiple fused rings and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls 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, etc. Cycloalkyls also include spirocycles (e.g., spirobicycles in which the two rings are connected by only one atom). Non-limiting examples of spirocyclic cycloalkyl 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, and the like.

[0659] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 15 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (including oxidized forms such as: ) and P (including oxidized forms such as: )(e.g., N, O, and S (including oxidized forms, such as: )) and at least one ring in the system is aromatic (but not necessarily a ring containing heteroatoms, such as tetrahydroisoquinolinyl, for example tetrahydroquinolinyl). In some embodiments, the heteroaryl group contains 1-4 (e.g., 1, 2, or 3) ring heteroatoms each independently selected from the group consisting of N, O, and S (including oxidized forms such as: ). The heteroaryl group may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl [b] [1,4] dioxolyl, benzo[d][1,3] dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolyl, etc. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furanyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazolyl, and pyrimidinyl. For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to the carbonyl group is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., ), pyrimidone (e.g., ), pyridazinones (e.g., ), pyrazinones (e.g., ) and imidazolones (e.g., ), wherein each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (ie, an oxo group (ie, "=O") herein is an integral part of a heteroaryl ring).

[0660] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system having 3-15 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-15 membered tricyclic ring system) and having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic or polycyclic), the heteroatoms being selected from O, N, S (including oxidized forms such as: ) and P (including oxidized forms such as: )(e.g., N, O, and S (including oxidized forms, such as: (e.g., if monocyclic, bicyclic, or tricyclic, having carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, S, or P, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. The term "saturated" as used in this context means that there are only single bonds between the constituent ring atoms and the other available valences occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Partially unsaturated heterocyclyl groups may have any degree of unsaturation, provided that there are one or more double bonds in the heterocyclyl, none of the rings in the ring system is aromatic, and the partially unsaturated heterocyclyl group is not fully saturated as a whole. Examples of partially unsaturated heterocyclyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl.

[0661] Heterocyclic groups may include multiple fused 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]pyrrolyl, 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. Heterocyclyl also includes spirocycles (e.g., spirobicycles 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, 2-oxaspiro[3.5]decyl, 4-azaspiro[3 ...decyl, 4-azaspiro[3.5]undecyl, 4-azaspiro[3.5]decyl, 4-azaspiro[3.5]undecyl, 4-azaspiro[3.5]undecyl, 4-azaspiro[3.5]undecyl, 4-azaspiro[3.5]undecyl, 4-azaspiro[3.5]undecyl, 4-azaspiro[3.5]undecyl, 4-azaspiro[3.5]undecyl, 4-azaspiro[3. Spiro[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, and the like.

[0662] As used herein, nitrogen-containing heterocyclic groups refer to heterocyclic groups having 1-2 ring nitrogen atoms and 0-2 additional ring heteroatoms selected from the group consisting of: O and S (including oxidized forms such as: ). The nitrogen-containing heterocyclic group can be monocyclic, bicyclic or polycyclic, as defined elsewhere herein. Examples of monocyclic nitrogen-containing heterocyclic groups include azetidinyl, 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]nonanyl, 2,6-diazaspiro[3.3]heptanyl, and the like.

[0663] As used herein, when a ring is described as being "partially unsaturated," it is meant that the ring has one or more additional unsaturations (in addition to the unsaturation attributable to the ring itself; for example, one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0664] For the avoidance of doubt, and unless otherwise indicated, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc., as described herein) containing a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic systems), it is understood that such rings and cyclic groups include those having fused rings, including those in which the points of fusion are between (i) adjacent ring atoms (e.g., a [xx0] ring system where 0 represents a zero atom bridge (e.g., )); (ii) a single ring atom (spiro-fused ring system) (e.g., ); or (iii) a continuous array of ring atoms (a bridged ring system with all bridge lengths > 0) (e.g., ) on the .

[0665] In addition, the atoms comprising the compounds of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0666] Furthermore, compounds disclosed herein generally or specifically are intended to include all tautomeric forms. Thus, as an example, a compound containing the following moiety: Included are tautomeric forms containing: Similarly, a pyridinyl or pyrimidinyl moiety described as optionally substituted with hydroxy includes the pyridone or pyrimidone tautomeric forms.

[0667] The compounds provided herein may encompass various stereochemical forms. These compounds also encompass diastereomers and optical isomers, such as mixtures of enantiomers including racemic mixtures, as well as single enantiomers and diastereomers, which are the result of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or represented by a structure without specifying stereochemistry and having one or more chiral centers, it should be understood that all possible stereoisomers of the compound are represented.

[0668] Treatment

[0669] Indications

[0670] Provided herein are methods for inducing BCL6 protein degradation. For example, provided herein are compounds capable of inducing BCL6 protein degradation, which compounds can be used to treat or prevent cancer. Exemplary compounds that bind to BCL6 are described, for example, in Cerchietti, Leandro C. et al. Cancer Cell 17.4 (2010): 400-411; Cardenas, Mariano G. et al. The Journal of Clinical Investigation 126(9) (2016): 3351-3362; Kerres, Nina et al. Cell Reports 20.12 (2017): 2860-2875; Yasui, Takeshi et al. Bioorganic & Medicinal Chemistry 25.17 (2017): 4876-4886; Kamada, Yusuke et al. Journal of Medicinal Chemistry 60.10 (2017): 4358-4368; McCull, William et al. ACS Chemical Biology [American Chemical Society Chemical Biology] 13.11 (2018): 3131-3141; Guo, Weikai et al. Journal of Medicinal Chemistry [Journal of Medicinal Chemistry] 63.2 (2020): 676-695; Teng, Mingxing et al., ACS Medicinal Chemistry Letters [American Chemical Society Medicinal Chemistry Letters] 11.6 (2020): 1269-1273; Pearce, Andrew C. et al., Journal of Biological Chemistry [Journal of Biological Chemistry] 297.2 (2021); Ding, Shu, Yu Rao, and Qianjin Lu, Cellular & Molecular Immunology [Cellular and Molecular Immunology] (2022): 1-3; Xing, Y. et al., Cancer 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 Publication Nos. WO 2008 / 066887; WO 2010 / 008436; WO 2014 / 204859; WO 2018 / 215798; WO 2018 / 215801; WO 2018 / 219281; WO 2019 / 119138; WO 2019 / 119144; WO 2019 / 119145; WO 2019 / 153080; WO 2019 / 197842; WO 2020 / 104820; WO 2021 / 074620; WO 2021 / 077010, and WO 2022 / 221673. .

[0671] The degradation efficacy of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II), or a pharmaceutically acceptable salt thereof, as provided herein, can be determined by DC 50 As used herein, DC 50refers to a concentration of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) that results in a 50% decrease in the concentration of a protein (e.g., BCL6 protein) in a cell compared to the concentration at which the cell is contacted with a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) that results in a 50% decrease in the concentration of a protein (e.g., BCL6 protein) in a cell compared to the concentration at which the cell is contacted with a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa) The concentration of the protein in cells having a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-a-3), or (I-a-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)) or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II) is lower than the concentration of the protein in cells having a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)) or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II). 50 Compounds with a higher DC 50 In some embodiments, DC 50The value can be determined in vitro or in vivo (e.g., using a HiBiT assay) (e.g., in tumor cells (e.g., cell lines such as 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; see also those disclosed in, e.g., Cardenas, Mariano G. et al. Clinical Cancer Research 23.4 (2017): 885-893, and International Publication Nos. WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673), these tumor cells express BCL6 protein). In some embodiments, cell lines that are independent of BCL6 and / or do not significantly express BCL6 (e.g., Toledo, H929, MM.1S, or OPM2) can be used as controls.

[0672] The degradation efficacy of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, as provided herein, can be determined by EC 50 As used herein, EC 50refers to a concentration of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) that results in a 50% decrease in the concentration of a protein (e.g., BCL6 protein) in a cell (relative to the trough concentration of the protein) compared to the concentration at which the cell is contacted with a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) )(e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)))), or Formula (II), or the concentration of the protein in cells that have not been contacted with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)))), or Formula (II). Has a lower EC 50 Compounds with higher EC values ​​(as determined under substantially similar conditions) 50 In some embodiments, EC 50The value can be determined in vitro or in vivo (e.g., using a HiBiT assay) (e.g., in tumor cells (e.g., cell lines such as 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 those disclosed in, e.g., Cardenas, Mariano G. et al. Clinical Cancer Research 23.4 (2017): 885-893, and International Publication No. WO 2021 / 080950, WO2021 / 077010, and WO 2022 / 221673), these tumor cells express BCL6 protein). In some embodiments, cell lines that are independent of BCL6 and / or do not significantly express BCL6 (e.g., Toledo, H929, MM.1S, or OPM2) can be used as controls.

[0673] The degradation efficacy of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II), or a pharmaceutically acceptable salt thereof, as provided herein, can be determined by Y min As used herein, Y minrefers to the trough concentration of a protein (e.g., a BCL6 protein) in a cell compared to the trough concentration of the protein before the cell was contacted with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II). As used herein, D is the ratio of the concentration of a protein to the concentration of a protein in a cell relative to the concentration of the protein in a cell not contacted with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), expressed as a percentage. max is 1-Y min .Y min Can be measured by HiBiT assay (as described in Example B1). min Compounds with a higher Y value (as determined under substantially similar conditions) are more likely to be min In some embodiments, Y minThe value can be determined in vitro or in vivo (e.g., using a HiBiT assay) (e.g., in tumor cells (e.g., cell lines such as 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 those disclosed in, e.g., Cardenas, Mariano G. et al. Clinical Cancer Research 23.4 (2017): 885-893, and International Publication Nos. WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673), these tumor cells express BCL6 protein). In some embodiments, cell lines that are independent of BCL6 and / or do not significantly express BCL6 (e.g., Toledo, H929, MM.1S, or OPM2) can be used as controls.

[0674] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y value of less than 70% (e.g., less than 50% or less than 30%) in a HiBiT-based degradation assay (e.g., an assay as described in Example B1). min In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y-value of less than 50% (e.g., less than 30%) in a HiBiT-based degradation assay. minIn some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y value of less than 30% in a HiBiT-based degradation assay. min .

[0675] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y value of less than 70% (e.g., less than 50% or less than 30%) in the assay described in Example B1. min In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y value of less than 50% (e.g., less than 30%) in the assay described in Example B1. min In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y value of less than 30% in the assay described in Example B1. min .

[0676] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y degradation of about 0% to about 70% (e.g., about 0% to about 50%, about 30% to about 50%, or about 0% to about 30%) in a HiBiT-based degradation assay (e.g., an assay as described in Example B1). min In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y reduction of about 0% to about 50% (e.g., about 30% to about 50% or about 0% to about 30%) in a HiBiT-based degradation assay. min In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y-value of about 0% to about 30% in a HiBiT-based degradation assay. min .

[0677] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y of about 0% to about 70% (e.g., about 0% to about 50%, about 30% to about 50%, or about 0% to about 30%) in the assay described in Example B1. min In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y of about 0% to about 50% (e.g., about 30% to about 50% or about 0% to about 30%) in the assay described in Example B1. min In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits a Y value of about 0% to about 30% in the assay described in Example B1. min .

[0678] It will be appreciated that the effects of protein degradation will typically increase over time, although the presence of degradation (e.g., percent degradation compared to a control, or parameter Y) will not be apparent. min 、DC 50 , and / or D max Degradation is typically measured in the art after a specified time period (e.g., 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 a percentage of degradation after 24 hours.

[0679] Exemplary assays for validating the degradation-inducing mechanism of compounds provided herein are known in the art and are described, for example, in Wu et al. Nature Structural & Molecular Biology 27.7 (2020): 605-614.

[0680] 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 immunoblotting, other immunoassays (e.g., MesoScale Discovery, Inc. (MSD) immunoassays), homogeneous time-resolved fluorescence (HTRF), and HiBiT. In some embodiments, cells can be contacted with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, incubated, and lysates can be prepared for gel electrophoresis (e.g., SDS-PAGE), followed by immunoblotting and quantification compared to a control (e.g., a DMSO-treated control). As another example, a cell line can be engineered to express HiBiT-tagged BCL6 protein, and the amount of fluorescence observed upon addition of a complementary LgBiT peptide can be compared between cells treated with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, and a control (e.g., a DMSO-treated control). See, e.g., Example B1. In some embodiments, the induction of off-target degradation of the proteins eukaryotic peptide chain release factor GTP-binding subunit ERF3A (GSPT1), Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3) and / or casein kinase I subtype α (CK1α) can be assessed.See also, for example, International Publication Nos. WO 2018 / 215798; WO 2018 / 215801; WO 2020 / 104820; McCull, William et al., ACS Chemical Biology 13.11 (2018): 3131-3141; Bellenie, Benjamin R. et al., Journal of Medicinal Chemistry 63.8 (2020): 4047-4068; Lloyd, Matthew G. et al., Journal of Medicinal Chemistry 64.23 (2021): 17079-17097.

[0681] The binding affinity of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) or a pharmaceutically acceptable salt thereof to BCL6 as provided herein can be determined by, for example, binding to IC 50 or K i value (e.g., using a competition assay) or by K D values ​​(e.g., using a biophysical assay). 50 Compounds with a higher binding IC value (as determined under substantially similar conditions) are compared to compounds with a higher binding IC value. 50 The compound with lower binding K i Compounds with higher binding K values ​​(as determined under substantially similar conditions) are compared to compounds with higher binding K values. i Similarly, compounds with lower K D Compounds with higher K values ​​(as determined under substantially similar conditions) are more likely to be D For example, K DValues ​​can be determined by surface plasmon resonance (SPR) or biomembrane interferometry; see, for example, Guo, Weikai et al., Journal of Medicinal Chemistry 63.2(2020):676-695; Lloyd, Matthew G. et al., Journal of Medicinal Chemistry 64.23(2021):17079-17097, and International Publication Nos. WO 2019 / 153080; WO 2019 / 119144; and WO 2019 / 119145.

[0682] The ability of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, as provided herein, to inhibit BCL6 can be determined using IC 50 With lower IC 50 Compounds with higher IC values ​​(as determined under substantially similar conditions) are compared to compounds with higher IC values. 50 Compounds with higher IC values ​​are more potent inhibitors. For example, 50The value can be calculated using a FRET (e.g., homogeneous time-resolved fluorescence (HTRF)) assay, wherein a labeled (e.g., His-tagged) BCL6 protein and a labeled (e.g., fluorophore-labeled (e.g., Alexa-Fluor 633)) corepressor peptide (e.g., BCOR) are incubated with a 5-well plate having formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), formula (Ia) (e.g., The FRET ratio can be measured relative to an appropriate control using a suitable FRET pair (e.g., an antibody that recognizes a labeled BCL6 protein (e.g., an anti-His-terbium cryptate). See, e.g., International Publication Nos. WO 2018 / 108704; WO 2018 / 215798; WO 2019 / 197842; WO 2020 / 104820; WO 2021 / 074620. As another example, IC 50 The value can be calculated using an enzyme-linked immunosorbent assay (ELISA) using a labeled (e.g., biotinylated) corepressor peptide (e.g., BCOR) and a labeled (e.g., FLAG-tagged) BCL6 (e.g., a domain thereof, such as the BTB domain) immobilized on a substrate, wherein the protein has formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), formula (Ia) (e.g., formula Compounds of Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II) can be used to prevent the interaction between the corepressor peptide and BCL6, and antibodies to the BCL6 construct (e.g., anti-FLAG antibodies) can be used to measure the interaction between the corepressor peptide and BCL6. See, e.g., Kamada, Yusuke et al., Journal of Medicinal Chemistry 60.10 (2017): 4358-4368. As yet another example, IC 50The value can be calculated using a fluorescence polarization assay with a fluorescently labeled corepressor peptide (e.g., SMRT), wherein a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II) can be used to prevent the interaction between the corepressor peptide and BCL6. See, e.g., International Publication No. WO 2019 / 119144. As another example, cell IC 50 The value can be calculated using a BRET (bioluminescence resonance energy transfer) assay, wherein a vector encoding BCL6 and a corepressor peptide (e.g., SMRT) (complementarily fused to NanoLuc or HaloTag) can be inserted into cells. The cells can be treated with a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, to determine the effect of the compound in inhibiting the BCL6-corepressor interaction. See, e.g., International Publication Nos. WO 2018 / 215798 and WO 2019 / 197842. In another example, an IC that inhibits BCL6 repressor function 50 Values ​​can be calculated using a luciferase assay, wherein cells are engineered to express luciferase under the control of one or more BCL6 repressor sites, and the cells can be incubated with a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, to determine the effect of the compound on BCL6 repressor function. See, e.g., International Publication Nos. WO 2019 / 119144; WO 2019 / 119145; WO 2019 / 153080.

[0683] Another exemplary method for evaluating the effect of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is to measure the induction (e.g., fold induction) of genes typically repressed by BCL6 (e.g., p53, ATR, CXCR3, CD69, and CDKN1A) using methods such as RT-PCR. See, e.g., Guo, Weikai et al., Journal of Medicinal Chemistry 63.2 (2020): 676-695.

[0684] Exemplary assays for determining the potency of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, include The effect of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, on cell proliferation and / or viability is measured. Cell proliferation assays can be performed in a variety of formats, including 2D and 3D. Similarly, cell proliferation assays can be performed with any appropriate 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 embodiments, cell lines that are independent of BCL6 and / or do not significantly express BCL6 (e.g., Toledo, H929, MM.1S, or OPM2) can be used as controls. As an illustrative example, a 3D cell proliferation assay can include culturing cells in a 3D culture medium, contacting the cells with a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, using an appropriate reagent (e.g., 3D) to measure cell proliferation, and then the signal of the experiment with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is measured. Comparison is made to a control experiment (e.g., lacking a signal of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof). As another illustrative example, a 2D cell proliferation assay can include plating cells on a growth surface, optionally growing the cells for a period of time, contacting the cells with a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, using an appropriate reagent (e.g., ) measuring cell proliferation, and then using a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, to measure the signal from the experiment. Comparison is made to a control experiment (e.g., lacking a signal from a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof). Additional cell viability assays include the MTT assay, which is a colorimetric assay based on the reduction of the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to an insoluble purple formazan, and other similar assays based on related tetrazolium salts, the ATPlite assay, and other methods are known in the art. See, e.g., Example B2. See also, for example, Guo, Weikai et al., Journal of Medicinal Chemistry 63.2(2020):676-695; McCull, William et al., ACS Chemical Biology 13.11(2018):3131-3141; Lloyd, Matthew G. et al., Journal of Medicinal Chemistry 64.23(2021):17079-17097; Bellenie, Benjamin R. et al., Journal of Medicinal Chemistry 63.8(2020):4047-4068; and International Publication Nos. WO 2018 / 215798; WO 2018 / 215801; WO 2018 / 219281; WO 2019 / 119145; WO 2019 / 153080; and WO 2020 / 104820.

[0685] Cell viability assays can be used to measure the effect of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) on cell death, or a pharmaceutically acceptable salt thereof. For example, cells expressing 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) with various concentrations of a molecule having formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa) -1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is incubated with a compound of Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), and then exposed to a detection reagent (e.g., using CELLTITER- In some embodiments, the effect on cell viability can be compared with a cell line that is not dependent on BCL6 and / or does not significantly express BCL6 (e.g., Toledo, H929, MM.1S, or OPM2).

[0686] Cell viability assays can be used to measure the effect of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent on cell death. For example, cells expressing 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) and various concentrations of an antibody having formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), formula A compound of Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent (e.g., any additional therapeutic agent described herein) (e.g., half-log dilution from 316 nM to 1 nM), incubated in a 7x7 dose matrix (e.g., for 72 hours or 120 hours), and then exposed to a detection agent (e.g., using CELLTITER- Cell viability assay kit) to determine cell viability. Combination activity can be evaluated by the Bliss independence model, where negative values ​​represent antagonism, positive values ​​represent synergy, and zero values ​​represent additive effects. The Bliss scores in the dose matrix can be summed to obtain a "Bliss sum" value to reflect the overall synergistic activity of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)) or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II) or a pharmaceutically acceptable salt thereof and another therapeutic agent in each cell line. In some embodiments, cell lines that are independent of BCL6 and / or do not significantly express BCL6 (eg, Toledo, H929, MM.1S, or OPM2) can be used as controls.

[0687] As another example, the potency and / or efficacy of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can be assessed in an animal model, such as a cell line-derived (CDX) xenograft model (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 (GEMMs), or patient-derived xenograft (PDX) models. For example, PDX models can be generated in immunodeficient mice (e.g., athymic nude mice, outbred homozygous mice (e.g., Crl:NU(NCr)-Foxn1 nu) or FoxChase SCID(CB17 / Icr-Prkdc scid The study was performed in mice (IcrIcoCrl). Mice were female and 6-12 weeks old at the time of tumor implantation, with free access to food and water. Approximately 70 mg of tumor was implanted subcutaneously in the right flank of each mouse. Tumors were measured weekly after implantation and were monitored once tumor volume reached 150-300 mm. 3 , mice can be randomly divided into treatment and control groups. In some embodiments, one or more experimental groups can be added to evaluate pharmacokinetics and / or pharmacodynamics. Mice can be treated with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)) or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II) or a pharmaceutically acceptable salt thereof (e.g., administered via IP or PO) and optionally another therapy or therapeutic agent (e.g., any other therapy or therapeutic agent described herein). Throughout the study, the health status, body weight, and tumor volume of the mice can be recorded weekly. Mice can be treated on day 28 or when the tumor reaches 1 cm 3 Patients are sacrificed at t≥10 days and tumors can be assessed (e.g., by tumor weight, tumor volume). At the end of each study, the best response can be calculated for each treatment group. The best response is defined as the delta volume at t≥10 days. tThe best response between the control group and the treatment group can be compared to determine whether the treatment group is better than the control group. In some embodiments, tumor samples can also be collected at the end of each study and related proteins (e.g., BCL6) can be measured to determine whether the treatment has better protein regulatory properties compared to the control. In some embodiments, tumor samples and / or blood samples can also be collected at the end of each study and the altered gene expression activity (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, IF (Expression levels of ITM2, 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 for efficacy studies. For example, for pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples can be obtained from mice on day 1, 3, and / or 5 (with samples collected 6, 12, and / or 24 hours after administration), relevant proteins can be measured in the tumor samples, and pharmacokinetic studies can be performed on blood samples or fractions thereof (e.g., plasma). In some embodiments, the PDX is a model of 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), DLBCL, FL, MCL, Burkitt lymphoma, or peripheral T-cell lymphoma (PTCL) (e.g., PTCL with T follicular helper phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (PTCL-NOS)).See, e.g., Guo, Weikai et al., Journal of Medicinal Chemistry 63.2 (2020): 676-695.

[0688] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, exhibits activity in a model of an autoimmune disease. For example, exemplary assays can be found in International Publication Nos. WO 2020 / 014599 and WO 2021 / 074620.

[0689] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can be evaluated for its ability to modulate (e.g., reduce) IgG antibody production and / or modulate (e.g., reduce) germinal center formation in an animal (e.g., a mouse) following challenge with a T cell-dependent antigen (e.g., keyhole limpet hemocyanin (KLH)). For example, KLH can be administered to mice (e.g., C57BL / 6 mice) followed by administration of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, for a period of time (e.g., 14 days). Following sacrifice, serum samples of the mice can be analyzed for KLH-specific IgG, for example, by ELISA. Similarly, germinal centers can be detected using immunohistological staining, for example, using peanut agglutinin (PNA). See, for example, Example 1 of WO 2020 / 014599.

[0690] In some embodiments, the ability of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, to modulate (e.g., decrease) the number of germinal center B cells in an animal (e.g., a mouse) following immunization with an antigen, can be assessed. For example, an animal (e.g., a mouse) can be immunized with complete Freund's adjuvant (CFA), 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 a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. The cells can then be analyzed, for example, for the number of germinal center B cells (e.g., by flow cytometry using lineage markers GL7 and CD95). See, for example, WO 2021 / 074620.

[0691] In some embodiments, the ability of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, to improve one or more symptoms, biomarkers, or other signs of an autoimmune disease in an animal model of an autoimmune disease, can be evaluated.

[0692] Experimental autoimmune encephalitis (EAE) can be used as an animal model for CNS inflammatory diseases, including multiple sclerosis (MS) and neuromyelitis optica. In some cases, EAE can be induced in animals (e.g., mice), for example, by treatment with recombinant human myelin oligodendrocyte glycoprotein (MOG) or a fragment thereof (e.g., MOG1-125 ), myelin basic protein and / or proteolipid protein immunization. After inducing EAE, animals can be treated with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. For example, animals can be assessed by EAE severity, B cell depletion, or both. See, e.g., Constantinescu, Cris S. et al. British Journal of Pharmacology 164.4 (2011): 1079-1106; Monson, Nancy L. et al. PLoS One 6.2 (2011): e17103.

[0693] In some embodiments, the autoimmune disease is anti-synthetase syndrome. For example, a model of anti-synthetase syndrome can be induced in susceptible mice (e.g., C57BL / 6, B6.G7 and / or NOD.Idd3 / 5) by immunization with histidyl-tRNA synthetase (e.g., mouse histidyl-tRNA synthetase or human histidyl-tRNA synthetase) or a fragment thereof. Treatment with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, can be initiated at the time of immunization and continued 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 mouse can be sacrificed. For example, the mouse can be assessed for the production of histidyl-tRNA synthetase-specific antibodies (e.g., via immunoprecipitation, ELISA, and / or flow cytometry), tissue (e.g., lung and / or muscle) inflammation (e.g., by pathologist review), or a combination thereof. See, e.g., Katsumata, Yasuhiro et al. Journal of Autoimmunity 29.2-3 (2007): 174-186; Katsumata, Yasuhiro et al. Journal of Autoimmunity 29.2-3 (2007): 174-186; Ascherman, Dana P. Current Rheumatology Reports 17 (2015): 1-7; and Konishi, Risa, Yuki Ichimura, and Naoko Okiyama. Immunological Medicine 46.1 (2023): 9-14.

[0694] In certain embodiments, autoimmune disease is arthritis (for example, rheumatoid arthritis or inflammatory arthritis).For example, it is possible to induce rheumatoid arthritis (i.e., collagen-induced arthritis (CIA)) in susceptible mice (for example, DBA / 1 or HLA-DR) by using type II collagen (CII) immunization.With formula (I) (for example, formula (I-aa) (for example, formula (I-aa-1), (I-aa-2), (I-aa-3) or (I-aa-4)), formula (Ia) (for example, formula (Ia-1), (Ia-2), (Ia-3) or (Ia-4)), formula (I-bb) (for example, formula (I-bb-1) or (I-bb-2)) or formula (Ib) (for example, formula (Ib-1) or (Ib-2))) or the treatment of the compound of formula (II) or its pharmaceutically acceptable salt can be started and continued for a period of time (for example, 6 weeks) when immunization. For example, the mouse can be assessed for clinical scores (e.g., inflammation of the arthritic limb, foot thickness, paw volume (e.g., using a foot swelling meter), or a combination thereof), production of CII-specific antibodies, B cell depletion, or a combination thereof. See, for example, Example 2 of WO 2020 / 014599; Brand, David D. et al. Nature Protocols [Nature Protocol] 2.5 (2007): 1269-1275. Additional animal models of arthritis (e.g., inflammatory arthritis) are known in the art, such as K / BxN mice. In some embodiments, such mice can be treated with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, and evaluated, for example, in a manner similar to that of mice immunized with CII, or alternatively, to titrate autoantibodies, such as antibodies to glucose-6-phosphate isomerase. See, e.g., Huang, Haochu, Christophe Benoist, and Diane Mathis. Proceedings of the National Academy of Sciences 107.10 (2010): 4658-4663; and Pigott, Elizabeth, and Laura Mandik-Nayak. Arthritis & Rheumatism 64.7 (2012): 2169-2178.

[0695] In some embodiments, the autoimmune disease is graft-versus-host disease (e.g., chronic graft-versus-host disease). In some cases, the animal model of graft-versus-host disease can be treated with high-dose cyclophosphamide and lethal total body irradiation (TBI), and rescued with bone marrow (optionally including allogeneic splenocytes or purified T cells) (e.g., mice). Subsequently, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)) or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II) or a pharmaceutically acceptable salt thereof can be administered for a period of time. Animals can be assessed by, for example, lung function tests, by immunohistochemistry to assess the presence of autoantibodies, or by examining spleen sections for germinal centers, 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; and Paz, Katelyn et al. Blood, The Journal of the American Society of Hematology 133.1 (2019): 94-99. See also, for example, Dubovsky, Jason A. et al. The Journal of Clinical Investigation 124.11 (2014): 4867-4876.

[0696] In certain embodiments, autoimmune disease is IgG4 related disease (IgG4-RD). In some cases, IgG4-RD animal model can be generated by injecting IgG (for example, IgG1 and / or IgG4) derived from human IgG4-RD patients into mice. Such mice can be treated with a compound of formula (I) (for example, formula (I-aa) (for example, formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), formula (Ia) (for example, formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), formula (I-bb) (for example, formula (I-bb-1) or (I-bb-2)) or formula (Ib) (for example, formula (Ib-1) or (Ib-2))) or formula (II) or a pharmaceutically acceptable salt thereof. Animals can be assessed by measuring, for example, pancreatic and / or salivary tissue damage, B cell depletion, or both. See, e.g., Shiokawa, Masahiro et al. Gut 65.8 (2016): 1322-1332.

[0697] In some embodiments, the autoimmune disease is lupus (e.g., lupus erythematosus). In some cases, the lupus animal model is MRL / lpr mice, which can show high expression of Tfh related molecules (such as ICOS, PD-1, BCL-6, and IL-21), and produce autoantibodies for nuclear components, causing nephritis, arthritis, and skin lesions. Such mice can be treated with a compound of formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), formula (I-bb) (e.g., formula (I-bb-1) or (I-bb-2)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or formula (II) or a pharmaceutically acceptable salt thereof. Animals can be assessed by, for example, 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 [Immunology] 179.5 (2007): 3351-3361; Shen, Chunxiu et al. Journal of Cellular and Molecular Medicine [Cellular and Molecular Medicine] 25.17 (2021): 8329-8337; and Marinov, Anthony D. et al. Arthritis & Rheumatology [Arthritis and Rheumatology] 73.5 (2021): 826-836. Additional animal models of lupus are known in the art, such as NZB / W mice, which can be treated with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, and evaluated in a manner similar to that of MRL / lpr mice.See, e.g., Wang, Wensheng et al. The Journal of Immunology 192.7 (2014): 3011-3020; and Kansal, Rita et al. Science Translational Medicine 11.482 (2019): eaav1648.

[0698] In some embodiments, the autoimmune disease is myasthenia gravis (e.g., myasthenia gravis that is positive for muscle-specific tyrosine kinase (MuSK)). For example, an animal model of myasthenia gravis (e.g., a rat model, a mouse model, or a rabbit model) can be produced by immunizing an animal with an acetylcholine receptor (from the genus Torpedo, such as Torpedo californica, or the genus Electrophorus, such as the electric organ of the electric eel), or a recombinant acetylcholine receptor protein or a fragment thereof. Treatment with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, can be initiated, for example, about 4 weeks after immunization, but can sometimes be initiated earlier or later. Rodents can be evaluated for clinical scores (e.g., grasping and / or lifting heavy objects while observing tremors, hunched posture, muscle strength, and signs of fatigue), body weight, compound muscle action potentials (e.g., using electromyography), anti-acetylcholine receptor antibodies, B cell depletion, or a combination thereof. See, e.g., Mori, Shuuichi et al. The American Journal of Pathology 180.2 (2012): 798-810; Xin, Ning et al. Molecular and Cellular Neuroscience 58 (2014): 85-94; and Losen, Mario et al. Experimental Neurology 270 (2015): 18-28.

[0699] In some embodiments, the autoimmune disease 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, an animal model of MS can be based on EAE, such as relapsing-remitting EAE in SJL / J mice (e.g., via induction of proteolipid protein (PLP)). 139-151 immunization), chronic EAE in C57BL / 6J mice (e.g., via immunization with MOG 35-55 immunization) or EAE in transgenic mice (e.g., by expressing MOG 35-55 In some embodiments, the animal (e.g., mouse) model is generated by infecting a picornavirus (e.g., Theiler murine encephalitis virus). In some embodiments, the animal (e.g., mouse) model is generated by feeding C57BL / 6 mice with cuprizone (e.g., 0.2% for 6 weeks). In some embodiments, the animal (e.g., mouse) model is generated by injection of lysolecithin (e.g., in SJL / J mice). After treatment with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, the animal can be analyzed, for example, for levels of myelin-specific T cells, B cell depletion, reduction in inflammatory lesions, axonal degeneration, protection or reversal of demyelination induced by biscyclohexanone oxalyldihydrazone or lysolecithin, or a combination thereof. See, e.g., Procaccini, Claudio et al. European Journal of Pharmacology 759 (2015): 182-191;

[0700] In some embodiments, the autoimmune disease is neuromyelitis optica (NMO). In some cases, animal models of NMO include administering antibodies against the astrocyte water channel aquaporin 4 (AQP4) (referred to as AQP4-IgG or NMO-IgG) to various CNS tissues (e.g., the brain). In some embodiments, the antibody is administered to animals with EAE. AQP4-IgG can be recombinant or derived from human NMO patients. Following treatment with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, animals sacrificed can be analyzed, for example, for the reduction or reversal of astrocyte demyelination, the number of macrophages, the number of activated microglia, the number of activated neutrophils, B cell depletion, or a combination thereof. See, e.g., 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; Saini, Harleen et al. BMC Neurology 13.1(2013):1-9; Oji, Satoru et al. PloS One 11.3(2016):e0151244; Peschl, Patrick et al. Journal of Neuroinflammation 14.1(2017):1-14; and Duan, Tianjiao, and Alan S. Verkman. Brain Pathology 30.1(2020):13-25.

[0701] In some embodiments, the autoimmune disease is pemphigus (e.g., pemphigus vulgaris). In some cases, an animal (e.g., mouse) model of pemphigus can be generated by adoptively transferring peripheral lymphocytes from a Dsg3 knockout animal into an immunodeficient recipient mouse that expresses desmocollin 3 to establish an artificial immune state in the recipient animal. In some cases, an animal (e.g., mouse) model of pemphigus can be generated using an animal that expresses the pemphigus-associated HLA-DRB1*0402 allele and has an MHC class II gene-deficient background, which produces anti-human DSG3 antibodies after immunization with recombinant human DSG3. After treatment of these models with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, the B cell repertoire of the animal can be analyzed, for example, for anti-desmosomal mucin B cell clones, B cell depletion, or both. See, e.g., Kasperkiewicz, Michael et al. Nature Reviews Disease Primers 3.1 (2017): 1-18.

[0702] In some embodiments, the autoimmune disease is Sjögren's syndrome. In some cases, the animal model of Sjögren's syndrome is the NOD mouse, which is sometimes further genetically manipulated or hybridized (e.g., NOD.B10.H2 bor C57BL / 6.NOTDc3.NODc1t) to reproduce the symptoms of the syndrome. Such mice can be treated with a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof. For example, an animal can be assessed for salivary and tear gland flow rates, salivary protein content, autoantibodies to 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 a combination thereof. Robinson, Christopher P., et al. Arthritis & Rheumatism 41.1 (1998): 150-156; Cha, Seunghee, et al. Arthritis & Rheumatism 46.5 (2002): 1390-1398; and Ohno, Seiji, et al. Autoimmunity 45.7 (2012): 540-546. Additional 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 for the same parameters as NOD mice. See, for example, Iizuka, Mana et al. Journal of Autoimmunity 35.4 (2010): 383-389; and Park, Young-Seok, Adrienne E Gauna, and Seunghee Cha. Current Pharmaceutical Design 21.18 (2015): 2350-2364.

[0703] The pharmacokinetic parameters of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model (e.g., a mouse model, a rat model, a dog model, or a non-human primate (e.g., cynomolgus monkey) model). Pharmacokinetic (PK) studies can be performed in an animal model (e.g., male CD-1 mouse) by two exemplary delivery routes: intravenous (IV) injection and oral (PO), such as oral gavage. Animals in the IV group (e.g., n=3) had free access to food and water; animals in the PO group had free access to food or were fasted for 6-8 hours before dosing. A compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can be formulated as a solution for the IV route and a solution or suspension for the PO route. On the day of the experiment, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, can be administered via intravenous injection via the IV route (e.g., 1 mg / kg), or oral gavage via the PO route (e.g., 3 to 90 mg / kg, or 3 to 10 mg / kg, such as 10 mg / kg).In some cases, animals can be orally administered a cytochrome P450 inhibitor (e.g., 1-aminobenzotriazole) prior to (e.g., 16 hours prior to) administration of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. Blood samples can be collected via serial blood sampling (e.g., at 8 time points between 0.83 and 24 hours after administration). At each time point, blood (e.g., about 30 μL to about 125 μL, or about 75 μL to about 125 μL) can be collected (e.g., via the saphenous vein) into a tube containing an anticoagulant (e.g., K2EDTA). The blood sample can be placed on wet ice and centrifuged (e.g., 2000 x g, 4-10 minutes) to obtain a plasma sample. The plasma sample 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 sample analysis. Pharmacokinetic parameters (including clearance (CL), volume of distribution (V), and PH) can be analyzed. d ), maximum plasma concentration (C max ), time of maximum plasma concentration (t max )), half-life (t 1 / 2 ), area under the curve (AUC) and oral bioavailability (%F) can be calculated using a non-compartmental model.

[0704] In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is at least 4%. In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is at least 10%. In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is at least 20%. In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is at least 30%.In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is at least 40%. In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is at least 60%. In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is at least 80%. In some embodiments, the %F of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is about 4% to about 90% (e.g., about 4% to about 80%, about 4% to about 60%, about 4% to about 40%, about 4% to about 20%, about 4% to about 10%, about 20% to about 40%, about 40% to about 60%, about 60% to about 80%, or about 70% to about 90%).In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is about 4% to about 20%. In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is about 20% to about 40%. In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is about 40% to about 60%. In some embodiments, the %F of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is about 50% to about 80%.

[0705] In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is not a substrate for human cytochrome P450 enzymes. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is not a substrate for a human cytochrome P450 enzyme, wherein ≥25% of the clearance is attributed to the enzyme. In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is not an inhibitor and / or inducer of one or more human cytochrome P450 enzymes. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is not an inhibitor and / or inducer of one or more human cytochrome P450 enzymes, wherein for one or more human cytochrome P450 enzymes, IC 50 and / or EC 50The concentrations are significantly higher than the estimated free fraction concentrations of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, at clinically relevant doses.

[0706] Exemplary human cytochrome P450 enzymes include those in the CYP1, CYP2, and CYP3 families, for example, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2J2, CYP2S1, CYP2E1, CYP3A4, and any one of CYP3A5. In some embodiments, no single cytochrome P450 enzyme is responsible for greater than or equal to 25% of the elimination of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof. Cytochrome P450 inhibition and / or induction activity can be determined using any appropriate assay, such as those described in the guidance document "In VitroDrug Interaction Studies—Cytochrome P450 Enzyme-and Transporter-MediatedDrug Interactions" provided by the U.S. Food and Drug Administration in January 2020. For example, cytochrome P450 inhibition can be assessed in a reversible and time-dependent manner in in vitro studies. In in vitro inhibition studies, the ratio of the intrinsic clearance values ​​of the probe substrate for the enzyme pathway in the absence and presence of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) or a pharmaceutically acceptable salt thereof can be calculated; for reversible inhibition, this ratio is referred to as R1, where R1 = 1 + (I max,u / K i,u ) and I max,uis the maximum unbound plasma concentration of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, and K i,u is the unbound inhibition constant determined in vivo. Specifically, for CYP3A, R 1,gut , where R 1,gut =1+(I gut +K i,u ) and wherein I gut is the intestinal lumen concentration of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, calculated as dose / 250 mL. The time-dependent inhibition rate, R2, can be similarly calculated, where R2 = (k obs +k deg ) / k deg And kobs (through k obs =(k inact *50*I max,u ) / (K I,u +50*I max,u ) is the observed (apparent first-order) inactivation rate of the affected cytochrome P450, k deg is the apparent first-order degradation rate constant of the affected cytochrome P450, K I,u is the unbound concentration of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, that results in half-maximal inactivation, and k inactis the maximum inactivation rate constant. If R1 ≥ 1.02, R2 ≥ 1.25, and / or R 1,gut ≥11, then the compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)) or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II) or a pharmaceutically acceptable salt thereof may be an inhibitor of cytochrome P450, and the potential for drug-drug interaction (DDI) can be further explored using mechanistic models and / or clinical DDI studies with sensitivity index substrates. For example, cytochrome P450 induction can be assessed via a fold change method, wherein the fold change in cytochrome P450 enzyme mRNA levels when incubated with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) is calibrated by using a cutoff value determined from known positive and negative controls. For example, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) or a pharmaceutically acceptable salt thereof is construed as an inducer if: (1) it increases mRNA expression of a cytochrome P450 enzyme in a concentration-dependent manner; and (2) the fold change in cytochrome P450 mRNA expression relative to a vehicle control at the expected liver drug concentration is ≥ 2-fold. As another example, cytochrome P450 induction can be assessed by a correlation method, where the correlation method is used to evaluate the relative induction score (RIS) or I of a panel of known inducers of the same cytochrome P450. max,u / EC 50The calibration curve predicts the magnitude of the clinical induction effect (e.g., the ratio of the AUC of the index substrate in the presence and absence of the inducer) of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof. If the predicted magnitude is greater than a predefined cutoff value (e.g., AUC ratio ≤ 0.8), the compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is considered to have in vivo induction potential.

[0707] In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is not a hERG inhibitor. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, inhibits hERG at an IC of 50For example, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) or a pharmaceutically acceptable salt thereof inhibits hERG with an IC of 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 In some embodiments, the compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC of greater than 500 nM (e.g., 1 μM, 3 μM, 5 μM, 10 μM, 20 μM, or 30 μM). 50 In some embodiments, the compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, inhibits hERG at an IC of greater than 1 μM (e.g., greater than 3 μM, 5 μM, 10 μM, 20 μM, or 30 μM). 50 In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC of50 Greater than 30μM.

[0708] In some cases, heterobifunctional degraders can induce the degradation of off-target proteins. For heterobifunctional degraders utilizing CRBN, common off-target proteins that can be degraded include GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α. It is generally believed that this degradation is due to the E3 binding portion 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 generally essential genes, so poor degradation of one or both of them may lead to nonspecific cytotoxicity. IKZF protein is a zinc finger transcription factor that is associated with cell fate in the hematopoietic process, and the degradation of these proteins is associated with hematotoxicity. See, for example, Moreau, Kevin et al. British Journal of Pharmacology [British Journal of Pharmacology] 177.8 (2020): 1709-1718.

[0709] In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II) or a pharmaceutically acceptable salt thereof can exhibit potent and selective induction of BCL6 protein degradation. In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can selectively target BCL6 protein. Instead of a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP (cathelicidin antimicrobial peptide), CCNA2 (cyclin A2), FSP1 (ferroptosis suppressor protein 1, also known as AIFM2), JCHAIN ​​(immunoglobulin J chain), NLRP7 (NACHT, LRR, PYD domain-containing protein 7), PTTG1 (separase inhibitory protein), and / or TPX2 (targeting 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 transitions of the cell cycle. FSP1 is an oxidoreductase that is an inhibitor of ferroptosis. JCHAIN ​​connects two monomeric units of IgM or IgA; J-chain-linked dimers are the nucleating units of IgM pentamers, while J-chain-linked dimers of IgA induce dimers or larger aggregates. NLRP7 inhibits CASP1 / caspase-1-dependent IL1B secretion. PTTG1 is critical for chromosome stability and negatively regulates TP53. TPX2 is required for normal assembly of the mitotic spindle.

[0710] As used herein, in a protein degradation assay, "selective" or "selectively" when referring to a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, means that the performance of the specified protein in the protein degradation assay is at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) greater than that of a comparator protein in the assay.

[0711] In some embodiments, the compounds provided herein can exhibit potency (e.g., nanomolar potency) against a BCL6 protein, while having minimal activity against a second protein (e.g., single-digit micromolar potency, e.g., a potency greater than 1 μM (e.g., greater than 3 μM, 5 μM, 10 μM, 20 μM, or 30 μM). In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit potent degradation of a BCL6 protein and, in the degradation (e.g., such as by Y min 、DC 50 , and / or D max In some embodiments, the inhibitory effect of ... min 、DC 50 , and / or D maxValue measured), compounds having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or pharmaceutically acceptable salts thereof, may exhibit greater induction of BCL6 protein degradation. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold induction of degradation of a BCL6 protein relative to induction of degradation of a second protein. In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold induction of BCL6 protein degradation relative to induction of degradation of a second protein. In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit degradation induction (e.g., such as by Y) relative to 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 maxIn some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit induction of BCL6 protein degradation by about 10-fold to about 100-fold relative to induction of degradation of a second protein. In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit about 100-fold to about 1000-fold induction of BCL6 protein degradation relative to induction of degradation of a second protein. In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit induction of BCL6 protein degradation of about 1000-fold to about 10,000-fold relative to induction of degradation of a 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.

[0712] In some embodiments, the compounds provided herein can exhibit potency against a BCL6 protein with similar activity to that against a second protein (i.e., the activity against the BCL6 protein is less than 2-fold greater than the activity against the second protein, and the activity against the second protein is no more than 2-fold greater than the activity against the BCL6 protein). In some embodiments, the compounds provided herein can exhibit potency against a BCL6 protein with similar activity to that against a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) with respect to induction of degradation (e.g., as induced by Y min 、DC 50 , and / or D maxValues ​​measured), compounds of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or pharmaceutically acceptable salts thereof, can exhibit similar induction of BCL6 protein degradation (i.e., the induction of BCL6 protein degradation is less than 2-fold the induction of degradation of a second protein, and the activity on the second protein is no more than 2-fold the activity on the BCL6 protein). In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit less than 2-fold induction of BCL6 protein degradation relative to induction of degradation of a 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.

[0713] In some embodiments, the compounds provided herein can exhibit potency against a BCL6 protein while exhibiting minimal activity against a second protein (e.g., as measured by a proteomic assay, e.g., a <20% reduction in protein abundance as measured in a proteomic assay described herein). In some embodiments, the compounds have Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula ( II) or a pharmaceutically acceptable salt thereof can exhibit potent degradation of BCL6 protein and have minimal efficacy (e.g., as measured by abundance in a proteomic assay (e.g., as described herein)) in degrading (e.g., as measured by abundance in a proteomic assay) a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG, and / or TPX2). In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit greater induction of degradation of a BCL6 protein relative to induction of degradation of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)).In some embodiments, the compound of formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), formula (I-bb) (e.g., formula (I-bb-1) or (I-bb-2)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)), or formula (Ib-3) I), or a pharmaceutically acceptable salt thereof, can exhibit at least a 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold induction of BCL6 protein degradation (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)) relative to induction of degradation of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2). In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit up to a 1000-fold induction of BCL6 protein degradation relative to induction of degradation of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)). In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit about 2-fold to about 10-fold induction of BCL6 protein degradation relative to induction of degradation of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)).In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit about 10-fold to about 100-fold induction of BCL6 protein degradation relative to induction of degradation of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)). In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit about 100-fold to about 1000-fold induction of BCL6 protein degradation relative to induction of degradation of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay 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 embodiments, the second protein is TPX2.

[0714] In some embodiments, the compounds provided herein can exhibit potency against BCL6 protein with minimal activity against any other detectable protein (e.g., <20% reduction in protein abundance as measured by a proteomic assay, e.g., as measured in a proteomic assay described herein). In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit potent degradation of BCL6 protein and have minimal potency in degrading any other detectable protein (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)). In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit greater induction of BCL6 protein degradation (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)) relative to the induction of degradation of any other detectable protein. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit at least a 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold induction of BCL6 protein degradation relative to induction of degradation of any other detectable protein (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)).In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold induction of BCL6 protein degradation relative to induction of degradation of any other detectable protein (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)). In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit about 2-fold to about 10-fold induction of BCL6 protein degradation relative to induction of degradation of any other detectable protein (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)). In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit about 10-fold to about 100-fold induction of BCL6 protein degradation relative to induction of degradation of any other detectable protein (e.g., as measured by abundance in a proteomic assay (e.g., a proteomic assay as described herein)).

[0715] In some embodiments, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can exhibit potent degradation of BCL6 protein and minimal efficacy in degrading one or more additional proteins, as measured by abundance in a proteomic assay. The following is an exemplary proteomic experiment. OCI-Ly1 (DSMZ: ACC 722) cells were incubated with 100 nM of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, or dimethyl sulfoxide (DMSO) for six hours. The cells were then washed twice with phosphate-buffered saline and collected. The cells were lysed to extract total protein and analyzed according to EASYPEP. TM Total proteins were prepared for mass spectrometry analysis according to the protocol of the MS sample preparation kit (Fisher Scientific). Briefly, proteins were reduced with dithiothreitol, alkylated with iodoacetamide, and digested with trypsin and LysC enzymes. The resulting peptides were purified using TMTPRO according to the manufacturer's protocol. TM 18plex reagent (Fisher Scientific). The labeled peptides of each sample were mixed together in equal volumes and the peptide mixture was separated by basic reverse phase chromatography. A total of 85 fractions were combined into 18 combined fractions. The combined fractions were dried with centrivap and resuspended in 5% acetonitrile, 0.1% formic acid for mass spectrometry analysis. The Vanquish Neo chromatography system (Fisher Scientific) and Orbitrap FUSION TM LUMOS TM Peptide abundance was quantified by tandem mass spectrometry using a mass spectrometer (Fisher Scientific). Briefly, two micrograms of total peptides were loaded onto a two-cm C8 capture column and subsequently onto a 50-cm C18 column. Data-dependent acquisition was performed to obtain peptide sequence and abundance information. Peptide and protein abundance was determined using PROTEOME DISCOVERER TMThe results were filtered to an FDR < 0.01, and the significance thresholds were set at p-value < 0.001 and abundance fold change < 50%.

[0716] Provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II ) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not received treatment for the cancer. In some embodiments, the subject has received one or more prior lines of cancer therapy.

[0717] Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutical composition thereof. In some embodiments, the subject is administered a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, as a monotherapy to the subject. In some embodiments, the subject has not received treatment for the cancer. In some embodiments, the subject has received one or more prior lines of cancer therapy.

[0718] Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy to the subject. In some embodiments, the subject has not received treatment for the cancer. In some embodiments, the subject has received one or more prior lines of cancer therapy.

[0719] Provided herein are uses of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating cancer (e.g., any of the cancers provided herein).

[0720] Provided herein are uses of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for treating cancer (e.g., any of the cancers provided herein).

[0721] Provided herein are uses of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer (e.g., any of the cancers provided herein).

[0722] Provided herein are compounds having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament. Also provided herein are compounds of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament for treating cancer (e.g., any of the cancers provided herein).

[0723] Provided herein are compounds having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in treating cancer (e.g., any of the cancers provided herein).

[0724] As used herein, cancer treatment can include treatment of a primary tumor (i.e., non-metastatic cancer) (e.g., as a first, second, third, or subsequent line therapy, including but not limited to the relapsed / refractory setting), treatment of a metastatic (or secondary) tumor, neoadjuvant therapy (e.g., prior to treatment with an additional therapy or therapeutic agent (e.g., surgery, radiation therapy, chemotherapy, or a line of therapy)), adjuvant therapy (e.g., following treatment with an additional therapy or therapeutic agent (e.g., surgery, radiation therapy, chemotherapy, or a line of therapy)), or maintenance therapy (e.g., treatment following response to an additional therapy or therapeutic agent (e.g., surgery, radiation therapy, chemotherapy, or a line of therapy)).

[0725] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a primary tumor. In some embodiments, the subject has not received treatment for the cancer. In some embodiments, the subject has received one or more lines of cancer therapy. In some embodiments, the patient 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 patient has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R 2 , R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapy, or two or more thereof. In some embodiments, the patient has received a regimen containing rituximab. In some embodiments, the patient has received a regimen containing obinutuzumab. In some embodiments, the patient has received a regimen containing motuzumab. In some embodiments, the patient has received a regimen containing icreluzumab. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient who has received one or more lines of systemic therapy for cancer. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient who has received two or more lines of systemic therapy for cancer.

[0726] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a metastatic tumor. In some embodiments, the subject has not received treatment for the metastatic tumor. In some embodiments, the subject has received one or more lines of secondary tumor therapy. In some embodiments, the patient 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 patient has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R 2 , R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapy, or two or more thereof. In some embodiments, the patient has received a regimen containing rituximab. In some embodiments, the patient has received a regimen containing obinutuzumab. In some embodiments, the patient has received a regimen containing motuzumab. In some embodiments, the patient has received a regimen containing icreluzumab. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient who has received one or more lines of systemic therapy for cancer. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient who has received two or more lines of systemic therapy for cancer.

[0727] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used as a neoadjuvant therapy. In some embodiments, neoadjuvant therapy precedes surgery (e.g., surgical resection, such as partial surgical resection or complete, total, or all surgical resection). In some embodiments, neoadjuvant therapy precedes radiation therapy. In some embodiments, neoadjuvant therapy precedes chemotherapy.

[0728] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is an adjuvant therapy. In some embodiments, the patient 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 patient has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R 2, R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapy, or two or more thereof. In some embodiments, the patient has received a regimen containing rituximab. In some embodiments, the patient has received a regimen containing obinutuzumab. In some embodiments, the patient has received a regimen containing motuzumab. In some embodiments, the patient has received a regimen containing icreluzumab. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient who has received one or more lines of systemic therapy for cancer. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient who has received two or more lines of systemic therapy for cancer. In some embodiments, adjuvant therapy is after surgery (e.g., surgical resection, such as partial surgical resection or complete, total, or all surgical resection). In some embodiments, adjuvant therapy is after radiation therapy. In some embodiments, adjuvant therapy is after chemotherapy.

[0729] In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is a maintenance therapy. In some embodiments, the patient 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), stem cell transplantation, or a combination thereof. In some embodiments, the patient has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R 2 , R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapy, or two or more thereof. In some embodiments, the patient has received a regimen containing rituximab. In some embodiments, the patient has received a regimen containing obinutuzumab. In some embodiments, the patient has received a regimen containing motuzumab. In some embodiments, the patient has received a regimen containing icreluzumab. In some embodiments, the patient has received a stem cell transplant. In some embodiments, the patient has received a cell-based therapy (e.g., CAR-T therapy). In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient who has received one or more lines of systemic therapy for cancer. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient who has received two or more lines of systemic therapy for cancer.

[0730] As used herein, "monotherapy" when referring to a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, means a monotherapy having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-a-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, means a monotherapy having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is the sole therapeutic agent or sole therapy (e.g., an anticancer agent or anticancer therapy) administered to the subject during a treatment cycle (e.g., no additional targeted therapy drug, anticancer agent, chemotherapeutic agent, or checkpoint inhibitor is administered to the subject during the treatment cycle). One of ordinary skill in the art will understand that monotherapy does not preclude the co-administration of drugs for the treatment of side effects or general symptoms associated with cancer or treatment, such as pain, rash, edema, photosensitivity, itching, skin discoloration, brittle hair, hair loss, brittle nails, cracked nails, nail discoloration, swollen cuticles, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms, including nausea, diarrhea, and loss of appetite.

[0731] As used herein, "the subject has previously received one or more therapeutic agents or therapies for cancer" means that during the previous treatment cycle, in addition to a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, the subject has previously been administered one or more therapeutic agents or therapies for cancer (e.g., anticancer agents or anticancer therapies). In some embodiments, the subject is intolerant to the one or more therapeutic agents or therapies previously administered for cancer. In some embodiments, the subject does not respond to the one or more therapeutic agents or therapies previously administered for cancer. In certain embodiments, subject does not have enough responses to one or more therapeutic agents or therapies previously administered for cancer.In certain embodiments, subject has stopped responding to one or more therapeutic agents or therapies previously administered for cancer.In certain embodiments, response lacks, insufficient responses or response interruption can be determined by objective criteria (for example, tumor volume, or standard such as RECIST 1.1).In certain embodiments, response lacks, insufficient responses or response interruption can be determined by subject's doctor.

[0732] As used herein, "the subject has not received treatment for cancer" means that the subject has not been previously administered one or more therapeutic agents or therapies for cancer.

[0733] 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 a tumor located at the site where the tumor begins to grow (i.e., the place where the tumor originates). As used herein, a "metastatic" (or "secondary") tumor is a tumor that spreads from the original tumor site to other parts of the body. In some embodiments, a metastatic or secondary tumor is a cancer of the same type as the primary tumor. In some embodiments, a metastatic or secondary tumor is genetically different from the primary tumor.

[0734] In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal breast cancer), cancer of central or peripheral nervous system tissue (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligoastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple neuroendocrine type I and II neoplasia, parathyroid cancer, pituitary tumor, thyroid cancer (e.g., papillary thyroid carcinoma)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, biliary tract cancer (e.g., bile duct cancer), colorectal cancer (e.g., colon cancer), adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor, liver cancer (e.g., hepatocellular carcinoma, intrahepatic biliary tract cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell carcinoma), small intestine cancer, or stomach cancer (e.g., gastric adenocarcinoma, gastric signet ring cell carcinoma)), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma, renal chromophobe cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), testicular cancer (e.g., testicular germ cell tumor), or ureteral cancer), gynecological cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ductal carcinoma), ovarian cancer (e.g., ureter ... ovarian cancer (e.g., ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, uterine endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine corpus endometrial cancer), or vulvar cancer), head and neck cancer (e.g., ear cancer (e.g., middle ear cancer), head and neck squamous cell carcinoma, nasal cavity cancer, oral cancer, pharyngeal cancer (e.g., hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), hematologic cancer (e.g., leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphocytic 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)), lymphoma lymphoma (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)), non-Hodgkin lymphoma (e.g., Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), diffuse histiocytic lymphoma (DHL), follicular lymphoma (FL), intravascular large B-cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL) (e.g., PTCL with T follicular helper phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (PTCL-NOS)), small lymphocytic lymphoma (SLL))), or myeloma (e.g.,multiple myeloma)), Ley-Fraumeni tumor, mesenteric cancer (e.g., omental cancer, peritoneal cancer), pleural cancer, respiratory tract cancer (e.g., laryngeal cancer, lung cancer (e.g., squamous cell lung carcinoma, adenocarcinoma, mesothelioma, non-small cell lung cancer (NSCLC)), tracheal cancer), sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing's sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancer (e.g., melanoma), thymic cancer (e.g., thymoma), or a combination thereof.

[0735] In some embodiments, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal breast carcinoma), cancer of central or peripheral nervous system tissue (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligoastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), thyroid cancer (e.g., papillary thyroid cancer)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., biliary tract cancer (e.g., bile duct cancer), colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), liver cancer (e.g., hepatocellular carcinoma), pancreatic cancer cancer (e.g., pancreatic adenocarcinoma), or stomach cancer (e.g., gastric adenocarcinoma, gastric signet ring cell carcinoma)), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma, renal chromophobe cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), or testicular cancer (e.g., testicular germ cell tumor)), gynecological cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), or uterine cancer (e.g., uterine carcinosarcoma, uterine endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine corpus endometrial carcinoma)), head and neck cancer (e.g., head and neck squamous cell carcinoma) , hematologic cancers (e.g., leukemias (e.g., chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) (e.g., B-cell lineage ALL (B-ALL), Philadelphia chromosome-positive ALL (e.g., Philadelphia chromosome-positive B-ALL), Philadelphia chromosome-negative ALL (e.g., Philadelphia chromosome-negative B-ALL)), acute myeloid leukemia (AML), chronic myeloid leukemia (CML)) or lymphomas (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)), non-Hodgkin lymphomas (e.g., Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), diffuse histiocytic lymphoma ( DHL), follicular lymphoma (FL), intravascular large B-cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL) (e.g., PTCL with T follicular helper phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (PTCL-NOS)), small lymphocytic lymphoma (SLL)), respiratory cancer (e.g., lung cancer (e.g., squamous cell carcinoma of the lung, adenocarcinoma of the lung, mesothelioma, non-small cell lung cancer (NSCLC))), sarcoma (e.g., leiomyosarcoma, myxofibrosarcoma), skin cancer (e.g., melanoma), thymic cancer (e.g., thymoma), or a combination thereof.

[0736] In some embodiments, the cancer is a hematologic cancer (e.g., lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), diffuse histiocytic lymphoma (DHL), intravascular large B-cell lymphoma (IVLBCL), peripheral T-cell lymphoma (PTCL) (e.g., PTCL with T follicular helper phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (PTCL-NOS)) , small lymphocytic lymphoma (SLL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL)) or leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) (e.g., B-cell lineage ALL (B-ALL), Philadelphia chromosome-positive ALL (e.g., Philadelphia chromosome-positive B-ALL), Philadelphia chromosome-negative ALL (e.g., Philadelphia chromosome-negative B-ALL)), chronic myeloid leukemia (CML))), breast cancer, gastrointestinal cancer, brain cancer (e.g., glioblastoma) or lung cancer (e.g., NSCLC). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), diffuse histiocytic lymphoma (DHL), intravascular large B-cell lymphoma (IVLBCL), small lymphocytic lymphoma (SLL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) or chronic myeloid leukemia (CML). In some embodiments, the cancer is a hematological cancer and is DLBCL, FL, MCL, BL, PTCL or ALL (e.g., B-ALL). In some embodiments, the cancer is FL or DLBCL. In some embodiments, the cancer is DLBCL, FL, MCL, or ALL (e.g., B-ALL).See, e.g., Leeman-Neill and Bhagat, Expert Opinion on Therapeutic Targets 22.2 (2018): 143-152; Mlynarczyk and Melnick. Immunological Reviews 288.1 (2019): 214-239; Hurtz, Christian et al., Journal of Experimental Medicine 208.11 (2011): 2163-2174; Deb, Dhruba et al., Cancer Research 77.11 (2017): 3070-3081; Cardenas, Mariano G. et al., Clinical Cancer Research [Clinical Cancer Research] 23.4 (2017): 885-893; Walker, Sarah R. et al., Oncogene [Oncogene] 34.9 (2015): 1073-1082; International Publication Nos. WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673.

[0737] In some embodiments, the cancer is a non-Hodgkin lymphoma (e.g., Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), diffuse histiocytic lymphoma (DHL), follicular lymphoma (FL), intravascular large B-cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL) (e.g., PTCL with T follicular helper phenotype (PTPCL-TFH)), or small lymphocytic lymphoma (SLL)). In some embodiments, the non-Hodgkin lymphoma is a B-cell non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is CD20 positive. In some embodiments, the non-Hodgkin lymphoma is a CD20-positive B-cell non-Hodgkin lymphoma. In some embodiments, the patient has not previously received treatment for non-Hodgkin lymphoma. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously received rituximab or obinutuzumab as a monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received rituximab monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received obinutuzumab monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received R-CHOP ( (rituximab), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) or G-CHOP ( In some cases, the patient has previously been treated with etoposide and R-CHOP (called R-EPOCH). In some cases, the patient has previously been treated with R-CHOP and lenalidomide (lenalidomide), venetoclax (venetoclax), ibrutinib (ibrutinib), acalabrutinib (acalabrutinib), obinutuzumab (obinutuzumab), polatuzumab (polatuzumab), pembrolizumab (pembrolizumab), durvalumab (durvalumab) or mosunetuzumab (mosunetuzumab) combination therapy. In certain embodiments, the patient has previously been treated with cyclophosphamide, vincristine and prednisone (CVP) (with or without rituximab or obinutuzumab). In certain embodiments, the patient has received one or more systemic therapy lines. In certain embodiments, the patient has received two or more systemic therapy lines. In some embodiments, the patient has previously been treated with 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). In some embodiments, the non-Hodgkin's lymphoma is non-progressive (including stable disease) non-Hodgkin's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is relapsed or refractory non-Hodgkin's lymphoma. In some embodiments, the patient is a patient who has relapsed after a rituximab-containing regimen or is refractory to a rituximab-containing regimen. In some embodiments, the patient is a patient who has relapsed after a rituximab-containing regimen or is refractory to a rituximab-containing regimen. In some such embodiments, the therapeutic effect 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 non-Hodgkin lymphoma and a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0738] In some embodiments, the cancer is DLBCL. In some embodiments, the DLBCL 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), NOTCH1 mutation (e.g., Q2394X, Q2501X, Q2459X, Y2 490X, G2427fs, Q2444X, P2514fs, or P2517S), 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, 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 deletion, 18q gain, or a combination thereof. In some embodiments, the DLBCL has a BCL6 rearrangement, a NOTCH2 mutation (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 a combination thereof. In some embodiments, DLBCL is a DLBCL of germinal center B cell (GCB) origin. In some embodiments, DLBCL is a BN2 type DLBCL (e.g., with BCL6 rearrangement and / or NOTCH2 mutation). In some embodiments, DLBCL is an EZB type DLBCL (e.g., with EZH2 mutation and / or BCL2 translocation). In some embodiments, DLBCL is a C1 genetic cluster DLBCL (e.g., with BCL6 rearrangement and / or NOTCH2 mutation). See, for example,Schmitz, Roland et al. New England Journal of Medicine 378.15(2018):1396-1407; Chapuy, Bjoern et al. Nature Medicine 24.5(2018):679-690 for more descriptions of these categories.

[0739] In some embodiments, the cancer is FL. In some embodiments, FL has a BCL2 translocation (e.g., a t(14;18) translocation). In some embodiments, FL has an EZH2 mutation (e.g., a Y646F, Y646N, A682G, or A692V mutation). See, e.g., Kridel, Robert, Laurie H. Sehn, and Randy D. Gascoyne. The Journal of Clinical Investigation 122.10 (2012): 3424-3431. In some embodiments, the cancer is FL, and a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[0740] In some embodiments, the cancer is B-ALL. In some embodiments, the B-ALL has an MLL rearrangement (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, is dependent on Ras signaling, has BCL2 amplification, has a JAK2 mutation (with or without high cytokine receptor-like factor 2 (CRLF2) expression), or a combination thereof. See, e.g., Knight, Thomas, and Julie Anne Elizabeth Irving. Frontiers in Oncology 4 (2014): 160; Geng, Huimin et al. Cancer Cell 27.3 (2015): 409-425; Jain, Nitin et al. Blood 129.5 (2017): 572-581; and Hurtz, Christian et al. Genes & Development 33.17-18 (2019): 1265-1279. In some embodiments, the cancer is B-ALL and a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient with B-ALL. In some embodiments, the B-ALL is relapsed or refractory B-ALL after two or more lines of systemic therapy.

[0741] In some embodiments, the patient has been previously treated with another anticancer agent, a chemotherapeutic agent, surgery, radiation, a multi-kinase inhibitor, or a combination thereof.

[0742] In some embodiments, the cancer is DLBCL. In some embodiments, the patient has not previously received treatment for DLBCL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously received rituximab or obinutuzumab as a monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received rituximab as a monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received obinutuzumab as a monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously been treated with lenalidomide in combination with rituximab or obinutuzumab. In some embodiments, the patient has previously been treated with cyclophosphamide, vincristine, and prednisone (CVP) (optionally in combination with rituximab or obinutuzumab). In some embodiments, the patient has previously been treated with R-CHOP ( (rituximab), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) or G-CHOP ( (otuzumab), cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone) treatment. In some cases, the patient has previously been treated with etoposide and R-CHOP (referred to as R-EPOCH). In some cases, the patient has previously been treated with R-CHOP in combination with lenalidomide, venetoclax, ibrutinib, acalabrutinib, olotuzumab, polotuzumab, pembrolizumab, durvalumab or motuzumab. In certain embodiments, the patient has previously been treated with a regimen containing rituximab. In certain embodiments, the patient has previously been treated with a regimen containing olotuzumab. In certain embodiments, the patient has previously been treated with a regimen containing motuzumab. In certain embodiments, the patient has previously been treated with a regimen containing icariin. In certain embodiments, the patient has previously been treated with a regimen containing icariin. In certain embodiments, the patient has received one or more systemic therapy lines. In certain embodiments, the patient has received two or more systemic therapy lines. In some embodiments, the patient has previously been treated with 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). In some embodiments, DLBCL is non-progressive (including stable disease) DLBCL. In some embodiments, DLBCL is relapsed or refractory DLBCL. In some embodiments, the patient is a patient who has relapsed after a rituximab-containing regimen or who is refractory to a rituximab-containing regimen. In some embodiments, the patient is a patient who has relapsed after a rituximab-containing regimen or who is refractory to a rituximab-containing regimen. In some such embodiments, the therapeutic effect 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 DLBCL, and a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient with DLBCL. In some embodiments, the DLBCL is relapsed or refractory DLBCL after two or more lines of systemic therapy.

[0743] In some embodiments, the cancer is FL. In some embodiments, the patient has not previously received treatment for FL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously received rituximab or obinutuzumab as a monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received rituximab as a monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received obinutuzumab as a monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously been treated with rituximab or obinutuzumab as a monotherapy. In some embodiments, the patient has previously been treated with bendamustine in combination with rituximab or obinutuzumab. In some embodiments, the patient has previously been treated with lenalidomide in combination with rituximab or obinutuzumab (the combination with rituximab is sometimes referred to as "R 2In some embodiments, the patient has previously been treated with cyclophosphamide, vincristine, and prednisone (CVP), optionally in combination with rituximab or obinutuzumab. In some embodiments, the patient has previously been treated with R-CHOP or G-CHOP. In some embodiments, the patient has received one or more lines of systemic therapy. In some embodiments, the patient has received two or more lines of systemic therapy. In some embodiments, the patient has previously been treated with 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). In some embodiments, non-Hodgkin's lymphoma is non-progressive (including stable disease) FL. In some embodiments, FL is relapsed or refractory FL. In some embodiments, the patient is a patient who has relapsed after a rituximab-containing regimen or is refractory to a rituximab-containing regimen. In some embodiments, the patient is a patient who has relapsed after a regimen containing obinutuzumab or is refractory to an obinutuzumab-containing regimen. In some such embodiments, the therapeutic effect can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, remission rate (e.g., overall remission rate, complete remission, partial remission, or a combination thereof), duration of remission, or a combination thereof. In some embodiments, the cancer is FL and has formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-a a-4), a compound of Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-a-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy. A compound of Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient with FL. In some embodiments, FL is relapsed or refractory FL after two or more lines of systemic therapy.

[0744] In some embodiments, the cancer is BL. In some embodiments, the patient has not previously received treatment for BL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously received rituximab or obinutuzumab as monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received rituximab as monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received obinutuzumab as monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously been treated with rituximab or obinutuzumab as monotherapy. In some embodiments, the patient has previously been treated with bendamustine in combination with rituximab or obinutuzumab. In some embodiments, the patient has previously been treated with R-CHOP or G-CHOP. In some embodiments, the patient has previously been treated with rituximab, cyclophosphamide, vincristine, doxorubicin, and methotrexate (R-CODOX-M). In some embodiments, the patient has previously been treated with rituximab, ifosfamide, etoposide, and cytarabine (R-IVAC). In some embodiments, the patient has previously been treated with rituximab and dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH-R). In some embodiments, the patient has received one or more systemic therapy lines. In some embodiments, the patient has received two or more systemic therapy lines. In some embodiments, the patient has previously been treated with 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). In some embodiments, BL is non-progressive (including stable disease) BL. In some embodiments, BL is relapsed or refractory BL. In some embodiments, the patient is a patient who relapses after a regimen containing rituximab or is refractory to a regimen containing rituximab. In some embodiments, the patient is a patient who relapses after a regimen containing obinutuzumab or is refractory to a regimen containing obinutuzumab. In some such embodiments, therapeutic 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 a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient with BL. In some embodiments, the BL is relapsed or refractory BL after two or more lines of systemic therapy.

[0745] In some embodiments, the cancer is PTCL (e.g., PTCL with T follicular helper phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (PTCL-NOS)). In some embodiments, the patient has not previously received treatment for PTCL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously received rituximab or obinutuzumab as a monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received rituximab as a monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously received obinutuzumab as a monotherapy or in combination with another therapy or therapeutic agent. In some embodiments, the patient has previously been treated with rituximab or obinutuzumab as a monotherapy. In some embodiments, the patient has previously been treated with bendamustine in combination with rituximab or obinutuzumab. In some embodiments, the patient has previously been treated with lenalidomide in combination with rituximab or obinutuzumab (the combination with rituximab is sometimes referred to as "R 2In some embodiments, the patient has been previously treated with cyclophosphamide, vincristine, and prednisone (CVP), optionally in combination with rituximab or obinutuzumab (R-CVP or G-CVP, respectively). In some embodiments, the patient has been previously treated with R-CHOP or G-CHOP. In some embodiments, the patient has received one or more lines of systemic therapy. In some embodiments, the patient has received two or more lines of systemic therapy. In some embodiments, the patient has been previously treated with 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) treatment. In some embodiments, PTCL is non-progressive (including stable disease) PTCL. In some embodiments, PTCL is relapsed or refractory PTCL. In some embodiments, the patient is a patient who has relapsed after a rituximab-containing regimen or is refractory to a rituximab-containing regimen. In some embodiments, the patient is a patient who has relapsed after a regimen containing obinutuzumab or is refractory to an obinutuzumab-containing regimen. In some such embodiments, the therapeutic effect can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, remission rate (e.g., overall remission rate, complete remission, partial remission, or a combination thereof), duration of remission, or a combination thereof. In some embodiments, the cancer is PTCL and has formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa -4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy. A compound of Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient with PTCL. In some embodiments, the PTCL is relapsed or refractory after two or more lines of systemic therapy.

[0746] In some embodiments, cancer is B-ALL. In some embodiments, B-ALL is Philadelphia chromosome positive B-ALL. In some embodiments, B-ALL is Philadelphia chromosome negative B-ALL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously been treated with at least one cycle of induction, consolidation, strengthening and optional maintenance. In some cases, induction therapy can include anthracyclines, vincristine, corticosteroids and cyclophosphamide. In some embodiments, anthracyclines are doxorubicin. In some embodiments, corticosteroids are dexamethasone. In some cases, the combination of doxorubicin, vincristine, dexamethasone and cyclophosphamide is referred to as CVAD. In some embodiments, induction therapy can further include a tyrosine kinase inhibitor (for example, for patients with this fusion, using a BCR-ABL inhibitor). In some embodiments, induction therapy can further include asparaginase (for example, for pediatric patients). In some cases, consolidation therapy can include methotrexate, cytarabine, vincristine, 6-mercaptopurine, 6-thioguanine, cyclophosphamide and etoposide. In some embodiments, consolidation therapy may further include a tyrosine kinase inhibitor (e.g., for patients with this fusion, a BCR-ABL inhibitor is used). In some embodiments, consolidation therapy may further include asparaginase (e.g., for pediatric patients). In some cases, intensive therapy may include anthracyclines, vincristine, corticosteroids, and cyclophosphamide. In some embodiments, intensive therapy may further include a tyrosine kinase inhibitor (e.g., for patients with this fusion, a BCR-ABL inhibitor is used). In some embodiments, intensive therapy may further include asparaginase (e.g., for pediatric patients). Typically, compared to adult regimens, child and adolescent regimens include higher cumulative doses of asparaginase and vincristine, but may have lower cumulative doses of anthracyclines and cyclophosphamide. In any of these cycle stages, anti-CD20 immunotherapy (e.g., rituximab) may be added for patients expressing CD20 protein on cells. See, e.g., Muffly, Lori, and Emily Curran. Hematology 2014, the American Society of Hematology Education Program Book 2019.1(2019):17-23. In some embodiments, the patient has received one or more lines of systemic therapy. In some embodiments, the patient has received two or more lines of systemic therapy. In some embodiments, the B-ALL is relapsed or refractory B-ALL.In some such embodiments, the therapeutic effect 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 a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)) or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is used to treat a patient with B-ALL. In some embodiments, the B-ALL is relapsed or refractory B-ALL after two or more lines of systemic therapy.

[0747] Also provided herein is a method of treating a subject having cancer, wherein the method comprises:

[0748] A therapeutically effective amount of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy or in combination with a first anticancer agent, to which the subject has been administered one or more doses of the first anticancer agent for a period of time.

[0749] Also provided herein is a method of treating a subject having cancer, wherein the method comprises:

[0750] (a) administering one or more doses of a first anticancer agent to the subject for a period of time; and

[0751] (b) following (a), administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, as a monotherapy or in combination with the first anticancer agent.

[0752] Also provided herein is a method of treating a subject having cancer, wherein the method comprises:

[0753] (a) administering one or more doses of a first anticancer agent to the subject for a period of time; and

[0754] (b) following (a), administering to the subject a therapeutically effective amount of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, as a monotherapy or in combination with a second anticancer agent.

[0755] In some embodiments of any of the methods of treating cancer provided herein, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered qd (once daily) to a subject. In some embodiments of any of the methods of treating cancer provided herein, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered bid (twice daily) to a subject. In some embodiments of any of the methods of treating cancer provided herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a subject tid (three times a day). In some embodiments of any of the methods of treating cancer provided herein, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered qid (four times a day) to a subject.In some embodiments of any of the methods of treating cancer provided herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a subject qod (every other day). In some embodiments of any of the methods of treating cancer provided herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a subject q.week (once a week). In some embodiments of any of the methods of treating cancer provided herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered biw (twice a week) to a subject. In some embodiments of any of the methods of treating cancer provided herein, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a subject tiw (three times a week).

[0756] BCL6 activity is also associated with autoimmunity. See, for example, Li, Qing et al. European Journal of Immunology 50.4 (2020): 525-536; Pearce, Andrew C. et al. Journal of Biological Chemistry 297.2 (2021); Venkatadri, Rajkumar et al. European Journal of Immunology 52.5 (2022): 825-834; Patel, Preeyam S. et al. Science Advances 8.25 (2022): eabo1782; Ding, Shu, Yu Rao, and Qianjin Lu. Cellular & Molecular Immunology 19.7 (2022): 863-865. Thus, also provided herein is a method of treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))). or a compound of formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), formula (I-bb) (e.g., formula (I-bb-1) or (I-bb-2)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0757] Provided herein are uses of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating an autoimmune disorder (e.g., any of the autoimmune disorders provided herein).

[0758] Provided herein are uses of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for treating an autoimmune disorder (e.g., any of the autoimmune disorders provided herein).

[0759] Provided herein are uses of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an autoimmune disorder (e.g., any of the autoimmune disorders provided herein).

[0760] Provided herein are compounds of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament for treating an autoimmune disorder (e.g., any of the autoimmune disorders provided herein).

[0761] Provided herein are compounds of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in treating an autoimmune disorder (e.g., any of the autoimmune disorders provided herein).

[0762] In some embodiments, the autoimmune disorder is acquired hemophilia, Addison's disease, ankylosing spondylitis, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA vasculitis), antisynthetase 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, The present invention relates to an autoimmune disorder comprising: a) thyroiditis, Hughes syndrome, IgG4-related disease, immune thrombocytopenic purpura (ITP), inflammatory bowel disease, localized scleroderma, multiple sclerosis, myasthenia gravis (MG), neuromyelitis optica spectrum disease (NMOSD) (e.g., neuromyelitis optica (NMO)), pemphigoid, pemphigus, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, seronegative spondyloarthropathies, Sjögren's syndrome, systemic lupus erythematosus, thrombocytopenic purpura, type 1 diabetes, ulcerative colitis, vitiligo, or a combination thereof. In some embodiments, the autoimmune disorder is rheumatoid arthritis, systemic lupus erythematosus, or a combination thereof. In some embodiments, the autoimmune disorder is ANCA vasculitis, GVHD (e.g., cGVHD), myasthenia gravis, NMO, or a combination thereof. In some embodiments, the autoimmune disorder is ANCA vasculitis, anti-synthetase syndrome, arthritis (e.g., rheumatoid arthritis or inflammatory arthritis), GVHD (e.g., cGVHD), IgG4-RD, lupus (e.g., 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 embodiments, the autoimmune disorder is ANCA vasculitis, anti-synthetase syndrome, GVHD (e.g., cGVHD), TIP, MG (e.g., muscle-specific tyrosine kinase (MuSK)-positive MG), NMOSD (e.g., NMO), pemphigus, or a combination thereof. In some embodiments, the autoimmune disorder is arthritis (e.g., rheumatoid arthritis or inflammatory arthritis), GVHD (e.g., cGVHD), IgG4-RD, lupus (e.g., 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); Ding, Shu, Yu Rao, and Qianjin Lu, Cellular & Molecular Immunology (2022): 1-3; Lee, Dennis SW, Olga L. Rojas, and Jennifer L. Gommerman, Nature Reviews Drug Discovery 20.3 (2021): 179-199; and International Publication Nos. WO 2020 / 014599; WO 2021 / 074620.

[0763] In some embodiments of any of the methods of treating an autoimmune disorder provided herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered qd (once daily) to a subject. In some embodiments of any of the methods of treating an autoimmune disorder provided herein, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered bid (twice daily) to a subject. In some embodiments of any of the methods of treating an autoimmune disorder provided herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a subject tid (three times a day). In some embodiments of any of the methods of treating an autoimmune disorder provided herein, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered qid (four times a day) to a subject.In some embodiments of any of the methods of treating an autoimmune disorder provided herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered qod (every other day) to a subject. In some embodiments of any of the methods of treating an autoimmune disorder provided herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered to a subject q.week. In some embodiments of any of the methods of treating an autoimmune disorder provided herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered biw (twice weekly) to a subject. In some embodiments of any of the methods of treating an autoimmune disorder provided herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered tiw (three times a week) to a subject.

[0764] Also provided herein is a method of treating a lymphoproliferative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (Ib-4)). (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)) or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or a pharmaceutical composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0765] Provided herein are uses of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a lymphoproliferative disorder (e.g., any of the lymphoproliferative disorders provided herein).

[0766] Provided herein are uses of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for treating a lymphoproliferative disorder (e.g., any of the lymphoproliferative disorders provided herein).

[0767] Provided herein are uses of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a lymphoproliferative disease, e.g., any of the lymphoproliferative diseases provided herein.

[0768] Provided herein are compounds of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament for treating a lymphoproliferative disorder (e.g., any of the lymphoproliferative disorders provided herein).

[0769] Provided herein are compounds of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in treating a lymphoproliferative disorder (e.g., any of the lymphoproliferative disorders provided herein).

[0770] In some embodiments, the lymphoproliferative disorder is an Epstein-Barr virus-associated lymphoproliferative disorder.

[0771] Also provided is a method for modulating (e.g., reducing) BCL6 protein activity in a cell, the method comprising contacting the cell with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is performed in vitro. In some embodiments, the contacting is performed in vivo. In some embodiments, contacting is performed in vivo, where the method comprises administering to the subject an effective amount of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein. As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a cell with a compound provided herein includes administering a compound provided herein to the cell in vitro or in vivo, including, for example, introducing a compound provided herein into a sample, organoid, or organism (e.g., an animal (e.g., a tumor-bearing animal) or a human) containing cells (e.g., grown in culture or derived from a patient).

[0772] Also provided is a method of modulating (e.g., reducing) the level of BCL6 protein in a cell, the method comprising contacting the cell with a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the level of BCL6 protein 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 a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is performed in vitro. In some embodiments, the contacting is performed in vivo. In some embodiments, contacting is performed in vivo, wherein the method comprises administering to a subject having a cell containing a BCL6 protein an effective amount of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein.

[0773] Also provided is a method of inducing ubiquitination of a BCL6 protein in a cell, the method comprising contacting the cell with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is performed in vitro. In some embodiments, the contacting is performed in vivo. In some embodiments, contacting is performed in vivo, wherein the method comprises administering to a subject having a cell containing a BCL6 protein an effective amount of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein.

[0774] Also provided is a method for forming a cell comprising a BCL6 protein having a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) or a pharmaceutically acceptable salt thereof and a CRBN protein. In some embodiments, the cell is provided with a method for producing a ternary complex of a cell line comprising contacting the cell with a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is performed in vitro. In some embodiments, the contacting is performed in vivo. In some embodiments, contacting is performed in vivo, wherein the method comprises administering to a subject having a cell containing a BCL6 protein an effective amount of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein.

[0775] Also provided herein is a method for inducing degradation of BCL6 protein in mammalian cells, comprising contacting the mammalian cells with an effective amount of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof.

[0776] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting the cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))) or Formula (II) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0777] Further provided herein is a method of increasing cell death in vitro or in vivo, comprising contacting the cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.

[0778] When used as a pharmaceutical, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, can be administered in the form of a pharmaceutical composition as described herein.

[0779] combination

[0780] In any of the indications described herein, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, can be used as a monotherapy. In some embodiments, a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, for a period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, reduces tumor size (e.g., tumor burden) prior to at least partial resection of the tumor.

[0781] In some embodiments, a subject in need thereof can be administered one or more doses of a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, for a period of time and receive one or more rounds of radiation therapy. In some embodiments, treatment with one or more doses of a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2))), or Formula (II), or a pharmaceutically acceptable salt thereof, reduces tumor size (e.g., tumor burden) prior to one or more cycles of radiation therapy.

[0782] In some embodiments of any of the methods described herein, a compound having Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or Formula (II), or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent (e.g., a chemotherapeutic agent).

[0783] Non-limiting examples of additional therapeutic agents include: RAS pathway targeted therapeutics (e.g., Ras / RAF / MEK / PI3K pathway inhibitors (e.g., Ras inhibitors, KRas targeted therapeutics, SOS1 inhibitors, SOS1 / Ras protein interaction inhibitors, SHP2 inhibitors, PI3K-AKT-mTOR pathway inhibitors)), kinase targeted therapeutics (e.g., MEK inhibitors, ERK inhibitors, Raf inhibitors (e.g., BRaf inhibitors), PI3K inhibitors, AKT inhibitors, BTK inhibitors, mTOR inhibitors, CDK4 / 5 inhibitors, CDK4 / 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, farnesyl transferase inhibitors, HSP90 inhibitors, PTEN inhibitors, polycomb protein repressive complex 2 (PRC2) inhibitors (e.g., EZH1 / 2 or EZH2 inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., BCL-2 inhibitors, BCL-X L inhibitors), XPO1 inhibitors, steroids, chemotherapeutic agents, angiogenesis-targeted therapies, immune-targeted agents (including immunomodulatory imide drugs (sometimes referred to as "IMiDs" or "CELMoDs")), immunotherapies (e.g., anti-PD1, anti-PD-L1, anti-CD19, anti-CD20, anti-CD22, anti-CD3, anti-CD30, anti-CD79B, or anti-CD47 therapies), including antibodies (e.g., single-targeted antibodies targeting one or more of PD1, PD-L1, CD19, CD20, CD22, CD3, CD30, CD79B, or CD47), bispecific antibodies that bind to one or more of CD30, CD79B or CD47 (including bispecific T cell engagers (BiTEs)), and antibody drug conjugates (ADCs) that bind to one or more of PD1, PD-L1, CD19, CD20, CD22, CD3, CD30, CD79B or CD47 antibodies) or antigen-binding fragments thereof, 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 radiation therapy.

[0784] As used herein, a biosimilar antibody refers to an antibody or antigen-binding fragment that has the same primary amino acid sequence as a reference antibody, and optionally may have detectable differences (e.g., different glycoforms) in post-translational modifications (e.g., glycosylation and / or phosphorylation) as compared to the reference antibody.

[0785] In some embodiments, the additional therapeutic agent is a PI3K inhibitor, an Abl inhibitor (e.g., a BCR-Abl inhibitor), a BTK inhibitor, a JAK inhibitor (e.g., a JAK2 inhibitor), a BRaf inhibitor, a MEK inhibitor, a menin inhibitor, a BCL-2 inhibitor, a BCL-X inhibitor, or a BRAF inhibitor. 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 a combination thereof.

[0786] Without being bound by any particular theory, it is believed that targeting BCL6 can lead to the induction of genes that it typically represses, such as BCL2. In some embodiments, the additional therapeutic agent is a BCL-2 inhibitor (e.g., venetoclax, navitoclax, lisaftoclax, obatoclax, pelcitoclax, AZD-0466, BGB-11417, UBX-1325, UBX-1967, ZN-d5, oblimersen (e.g., oblimersen sodium), or beclanorsen).

[0787] In some embodiments, the PI3K inhibitor is alpelisib (BYL719), amdizalisib, apitolisib (GDC-0980), bimiralisib, buparlisib (BKM120), copanlisib (ALIQOPA TM, BAY80-6946) (e.g., copanisib dihydrochloride or copanisib dihydrochloride hydrate), dactolisib (NVP-BEZ235, BEZ-235), dezapelisib, dordaviprone, duvelisib (e.g., duvelisib hydrate), eganelisib, fimepinostat, gedatolisib (PF-05212384, PKI-587), idelalisib, inavolisib, lenilisib (e.g., hydrate of duvelisib), iolisib) (e.g., 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 a combination thereof.In some embodiments, the PI3K inhibitor is apellisib, andilisib, atolisib, bimilisib, bupalixib, copanisib (e.g., copanisib dihydrochloride or a hydrate of copanisib dihydrochloride), datolisib, dezalisib, dodavidon, duvilisib (e.g., a hydrate of duvilisib), ilgalisib, feminostat, gidalisib, ailalisib, inalisib, lenilisib (e.g., lenilisib phosphate), limprisib, pasalisib, pasalisib, resolisib, celalisib, ceralisib, sonalisib, tenalisib, erbulisib (e.g., erbulisib tosylate), zandalisib, PF-04691502, SHC-014748-M, TQ-B-3525, or a combination thereof.

[0788] In some embodiments, the Abl inhibitor (e.g., BCR-Abl inhibitor) is asciminib (e.g., asciminib 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., nilotinib monochloride monohydrate), olverembatinib (e.g., orebatininib mesylate), ponatinib (e.g., ponatinib hydrochloride), radotinib (e.g., radotinib dihydrochloride), ruserontinib, vandetanib, AN-019, AT-9283, IkT-148009, NPB-001-056, or a combination thereof.

[0789] In some embodiments, the cancer is B-ALL and the additional therapy or therapeutic agent is an Abl inhibitor. In some embodiments, the cancer is Philadelphia chromosome-positive B-ALL and the additional therapy or therapeutic agent is an Abl inhibitor. In some embodiments, the cancer is Philadelphia chromosome-like B-ALL and the additional therapy or therapeutic agent is an Abl inhibitor. In some embodiments, the Abl inhibitor is selected from the group consisting of imatinib, dasatinib, ponatinib, or a combination thereof.

[0790] In some embodiments, the BTK inhibitor is abivertinib, acalabrutinib, atuzabrutinib, branebrutinib, dasatinib (e.g., dasatinib monohydrate), edralbrutinib (SHR-1459), elsubrutinib, evobrutinib, fenebrutinib, ibrutinib, luxeptinib, nemtabrutinib, olafertinib, nemtabrutinib, or abrutinib. orelabrutinib, 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 a combination thereof. In some embodiments, the BTK inhibitor is abitinib, acalabrutinib, atulatinib, brembrutinib, dasatinib (e.g., dasatinib monohydrate), edelabrutinib, esubrutinib, evobrutinib, fenibrutinib, ibrutinib, nemustatinib, orelabrutinib, pitobrutinib, ribrutinib, rizabrutinib, suvotinib, tilabrutinib (e.g., tilabrutinib hydrochloride), tolebrutinib, zanubrutinib, AC-0058, BMS-986142, DTRMWXHS-12, LY-3337641, TAS-5315, or a combination thereof.

[0791] In some embodiments, the cancer is B-ALL and the additional therapy or therapeutic agent is a BTK inhibitor. In some embodiments, the cancer is pre-BCR+ B-ALL and the additional therapy or therapeutic agent is a BTK inhibitor. In some embodiments, the cancer is B-ALL that relies on Ras signaling and the additional therapy or therapeutic agent is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or acalabrutinib.

[0792] In some embodiments, the J...

Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from the group consisting of: H, halo, cyano, and R b1 ; m3 is 0, 1, 2, or 3; Each X 3 Independently selected from the group consisting of: -O-, -NR f -, -C(=O)- and optionally 1 to 3 R c Substituted C 1-3 Alkylene; The condition is N-(X 3 ) m3 -R 1 The part does not contain any OO, NO, NN, O-halogenated or N-halogenated bonds; Each R 2 are independently selected from the group consisting of: H, halo, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -OH, and -NR d R e ; R 3 Selected from the group consisting of: -A 1 -C(R 4 R 4 )-A 2 and -CH=CH-A 2 ,in: A 1 is -O- or -S-; Each R 4 Independently selected from the group consisting of: H, C 1-6 Alkyl and C 1-6 haloalkyl; or The R 4 The pairs together with their respective attached carbon atoms form C 3-6 A cycloalkyl ring or a 4-8 membered heterocyclyl ring, wherein the C 3-6 The cycloalkyl ring or the 4-8 membered heterocyclyl ring is optionally substituted by 1-3 R g replace; A 2 Selected from the group consisting of: -C(O)OH, -C(O)NH2, -C(O)R 3A 、-C(O)OR 3A 、-C(O)NR 3A R f 、-S(O) 1-2 (C 1-6 alkyl), -P(O)-(C 1-6 -C(=NH)NH2, wherein: R 3A Selected from the group consisting of: C 1-6 Alkyl, C 3-6 Alkenyl, C 3-6 Alkynyl, C 3-6 Cycloalkyl and 3-8 membered heterocyclyl, each of which is optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and-(C 0-3 Alkylene)-R b1 ; X a and X c are independently selected from the group consisting of: N, CH and CF, provided that X a and X c One or two of them are N; X b Selected from the group consisting of: N and CR x1 ; R 6 and R x1 Each independently selected from the group consisting of: H, halo, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, CN, and -C≡CH; L is -(L A ) n1 -, where L A and n1 is defined according to (AA) or (BB): (AA) n1 is an integer from 1 to 15; and Each L A Independently selected from the group consisting of: L A1 , L A3 , and L A4 , the condition is 1-3 occurrences of L A YesL A4 ; (BB) n1 is an integer from 0 to 20; and Each L A Independently selected from the group consisting of: L A1 and L A3 ; Each L A1 Independently selected from the group consisting of: -CH2-, -CHR L -, and -C(R L )2-; Each L A3 Independently selected from the group consisting of: -N(R d )-、-N(R b )-、-O-、-S(O) 0-2 -, and C(=O); Each L A4 Independently selected from the group consisting of: (a)C 3-15 Cycloalkylene or 3-15 membered heterocyclylene, each of which is optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and R b ;as well as (b)C 6-15 arylene or 5-15 membered heteroarylene, each of which is optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and R b ; Provided that L does not contain any NO, OO, NN, NS(O)0 or OS(O) 0-2 key; Each R L are independently selected from the group consisting of: halo, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e 、C(=O)N(R f )2. S(O) 0-2 (C 1-6 Alkyl), S(O) 0-2 (C 1-6 Haloalkyl), S(O) 1-2 N(R f )2. -R b , and optionally 1-6 R c Substituted C 1-6 alkyl; Ring C is selected from the group consisting of: c1 is 0, 1, 2, or 3; Each R Y Independently selected from the group consisting of: R a and R b ; R aN is H or optionally 1-3 R c Substituted C 1-6 alkyl; Y 1 and Y 2 are independently N, CH, or CR Y ; yy represents the point of attachment to L; X is CH, C, or N; is a single bond or a double bond; L C Selected from the group consisting of: bond, -CH2-, -CHR a -、-C(R a )2-、-C(=O)-、-N(R d )-, and O, provided that when X is N, L C is not O; and With further proviso that when ring C is attached to -L via the ring nitrogen C -, X is CH, and L C is the key; Each R a Independently selected from the group consisting of: (a) halogenated; (b) cyano; (c) -OH; (d) oxo; (e) optionally 1 to 6 R c Substituted C 1-6 Alkoxy; (f)-NR d R e ; (g) optionally 1 to 6 R c Substituted C(=O)C 1-6 alkyl; (h) C(═O)OH; (i) C(=O)OC 1-6 alkyl; (j)C(=O)OC 1-6 Haloalkyl; (k)C(=O)N(R f )2; (l)S(O) 0-2 (C 1-6 alkyl); (m)S(O) 0-2 (C 1-6 haloalkyl); (n)S(O) 1-2 N(R f )2; and (o)C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R c replace; Each R b Independently selected from the group consisting of: -(L b ) b -R b1 and -R b1 ,in: Each b is independently 1, 2, or 3; Each -L b are independently selected from the group consisting of: -O-, -N(H)-, -N(C 1-3 Alkyl)-, -S(O) 0-2 -, C(=O), and C 1-3 an alkylene group; and Each R b1 Independently selected from the group consisting of: C 3-10 Cycloalkyl, 4-10 membered heterocyclic group, C 6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted by 1-3 R g replace; Each R c are independently selected from the group consisting of: halo, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e 、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)OH, C(=O)N(R f )2. S(O) 0-2 (C 1-6 Alkyl), S(O) 0-2 (C 1-6 haloalkyl), and S(O) 1-2 N(R f )2; Each R d and R e Independently selected from the group consisting of: 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), S(O) 1-2 (C 1-6 Haloalkyl), S(O) 1-2 N(R f )2, and optionally 1-3 R h Substituted C 1-6 alkyl; Each R f are independently selected from the group consisting of: H and optionally 1-3 R h Substituted C 1-6 alkyl; Each R g Independently selected from the group consisting of: R h , oxo, C 1-3 Alkyl, and C 1-3 haloalkyl; and Each R h are independently selected from the group consisting of: halo, 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, Provided that when X is N, ring C is 2. The compound of claim 1, wherein R 3 Yes-A 1 -C(R 4 R 4 )-A 2 .

3. The compound according to claim 1 or 2, wherein A 1 Yes -O-.

4. The compound of any one of claims 1 to 3, wherein each R 4 It's H.

5. The compound of any one of claims 1 to 4, wherein A 2 is -C(O)NH2 or -C(O)NR 3A R f .

6. The compound of claim 5, wherein R 3A is optionally replaced by 1-6 R c Substituted C 1-3 alkyl.

7. The compound of claims 1-5, wherein A 2 It is -C(O)NH2, -C(O)NHMe or -C(O)NMe2.

8. The compound of claim 1, wherein R 3 yes 9. The compound of any one of claims 1 to 8, wherein X a Yes N; X c is N; and X b Yes CR x1 (e.g., CH); or X a is CH; X c is N; and X b Yes CR x1 (e.g., CH).

10. The compound of any one of claims 1 to 9, wherein R 6 It is -Cl or -F.

11. The compound of any one of claims 1 to 10, wherein each R 2 It's H.

12. A compound as described in any one of claims 1 to 11, wherein m3 is 0; or m3 is 1; and X 3 It is C 1-3 Alkylene.

13. A compound as described in any one of claims 1 to 12, wherein R 1 It's H.

14. A compound as described in any one of claims 1 to 11, wherein m3 is 1; X 3 is methylene, ethylene or isopropylene; and R 1 It's H.

15. The compound of claim 1, wherein R 3 Yes-A 1 -C(R 4 R 4 )-A 2 , where A 1 is O; each R 4 is H; and A 2 is -C(O)NH2 or -C(O)NR 3A R f , where R 3A is optionally replaced by 1-6 R c Substituted C 1-3 alkyl; Each R 2 It is H; X a is N or CH; X c is N; X b is CH; and R 6 It is -F or -Cl.

16. The compound of claim 15, wherein m3 is 1; X 3 is methylene, ethylene or isopropylene; and R 1 It's H.

17. The compound of claim 15 or 16, wherein X a It is N.

18. A compound as described in any one of claims 15-17, wherein A 2 It is C(O)NHMe.

19. The compound of any one of claims 1 to 18, wherein ring C is or ring C is or Ring C is 20. The compound of any one of claims 1-19, wherein c1 is 0; or c1 is 1; and R Y is halogenated (eg, -F).

21. The compound of any one of claims 1-20, wherein X is CH.

22. A compound as described in any one of claims 1 to 21, wherein R aN It is C 1-3 Alkyl (eg, methyl).

23. A compound as described in any one of claims 1 to 22, wherein L C is the key.

24. A compound as described in any one of claims 1 to 18, wherein the The portion is selected from the group consisting of: or Should The portion is selected from the group consisting of:

25. The compound of claim 1, wherein Part is in: m3 is 1; X 3 It is C 1-3 Alkylene; R 1 It is H; X a is CH or N; X c is N; R 6 is -F or -Cl; and Should The portion is selected from the group consisting of:

26. The compound of claim 25, wherein -(X 3 ) m3 -R 1 It is methyl, ethyl, or isopropyl.

27. The compound of claim 25 or 26, wherein X a is CH; or X a It is N.

28. A compound as described in any one of claims 1-27, wherein L is -(L A ) n1 -, where L A and n1 are defined according to (AA).

29. A compound as described in any one of claims 1 to 28, wherein n1 is an integer from 1 to 5; or n1 is an integer from 2 to 4 (eg, 2 or 3).

30. The compound of any one of claims 1-29, wherein L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -L A4 - bb ; -L A4 -L A3 -L A4 - bb ;and -L A4 -L A1 -L A4 -L A3 - bb , where bb represents the point of attachment to ring C.

31. The compound of claim 30, wherein each L A4 Independently C 3-10 cycloalkylene or 4-12 membered heterocyclylene, each of which is optionally substituted by 1-6 R a replace; or Each L A4 are independently optionally substituted by 1-3 R a a substituted 4-12 (e.g., 4-10) membered nitrogen-containing heterocyclylene group; or Each L A4 are independently optionally substituted by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; or One L A4 is optionally replaced by 1-3 R a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene; and another L A4 is optionally replaced by 1-3 R a a substituted bicyclic 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group; or One L A4 is optionally replaced by 1-3 R a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene; and another L A4 is optionally replaced by 1-3 R a a substituted bicyclic spiro 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group; or One L A4 is optionally replaced by 1-3 R a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene; and another L A4 is optionally replaced by 1-3 R a The substituted bicyclic ring bridges a 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group.

32. The compound of claim 31, wherein each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

33. The compound of claim 31 or 32, wherein L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

34. A compound as described in any one of claims 30-33, wherein L is -L A4 -L A1 -L A4 - bb .

35. The compound of claim 34, wherein L A1 It is -CH2-, -CHMe-, or -CMe2-.

36. A compound as described in any one of claims 30-33, wherein L is -L A4 -L A3 -L A4 - bb .

37. The compound of claim 36, wherein L A3 It is -C(=O) or -O-.

38. A compound as described in any one of claims 30-33, wherein L is -L A4 -L A1 -L A4 -L A3 - bb , and L A3 It is C(=O).

39. The compound of any one of claims 1-29, wherein L is selected from the group consisting of: -L A4 -L A3 - bb ; -L A4 -L A1 - bb ;and -L A4 -L A1 -L A3 - bb , where bb represents the point of attachment to ring C.

40. The compound of claim 39, wherein L is -L A4 -L A3 - bb .

41. The compound of claim 40, wherein L A3 is -NH- or -N(C 1-3 alkyl)-(e.g., -NH-).

42. A compound as described in any one of claims 39-41, wherein L A4 is optionally replaced by 1-6 R a a substituted 4-12 membered heterocyclylene; or L A4 is optionally replaced by 1-3 R a a substituted 4-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene group; or L A4 is optionally replaced by 1-3 R a a substituted bicyclic spiro 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene group; or L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

43. The compound of claim 42, wherein L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

44. The compound of any one of claims 1-29, wherein L is selected from the group consisting of the moieties depicted in Table L1-a, wherein bb represents the point of attachment to ring C.

45. The compound of claim 1, wherein the compound is a compound having formula (I-aa): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -OL A4 - bb ; -L A4 -C(=O)-L A4 - bb ;and -L A4 -L A1 -L A4 -C(=O)- bb , where bb represents the point of attachment to ring C; L A1 is CH2, CHMe, or CMe2; and Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -OL A4 - bb ; -L A4 -C(=O)-L A4 - bb ;and -L A4 -L A1 -L A4 -C(=O)- bb , where bb represents the point of attachment to ring C; L A1 is CH2, CHMe, or CMe2; and Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (I-aa-1): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe, or CMe2; and Each L A4 are independently optionally substituted by 1-3 R a A substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group, wherein: Each L A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms, and L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-1): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L A1 is CH2, CHMe, or CMe2; and Each L A4 are independently optionally substituted by 1-3 R a A substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group, wherein: Each L A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms, and L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (I-aa-2): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe, or CMe2; Z 1 and Z 2 Independently selected from the group consisting of: CH, CR a4 , and N; Z 3 and Z 4 Independently selected from the group consisting of: CH, CR a5 , and N, The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When N is 3 Is CH or CR a5 ; m4 and m5 are independently selected from the group consisting of: 0, 1, and 2; and Each R a4 and R a5 Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-2): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L A1 is CH2, CHMe, or CMe2; Z 1 and Z 2 Independently selected from the group consisting of: CH, CR a4 , and N; Z 3 and Z 4 Independently selected from the group consisting of: CH, CR a5 , and N, The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When N is 3 Is CH or CR a5 ; m4 and m5 are independently selected from the group consisting of: 0, 1, and 2; and Each R a4 and R a5 Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (I-aa-3): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe, or CMe2; and One L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and Another L A4 is optionally replaced by 1-3 R a A substituted bicyclic 6-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-3): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L A1 is CH2, CHMe, or CMe2; and One L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and Another L A4 is optionally replaced by 1-3 R a A substituted bicyclic 6-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (I-bb): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L is -L A4 -L A3 - bb or -L A4 -L A1 -L A3 - bb , where bb represents the point of attachment to ring C; and L A4 is optionally replaced by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ib): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: L is -L A4 -L A3 - bb or -L A4 -L A1 -L A3 - bb , where bb represents the point of attachment to ring C; and L A4 is optionally replaced by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 alkyl.

46. ​​The compound of claim 1, wherein the compound is selected from the group consisting of a compound in Table C1 or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising a compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

48. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

49. The method of claim 48, wherein the cancer is a hematological cancer, breast cancer, gastrointestinal cancer, brain cancer, lung cancer, or a combination thereof.

50. The method of claim 49, wherein the hematological cancer is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), diffuse histiocytic lymphoma (DHL), intravascular large B-cell lymphoma (IVLBCL), small lymphocytic lymphoma (SLL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or chronic myeloid leukemia (CML); or The hematological cancer is selected from the group consisting of: DLBCL, FL, MCL, BL, PTCL, and ALL (e.g., B-ALL); or The hematological cancer is FL or DLBCL; or The blood cancer is DLBCL; or The hematological cancer is FL; or The hematologic cancer is BL, or The blood cancer is PTCL; or The hematological cancer is ALL (eg, B-ALL).

51. The method of any one of claims 48-50, wherein the therapeutically effective amount of the compound of any one of claims 1-46 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 47 is administered to the subject as a monotherapy.

52. The method of any one of claims 48-50, comprising administering to the subject an additional therapy or therapeutic agent.

53. The method of claim 52, 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, a BCL-X inhibitor, a L inhibitors, XPO1 inhibitors, inhibitors of polycomb repressive complex 2 (PRC2), immunomodulatory imide drugs, anti-CD19 therapy, anti-CD20 therapy, anti-CD3 therapy, chemotherapy, or a combination thereof.

54. A method for treating an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 47.

55. A method for treating a lymphoproliferative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 47.

56. Any of the compounds, compositions, combinations, pharmaceutical compositions, methods, uses and processes substantially as provided herein.

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