Quinolone BCL6 Bifunctional Degraders

Abstract

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 a pharmaceutically acceptable salt thereof, which induce degradation of BCL6 protein. These compounds are useful, for example, for treating cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the compounds, as well as methods of using and preparing them.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application Nos. 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 / 420,421, filed October 28, 2022; and 63 / 420,421, filed October 28, 2022. This application claims priority to application Ser. Nos. 63 / 420,411, filed Aug. 5, 2022; 63 / 395,638, filed Aug. 5, 2022; 63 / 395,630, filed Aug. 5, 2022; 63 / 351,715, filed June 13, 2022; and 63 / 351,697, filed June 13, 2022, each of which is incorporated by reference in its entirety.

[0002] Instructions for electronically submitted text files This application contains a Sequence Listing that has been 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.

[0003] Technical Field 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 a pharmaceutically acceptable salt thereof, which induce degradation of BCL6 protein. These compounds are useful, for example, for treating cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the compounds, as well as methods of using and preparing them. [Background technology]

[0004] background 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 GC function and regulates the activity of signaling mediators in the maturation of GC B cells. There are over 1,000 known or putative BCL6 target genes, including MYC, BCL2, genes involved in DNA damage response (e.g., ATR, TP53), and cell cycle checkpoint control (e.g., CDKN1A, CDKN1B). BCL6 is expressed in GC dark zone cells, where somatic hypermutation can occur to generate high-affinity B-cell receptors. Overexpression or loss of regulation of BCL6, for example by translocation, can maintain BCL6's hypermutation function and abrogate its antitumor function. Summary of the Invention

[0005] overview Formula (I): TIFF2025525325000001.tif47170 or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 is H, halo, cyano and R b1 is selected from the group consisting of m3 is 0, 1, 2, or 3; each X 3 -O-, -NR f -, -C(=O)-, and 1 to 3 R c C optionally substituted with 1~3 alkylene; However, N-(X 3 ) m3 -R 1 the moiety does not contain an OO, NO, -NN, O-halo or N-halo bond; Each R 2 H, halo, cyano, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3Haloalkoxy, -OH and -NR d R e are independently selected from the group consisting of R 3 -A 1 -C(R 4 R 4 )-A 2 and -CH=CH-A 2 wherein A is selected from the group consisting of 1 is -O- or -S-, Each R 4 is H, C 1~6 Alkyl, and C 1~6 haloalkyl; R 4 The pair of carbon atoms, together with the carbon atoms to which they are bonded, form C 3~6 Forms a cycloalkyl ring or a 4- to 8-membered heterocyclyl ring, wherein C 3~6 The cycloalkyl ring or the 4- to 8-membered heterocyclyl ring may have 1 to 3 R g may be substituted with A 2 is -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)NH; R 3A is R a and -(C 0~3 alkylene)-R b1 C, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of 1~6 Alkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 3~6 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; X a and X c are independently selected from the group consisting of N, CH, and CF, with the proviso that Xa and X c one or both of are N; X b N and CR x1 is selected from the group consisting of R 6 and R x1 H, halo, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 are each independently selected from the group consisting of alkoxy, CN, and —C≡CH; L is -(L A ) n1 - and L A and n1 is defined according to (AA) or (BB): (AA) n1 is an integer from 1 to 15, Each L A L A1 , L A3 , and L A4 independently selected from the group consisting of: A 1 to 3 occurrences of L A4 and (BB) n1 is an integer from 0 to 20, Each L A L A1 and L A3 are independently selected from the group consisting of Each L A1 -CH2-, -CHR L - and -C(R L )2-, Each L A3 is -N(R d )-, -N(R b )-, -O-, -S(O) 0~2 -, and C(=O), Each L A4 teeth, (a)R a and R b C, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of 3~15cycloalkylene or 3- to 15-membered heterocyclylene, and (b)R a and R b C, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of 6~15 Arylene or 5- to 15-membered heteroarylene are independently selected from the group consisting of However, L can be any of NO bond, OO bond, NN bond, NS(O)0 bond, and OS(O) 0~2 Does not include bonds, Each R L are 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 1 to 6 R c C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Ring C is TIFF2025525325000002.tif25128; c1 is 0, 1, 2, or 3; Each R Y is R a and R b are independently selected from the group consisting of R aN is H or 1 to 3 R c C optionally substituted with 1~6 is alkyl, Y 1 and Y 2 are independently N, CH or CR Y and yy represents the point of attachment to L; X is CH, C or N; TIFF2025525325000003.tif6170 is a single or double bond, L C is a bond, -CH2-, -CHR a -, -C(R a )2-, -C(=O)-, -N(R d )-, and O, provided that when X is N, then L C is other than O, Further, provided that ring C is -L C -, X is CH, and L C is a bond, Each R a teeth, (a) Halo; (b) cyano; (c) -OH; (d) oxo; (e) 1 to 6 R c C optionally substituted with 1~6 Alkoxy; (f)-NR d R e ; (g) 1 to 6 R c C(=O)C optionally substituted with 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) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 Alkynyl are independently selected from the group consisting of Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of each b is independently 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O) and C 1~3 alkylene; Each R b1 is 1 to 3 R g each of which may be substituted with C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 independently selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; Each R c are 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 independently selected from the group consisting of: Each R d and R e is 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 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R g is R h , Oxo, C 1~3 Alkyl and C 1~3 haloalkyl; Each R h are 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 herein are compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0006] Also provided herein is 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0007] Provided herein is a method for treating cancer in a subject in need thereof, the method 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0008] Also provided herein is a BCL6 protein non-covalently bound 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.

[0009] Also provided herein is a ternary complex comprising a BCL6 protein, 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, and a CRBN protein or a portion thereof.

[0010] A number of additional terms are provided to facilitate understanding of the disclosure set forth herein. Generally, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry, and pharmacology described 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 skilled in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications mentioned throughout this specification and the attached appendix is incorporated herein by reference in its entirety. In the event of a conflict between this disclosure and any content incorporated by reference, the present disclosure shall prevail.

[0011] 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 OF THE INVENTION

[0012] Detailed Description 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 a pharmaceutically acceptable salt thereof, which induce degradation of BCL6 protein. These compounds are useful, for example, for treating cancer. The present disclosure also provides compositions containing the compounds provided herein, as well as methods of using and preparing them.

[0013] Upon antigen stimulation, germinal centers (GCs) form within lymphoid follicles, and B cells in the dark zone of GCs undergo rapid proliferation and somatic hypermutation, producing both immunoglobulin variable genes and high-affinity B cell receptors, as well as other genes, including BCL6. BCL6 is often considered the "master regulator" of the GC response. In some cancers, BCL6 may be mutated, translocated, and / or its expression may be upregulated. See, for example, Leeman-Neill and Bhagat, Expert Opinion on Therapeutic Targets 22.2(2018):143-152; Mlynarczyk and Melnick, Immunological Reviews 288.1(2019):214-239.

[0014] The BCL6 protein has multiple domains, including a BTB domain, an RD2 domain, and a DNA-binding domain. The N-terminal BTB domain is the site of BCL6 homodimerization, and the monomer interface forms a "lateral groove," which is the binding site for endogenous co-repressors of BCL6, such as SMRT, NCOR, and BCOR. See, for example, Cardenas, Mariano G., et al. Clinical Cancer Research 23.4(2017):885-893.

[0015] Compounds that induce target protein degradation are sometimes referred to as heterobifunctional compounds, PROTACs, or degraders. Such compounds generally contain a portion that binds to the target protein and a portion that binds to a ubiquitin E3 ligase (sometimes referred to as E3 ligase or simply E3), with these two portions optionally separated by a linker. To induce degradation, the heterobifunctional compound is thought to induce the formation of a ternary complex between the target protein, the compound, and the E3 ligase. The formation of the ternary complex is then followed by ubiquitination of the target protein and degradation of the ubiquitinated target protein by the proteosome. Several E3 ligases have been used as partner E3 ligases for heterobifunctional degraders. Herein, cereblon (CRBN) E3 ligase (also referred to herein as CRBN protein) is used.

[0016] Target protein degradation approaches may have potential advantages over, for example, small molecule inhibition of target proteins. One potential advantage is that the duration of effect of heterobifunctional compounds is generally based on the rate of target protein resynthesis. Another potential advantage is that many heterobifunctional compounds are thought to be released from the ubiquitinated target protein-E3 ligase complex and become available for further ternary complex formation, sometimes referred to as "catalytic" turnover of the heterobifunctional compound. Target protein degradation may be advantageous over small molecule inhibition in some cases, as degradation may impair the scaffolding function of the target protein, whereas small molecules may not. Furthermore, it is generally believed that ternary complex formation does not necessarily require high affinity for the target protein.

[0017] Heterobifunctional compounds are described, for example, in WO 2021 / 077010 and WO 2022 / 221673; McCoull, 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.

[0018] Compound Embodiments Formula (I): TIFF2025525325000004.tif47170 or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 is H, halo, cyano and R b1 is selected from the group consisting of m3 is 0, 1, 2, or 3; each X 3 -O-, -NR f -, -C(=O)-, and 1 to 3 R c C optionally substituted with 1~3 alkylene; However, N-(X 3 ) m3 -R 1 the moiety does not contain an OO, NO, NN, O-halo or N-halo bond; Each R 2 H, halo, cyano, C 1~3 Alkyl, C 1~3 Haloalkyl, C1~3 Alkoxy, C 1~3 Haloalkoxy, -OH and -NR d R e are independently selected from the group consisting of R 3 -A 1 -C(R 4 R 4 )-A 2 and -CH=CH-A 2 wherein A is selected from the group consisting of 1 is -O- or -S-, Each R 4 is H, C 1~6 Alkyl, and C 1~6 haloalkyl; R 4 The pair of carbon atoms, together with the carbon atoms to which they are bonded, form C 3~6 Forms a cycloalkyl ring or a 4- to 8-membered heterocyclyl ring, wherein C 3~6 The cycloalkyl ring or the 4- to 8-membered heterocyclyl ring may have 1 to 3 R g may be substituted with A 2 is -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)NH; R 3A is R a and -(C 0~3 alkylene)-R b1 C, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of 1~6 Alkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 3~6 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; X a and X care independently selected from the group consisting of N, CH, and CF, with the proviso that X a and X c one or both of are N; X b N and CR x1 is selected from the group consisting of R 6 and R x1 H, halo, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 are each independently selected from the group consisting of alkoxy, CN, and —C≡CH; L is -(L A ) n1 - and L A and n1 is defined according to (AA) or (BB): (AA) n1 is an integer from 1 to 15, Each L A L A1 , L A3 , and L A4 independently selected from the group consisting of: A 1 to 3 occurrences of L A4 and (BB) n1 is an integer from 0 to 20, Each L A L A1 and L A3 are independently selected from the group consisting of Each L A1 -CH2-, -CHR L - and -C(R L )2-, Each L A3 is -N(R d )-, -N(R b )-, -O-, -S(O) 0~2 -, and C(=O), Each L A4 teeth, (a)R a and R bC, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of 3~15 cycloalkylene or 3- to 15-membered heterocyclylene, and (b)R a and R b C, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of 6~15 Arylene or 5- to 15-membered heteroarylene are independently selected from the group consisting of However, L can be any of NO bond, OO bond, NN bond, NS(O)0 bond, and OS(O) 0~2 Does not include bonds, Each R L are 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 1 to 6 R c C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Ring C is TIFF2025525325000005.tif25128; c1 is 0, 1, 2, or 3; Each R Y is R a and R b are independently selected from the group consisting of R aN is H or 1 to 3 R c C optionally substituted with 1~6 is alkyl, Y 1 and Y 2 are independently N, CH or CR Y and yy represents the point of attachment to L; X is CH, C or N; TIFF2025525325000006.tif5170 is a single or double bond, L C is a bond, -CH2-, -CHR a -, -C(R a )2-, -C(=O)-, -N(R d )-, and O, provided that when X is N, then L C is other than O, Further, provided that ring C is -L C -, X is CH, and L C is a bond, Each R a teeth, (a) Halo; (b) cyano; (c) -OH; (d) oxo; (e) 1 to 6 R c C optionally substituted with 1~6 Alkoxy; (f)-NR d R e ; (g) 1 to 6 R c C(=O)C optionally substituted with 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) 1 to 6 R c each of which may be substituted with C1~6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl are independently selected from the group consisting of Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of each b is independently 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O) and C 1~3 alkylene; Each R b1 is 1 to 3 R g each of which may be substituted with C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 independently selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; Each R c are 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 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6Alkyl, 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 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R g is R h , Oxo, C 1~3 Alkyl and C 1~3 haloalkyl; Each R h are 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 herein are compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0019] In some embodiments, when X is N, ring C is The file is TIFF2025525325000007.tif24170.

[0020] In some embodiments, R 3 -A 1 -C(R 4 R 4 )-A 2is.

[0021] In some embodiments, A 1 is -O-.

[0022] In some embodiments, each R 4 is H.

[0023] In some embodiments, A 2 is -C(O)NH2 or -C(O)NR 3A R f In some embodiments, R 3A is 1 to 6 R c C optionally substituted with 1~3 It is an alkyl. For example, A 2 can be —C(O)NH, —C(O)NHMe, or —C(O)NMe. For example, A 2 can be —C(O)NHMe.

[0024] In some embodiments, R 3 teeth, TIFF2025525325000008.tif15170.

[0025] In some embodiments, X a is N and X c is N and X b is CR x1 (e.g., CH).

[0026] In some embodiments, X a is CH and X c is N and X b is CR x1 (e.g., CH).

[0027] In some embodiments, R 6 is —Cl or —F.

[0028] In some embodiments, each R 2 is H.

[0029] In some embodiments, one R 2 Halo, Cyano, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, and C 1~3 haloalkoxy, and each remaining R 2 is H.

[0030] In some embodiments, m3 is 0.

[0031] In some embodiments, m3 is 1 and X 3 is C 1~3 It is alkylene.

[0032] In some embodiments, R 1 is H.

[0033] In some embodiments, m3 is 1 and X 3 is methylene, ethylene or isopropylene, and R 1 is H.

[0034] In some embodiments, R 3 -A 1 -C(R 4 R 4 )-A 2 where A 1 is O and each R 4 is H and A 2 is -C(O)NH2 or -C(O)NR 3A R f where R 3A is 1 to 6 R c C optionally substituted with 1~3 alkyl, and each R 2 is H and X a is N or CH, and X c is N and X b is CH and R 6 is -F or -Cl. In some embodiments, m3 is 1 and X 3 is methylene, ethylene or isopropylene, and R1 is H. In some embodiments, X a is N. In some embodiments, A 2 is C(O)NHMe.

[0035] In some embodiments, ring C is TIFF2025525325000009.tif23170. In some embodiments, ring C is TIFF2025525325000010.tif21170. In some embodiments, ring C is TIFF2025525325000011.tif29170. 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 is C 1~3 It is alkyl (eg, methyl).

[0036] In some embodiments, ring C is TIFF2025525325000012.tif18170. 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 is C 1~3 It is alkyl (eg, methyl).

[0037] In some embodiments, c1 is 0. In some embodiments, c1 is 1 and R Y is halo (e.g., -F).

[0038] In some embodiments, X is CH.

[0039] In some embodiments, L C is a bond.

[0040] In some embodiments, The TIFF2025525325000013.tif18170 part is TIFF2025525325000014.tif50130.

[0041] In some embodiments, The TIFF2025525325000015.tif19170 part is TIFF2025525325000016.tif25170.

[0042] In some embodiments, The TIFF2025525325000017.tif36170 part is TIFF2025525325000018.tif36170, m3 is 1, X 3 is C 1~3 alkylene, and R 1 is H and X a is CH or N, and X c is N and R 6 is -F or -Cl, The TIFF2025525325000019.tif20170 part is TIFF2025525325000020.tif24170. In some embodiments, -(X 3 ) m3 -R 1 is methyl, ethyl, or isopropyl. a is CH. In some embodiments, X a is N.

[0043] In some embodiments, L is -(L A ) n1 - and L A and n1 is defined according to (AA).

[0044] In some embodiments, n1 is an integer from 1 to 5.

[0045] In some embodiments, n1 is an integer from 2 to 4 (eg, 2 or 3).

[0046] In some embodiments, L is -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 is selected from the group consisting of bb represents the point of attachment to ring C.

[0047] In some embodiments, each L A4 independently, C 3~10 cycloalkylene or 4- to 12-membered heterocyclylene, each of which has 1 to 6 R a In some embodiments, each L A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 alkyl.

[0048] In some embodiments, each L A4 are independently 1 to 3 R a In some embodiments, each L is a 4- to 12- (e.g., 4- to 10-) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. A4Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 alkyl.

[0049] In some embodiments, each L A4 are independently 1 to 3 R a In some embodiments, each L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 alkyl.

[0050] In some embodiments, one L A4 However, 1 to 3 R a and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by A4 is 1 to 3 R a In some embodiments, each L is a bicyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 alkyl.

[0051] In some embodiments, one L A4 However, 1 to 3 R a and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by A4 is 1 to 3 R aIn some embodiments, each L is a bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 alkyl.

[0052] In some embodiments, one L A4 However, 1 to 3 R a and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by A4 is 1 to 3 R a In some embodiments, each L is a bicyclic bridged 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 alkyl.

[0053] In some embodiments, each L A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 alkyl.

[0054] In some embodiments, L is -L A4 -L A1 -L A4 - bbIn some embodiments, L A1 is -CH2-, -CHMe- or -CMe2-.

[0055] In some embodiments, L is -L A4 -L A3 -L A4 - bb In some embodiments, L A3 is —C(═O) or —O—.

[0056] In some embodiments, L is -L A4 -L A1 -L A4 -L A3 - bb and L A3 is C(=O).

[0057] In some embodiments, L is -L A4 -L A3 - bb ; -L A4 -L A1 - bb and -L A4 -L A1 -L A3 - bb is selected from the group consisting of bb represents the point of attachment to ring C.

[0058] 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 1 to 6 R a In some embodiments, L is a 4- to 12-membered heterocyclylene optionally substituted with A4 is 1 to 3 R aIn some embodiments, L is a 4- to 12- (e.g., 6- to 10-) membered nitrogen-containing heterocyclylene optionally substituted with A4 is 1 to 3 R a In some embodiments, L is a bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 alkyl.

[0059] In some embodiments, L is selected from the group consisting of the moieties shown in Table L.

[0060] [Table L] TIFF2025525325000022.tif243170TIFF2025525325000023.tif248170TIFF2025525325000024.tif115170bb represents the attachment point to ring C.

[0061] In some embodiments, L is selected from the group consisting of the moieties shown in Table L1-a.

[0062] [Table L1-a] bb represents the point of attachment to ring C.

[0063] In some embodiments, L is selected from the group consisting of the moieties shown in Table L2-a.

[0064] [Table L2-a] bb represents the point of attachment to ring C.

[0065] In some embodiments, the compound of Formula (I) has the formula (I-aa): TIFF2025525325000027.tif42170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000028.tif28128, where c1 is 0 or 1; R Y is halo (e.g., -F), and C optionally substituted with 1 to 3 F. 1~3 alkyl; R aN is C 1~3 is alkyl, L is -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 is selected from the group consisting of bb represents the attachment point to ring C, L A1 is CH2, CHMe, or CMe2, Each L A4 are independently 1 to 3 R a is a 4- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L A4Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, A compound of formula (I-aa) or a pharmaceutically acceptable salt thereof:

[0066] In some embodiments of Formula (I-aa), each L A4 are independently 1 to 3 R a and each L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0067] In some embodiments of Formula (I-aa), one L A4 is 1 to 3 R a and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by A4 is 1 to 3 R a and each L is a bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0068] In some embodiments of Formula (I-aa), one L A4 is 1 to 3 R a is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by The other L A4 is 1 to 3 R a a bicyclic bridged 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with Each L A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0069] In some embodiments of Formula (I-aa), L is -L A4 -L A1 -L A4 - bband L A1 is CH2 or CHMe.

[0070] In some embodiments of Formula (I-aa), L is selected from the group consisting of the moieties shown in Table L1-a.

[0071] In some embodiments of Formula (I-aa), L is selected from the group consisting of the moieties shown in Table LIa, where bb represents the point of attachment to ring C.

[0072] [Table LIa]

[0073] In some embodiments, the compound of formula (I-aa) has the formula (I-aa-1): TIFF2025525325000030.tif43170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000031.tif28128, wherein c1 is 0 or 1; R Y is halo (e.g., -F), and C optionally substituted with 1 to 3 F. 1~3 alkyl; R aN is C 1~3 is alkyl, L A1 is CH2, CHMe, or CMe2, Each L A4 are independently 1 to 3 R a is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by Each L A4contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms; L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, A compound of formula (I-aa-1) or a pharmaceutically acceptable salt thereof:

[0074] In some embodiments of Formula (I-aa-1), -L A4 -L A1 -L A4 The - moiety is selected from the group consisting of the moieties shown in Table LIa-1, where bb represents the point of attachment to ring C.

[0075] [Table LIa-1]

[0076] In some embodiments, the compound of formula (I-aa) has the formula (I-aa-2): TIFF2025525325000033.tif51170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000034.tif25128, wherein c1 is 0 or 1; R Y is halo (e.g., -F), and C optionally substituted with 1 to 3 F. 1~3 alkyl; R aN is C 1~3 is alkyl, LA1 is CH2, CHMe, or CMe2, Z 1 and Z 2 , CH, CR a4 and N, Z 3 and Z 4 , CH, CR a5 and N, However, Z 1 and Z 2 At least one of them is N, and Z 3 and Z 4 At least one of is N, and Z 2 If N, then Z 3 is CH or CR a5 and m4 and m5 are independently selected from the group consisting of 0, 1, and 2; Each R a4 and R a5 -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, A compound of formula (I-aa-2) or a pharmaceutically acceptable salt thereof:

[0077] 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 is N and Z 2 is CH or CR a4 and Z 3 is N.

[0078] In some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH or CR a4 and Z 3 is N and Z 4 is CH or CRa5 is.

[0079] In some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is CH, and m4 and m5 are both 0. In some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH and Z 3 is N and 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 is N and Z 2 is CH and Z 3 is N and Z 4 is CH, one of m4 and m5 is 1, the other of m4 and m5 is 0, and, if present, R a4 or R a5 is methyl. In some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is CH, m4 is 1, and m5 is 0. In some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is CH, m4 is 1, m5 is 0, and R a4 is methyl.

[0080] In some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is CR a5 (e.g., CF). In some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z4 is CF, and m4 and m5 are both 0.

[0081] In some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH or CR a4 and Z 3 is N and Z 4 is N, and in some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is N, and m4 and m5 are both 0. In some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH and Z 3 is N and 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 is N and Z 2 is CH and Z 3 is N and Z 4 is N, one of m4 and m5 is 1, the other of m4 and m5 is 0, and if present, R a4 or R a5 is methyl. In some embodiments of Formula (I-aa-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is N, m4 is 1, and m5 is 0. In some embodiments, R a4 is methyl.

[0082] In some embodiments of Formula (I-aa-2), The TIFF2025525325000035.tif22170 moiety is selected from the group consisting of the moieties shown in Table LIa-2, where bb represents the point of attachment to ring C.

[0083] [Table LIa-2]

[0084] In some embodiments, the compound of formula (I-aa) has formula (I-aa-3): TIFF2025525325000037.tif43170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000038.tif28128, where c1 is 0 or 1; R Y is halo (e.g., -F), and C optionally substituted with 1 to 3 F. 1~3 alkyl; R aN is C 1~3 is alkyl, L A1 is CH2, CHMe, or CMe2, One L A4 is 1 to 3 R a and The other L A4 is 1 to 3 R a is a bicyclic 6- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, A compound of formula (I-aa-3) or a pharmaceutically acceptable salt thereof:

[0085] In some embodiments of Formula (I-aa-3), each LA4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0086] In some embodiments of Formula (I-aa-3), one L A4 is 1 to 3 R a and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by A4 is 1 to 3 R a In some embodiments, each L is a bicyclic spirocyclic 6-12 (e.g., 7, 9, or 11) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0087] In some embodiments of Formula (I-aa-3), one L A4 is 1 to 3 R a and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by A4 is 1 to 3 R a In some embodiments, each L is a bicyclic bridged 6-12 (e.g., 7, 8, or 9) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0088] In some embodiments of Formula (I-aa-3), one L A4 is 1 to 3 R a and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by A4 is 1 to 3 R a In some embodiments, each L is a bicyclic fused 6-12 (e.g., 6) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0089] In some embodiments of Formula (I-aa-3), -L A4 -L A1 -L A4The - moiety is selected from the group consisting of the moieties shown in Table LIa-3, where bb represents the point of attachment to ring C.

[0090] [Table LIa-3]

[0091] In some embodiments, the compound of formula (I-aa) has formula (I-aa-4): TIFF2025525325000040.tif43170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000041.tif25128, wherein c1 is 0 or 1; R Y is halo (e.g., -F), and C optionally substituted with 1 to 3 F. 1~3 alkyl; R aN is C 1~3 is alkyl, Each L A4 are independently 1 to 3 R a is a 4- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, A compound of formula (I-aa-4) or a pharmaceutically acceptable salt thereof:

[0092] In some embodiments of Formula (I-aa-4), each L A4are independently 1 to 3 R a and each L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms. For example, each L A4 can be independently selected from the group consisting of piperazinylene and piperidinylene.

[0093] In some embodiments of Formula (I-aa-4), -L A4 -C(=O)L A4 The - moiety is selected from the group consisting of the moieties shown in Table LIa-4, where bb represents the point of attachment to ring C.

[0094] [Table LIa-4]

[0095] In some embodiments, the compound has the formula (Ia): TIFF2025525325000043.tif42170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000044.tif29170; L is -L A4 -L A1 -L A4 - bb ; -L A4 -OL A4 - bb ; -L A4 -C(=O)-L A4 - bband -L A4 -L A1 -L A4 -C(=O)- bb is selected from the group consisting of bb represents the attachment point to ring C, L A1 is CH2, CHMe, or CMe2, Each L A4 are independently 1 to 3 R a is a 4- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, A compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0096] In some embodiments of Formula (Ia), each L A4 are independently 1 to 3 R a is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by Each L A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0097] In some embodiments of Formula (Ia), one L A4 is 1 to 3 R a is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by The other L A4 is 1 to 3 R a a bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted by Each L A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0098] In some embodiments of Formula (Ia), one L A4is 1 to 3 R a is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by The other L A4 is 1 to 3 R a a bicyclic bridged 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with Each L A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0099] In some embodiments of Formula (Ia), L is -L A4 -L A1 -L A4 - bb and L A1 is CH2 or CHMe.

[0100] In some embodiments of Formula (Ia), L is selected from the group consisting of the moieties shown in Table L1-a.

[0101] In some embodiments of Formula (Ia), L is selected from the group consisting of the moieties shown in Table LIa (supra), where bb represents the point of attachment to ring C.

[0102] In some embodiments, the compound of Formula (Ia) has the formula (Ia-1): TIFF2025525325000045.tif47170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000046.tif28170; L A1 is CH2, CHMe, or CMe2, Each LA4 are independently 1 to 3 R a is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by Each L A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms; L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, The compound of formula (Ia-1) or a pharmaceutically acceptable salt thereof:

[0103] In some embodiments of Formula (Ia-1), -L A4 -L A1 -L A4 The - moiety is selected from the group consisting of the moieties shown in Table 1a-1 (supra), where bb represents the point of attachment to ring C.

[0104] In some embodiments, the compound of Formula (Ia) has the formula (Ia-2): TIFF2025525325000047.tif51170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000048.tif29170; L A1 is CH2, CHMe, or CMe2, Z 1 and Z 2 , CH, CR a4 and N, Z3 and Z 4 , CH, CR a5 and N, However, Z 1 and Z 2 At least one of them is N, and Z 3 and Z 4 At least one of is N, and Z 2 If N, then Z 3 is CH or CR a5 and m4 and m5 are independently selected from the group consisting of 0, 1, and 2; Each R a4 and R a5 -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, The compound of formula (Ia-2) or a pharmaceutically acceptable salt thereof:

[0105] 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 is N and Z 2 is CH or CR a4 and Z 3 is N.

[0106] In some embodiments of Formula (Ia-2), Z 1 is N and Z 2 is CH or CR a4 and Z 3 is N and Z 4 is CH or CR a5 is.

[0107] In some embodiments of Formula (Ia-2), Z 1 is N and Z 2 is CH and Z 3is N and Z 4 is CH, and m4 and m5 are both 0. In some embodiments of Formula (Ia-2), Z 1 is N and Z 2 is CH and Z 3 is N and 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 is N and Z 2 is CH and Z 3 is N and Z 4 is CH, one of m4 and m5 is 1, the other of m4 and m5 is 0, and, if present, R a4 or R a5 is methyl. In some embodiments of Formula (Ia-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is CH, m4 is 1, and m5 is 0. In some embodiments of Formula (Ia-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is CH, m4 is 1, m5 is 0, and R a4 is methyl.

[0108] In some embodiments of Formula (Ia-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is CR a5 (e.g., CF). In some embodiments of formula (Ia-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is CF, and m4 and m5 are both 0.

[0109] In some embodiments of Formula (Ia-2), Z 1 is N and Z 2 is CH or CRa4 and Z 3 is N and Z 4 is N, and in some embodiments of formula (Ia-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is N, and m4 and m5 are both 0. In some embodiments of formula (Ia-2), Z 1 is N and Z 2 is CH and Z 3 is N and 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 is N and Z 2 is CH and Z 3 is N and Z 4 is N, one of m4 and m5 is 1, the other of m4 and m5 is 0, and if present, R a4 or R a5 is methyl. In some embodiments of Formula (Ia-2), Z 1 is N and Z 2 is CH and Z 3 is N and Z 4 is N, m4 is 1, and m5 is 0. In some embodiments, R a4 is methyl.

[0110] In some embodiments of Formula (Ia-2), The TIFF2025525325000049.tif23170 moiety is selected from the group consisting of the moieties shown in Table LIa-2 (supra), where bb represents the point of attachment to ring C.

[0111] In some embodiments, the compound of Formula (Ia) has the formula (Ia-3): TIFF2025525325000050.tif45170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000051.tif28170; L A1 is CH2, CHMe, or CMe2, One L A4 is 1 to 3 R a and The other L A4 is 1 to 3 R a is a bicyclic 6- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, The compound of formula (Ia-3) or a pharmaceutically acceptable salt thereof:

[0112] In some embodiments of Formula (Ia-3), each L A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0113] In some embodiments of Formula (Ia-3), one L A4 is 1 to 3 R a and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by A4 is 1 to 3 R a In some embodiments, each L is a bicyclic spirocyclic 6-12 (e.g., 7, 9, or 11) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0114] In some embodiments of Formula (Ia-3), one L A4 is 1 to 3 R a and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by A4 is 1 to 3 R a In some embodiments, each L is a bicyclic bridged 6-12 (e.g., 7, 8, or 9) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0115] In some embodiments of Formula (Ia-3), one L A4 is 1 to 3 R a and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by A4 is 1 to 3 R a In some embodiments, each L is a bicyclic fused 6-12 (e.g., 6) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0116] In some embodiments of Formula (Ia-3), -L A4 -L A1 -L A4 The - moiety is selected from the group consisting of the moieties shown in Table LIa-3 (supra), where bb represents the point of attachment to ring C.

[0117] In some embodiments, the compound of Formula (Ia) has the formula (Ia-4): TIFF2025525325000052.tif42170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000053.tif28170, and Each L A4 are independently 1 to 3 R a is a 4- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, The compound of formula (Ia-4) or a pharmaceutically acceptable salt thereof:

[0118] In some embodiments of Formula (Ia-4), each L A4 are independently 1 to 3 R a and each L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms. For example, each L A4 can be independently selected from the group consisting of piperazinylene and piperidinylene.

[0119] In some embodiments of Formula (Ia-4), -L A4 -C(=O)-L A4 The - moiety is selected from the group consisting of the moieties shown in Table LIa-4 (supra), and bb represents the point of attachment to ring C.

[0120] In some embodiments, the compound of Formula (I) has the formula (I-bb): TIFF2025525325000054.tif44170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1is H, Ring C is TIFF2025525325000055.tif28128, wherein c1 is 0 or 1; R Y is halo (e.g., -F), and C optionally substituted with 1 to 3 F. 1~3 alkyl; R aN is C 1~3 is alkyl, L is -L A4 -L A3 - bb or -L A4 -L A1 -L A3 - bb and bb represents the point of attachment to ring C. L A4 is 1 to 3 R a is a 4- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, A compound of formula (I-bb) or a pharmaceutically acceptable salt thereof:

[0121] In some embodiments of Formula (I-bb), L is -L A4 -L A3 - bb and L A3 is -NH-.

[0122] In some embodiments of Formula (I-bb), L A4 is 1 to 3 R a is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by Each L A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0123] In some embodiments of Formula (I-bb), L A4is 1 to 3 R a and each L is a bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0124] In some embodiments of Formula (I-bb), L is selected from the group consisting of the moieties shown in Table L2-a.

[0125] In some embodiments of Formula (I-bb), L is selected from the group consisting of the moieties shown in Table LIb, where bb represents the point of attachment to ring C.

[0126] [Table LIb]

[0127] In some embodiments, the compound of formula (I-bb) has the formula (I-bb-1): TIFF2025525325000057.tif43170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000058.tif25128, where c1 is 0 or 1; R Y is halo (e.g., -F), and C optionally substituted with 1 to 3 F. 1~3 alkyl; R aN is C 1~3 is alkyl, L A4 is 1 to 3 R aand optionally substituted 6- to 12-membered nitrogen-containing heterocyclylene, wherein L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, L A3 -NH-, -N(C 1~3 alkyl)- or -O-; A compound of formula (I-bb-1) or a pharmaceutically acceptable salt thereof:

[0128] In some embodiments of Formula (I-bb-1), L A4 is 1 to 3 R a bicyclic spirocyclic 6-12 (e.g., 8-10 (e.g., 9)) membered nitrogen-containing heterocyclylene optionally substituted by A4 contains 1 to 2 (eg, 1) ring nitrogen atoms and no additional ring heteroatoms.

[0129] In some embodiments of Formula (I-bb-1), -L A4 -L A3 - is selected from the group consisting of the moieties shown in Table LIb-1, where bb represents the point of attachment to Ring C.

[0130] [Table LIb-1]

[0131] In some embodiments, the compound of formula (I-bb) has the formula (I-bb-2): TIFF2025525325000060.tif52170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000061.tif25128, where c1 is 0 or 1, and R Y is halo (e.g., -F), and C optionally substituted with 1 to 3 F. 1~3 alkyl; R aN is C 1~3 is alkyl, L A3 -NH-, -N(C 1~3 alkyl)- or -O-; m4 is selected from the group consisting of 0, 1, and 2; Each R a4 -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, The compound of formula (I-bb-2) or a pharmaceutically acceptable salt thereof:

[0132] In some embodiments of Formula (I-bb-2), m4 is 0 or 1, and, if present, R a4 is methyl.

[0133] In some embodiments, the compound has the formula (Ib): TIFF2025525325000062.tif43170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000063.tif29170; L is -LA4 -L A3 - bb or -L A4 -L A1 -L A3 - bb and bb represents the point of attachment to ring C. L A4 is 1 to 3 R a is a 4- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, A compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

[0134] In some embodiments of Formula (Ib), L is -L A4 -L A3 - bb and L A3 is -NH-.

[0135] In some embodiments of Formula (Ib), L A4 is 1 to 3 R a and each L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted with A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0136] In some embodiments of Formula (Ib), L A4 is 1 to 3 R a and a bicyclic spirocyclic 6-12 (eg, 6-10) membered nitrogen-containing heterocyclylene optionally substituted with: Each L A4 contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

[0137] In some embodiments of Formula (Ib), L is selected from the group consisting of the moieties shown in Table L2-a.

[0138] In some embodiments of Formula (Ib), L is selected from the group consisting of the moieties shown in Table LIb (supra), where bb represents the point of attachment to ring C.

[0139] In some embodiments, the compound of formula (Ib) has the formula (Ib-1): TIFF2025525325000064.tif45170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000065.tif28170; L A4 is 1 to 3 R a and optionally substituted 6- to 12-membered nitrogen-containing heterocyclylene, wherein L A4 Each R on a -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, L A3 -NH-, -N(C 1~3 alkyl)- or -O-; The compound of formula (Ib-1) or a pharmaceutically acceptable salt thereof:

[0140] In some embodiments of Formula (Ib-1), L A4 is 1 to 3 R a bicyclic spirocyclic 6-12 (e.g., 8-10 (e.g., 9)) membered nitrogen-containing heterocyclylene optionally substituted by A4 contains 1 to 2 (eg, 1) ring nitrogen atoms and no additional ring heteroatoms.

[0141] In some embodiments of Formula (Ib-1), -L A4 -L A3 - is selected from the group consisting of the moieties shown in Table LIb-1 (supra), where bb represents the point of attachment to Ring C.

[0142] In some embodiments, the compound of formula (Ib) has formula (Ib-2): TIFF2025525325000066.tif52170 or a pharmaceutically acceptable salt thereof, During the ceremony, X a is N or CH, R 6 is -F or -Cl, m3 is 1 and X 3 is C 1~3 alkylene, and R 1 is H, Ring C is TIFF2025525325000067.tif28170; L A3 -NH-, -N(C 1~3 alkyl)- or -O-; m4 is selected from the group consisting of 0, 1, and 2; Each R a4 -F, CN, C 1~3 C optionally substituted with alkoxy, OH, and 1 to 3 F 1~3 independently selected from the group consisting of alkyl, The compound of formula (Ib-2) or a pharmaceutically acceptable salt thereof:

[0143] In some embodiments of Formula (Ib-2), m4 is 0 or 1, and when present, R a4 is methyl.

[0144] 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 is N.

[0145] 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 is CH.

[0146] 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 is N.

[0147] 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 is CH.

[0148] In some embodiments, the compound is selected from the group consisting of the compounds of Table C1 or a pharmaceutically acceptable salt thereof.

[0149] [Table C1] TIFF2025525325000069.tif239170TIFF2025525325000070.tif235170TIFF2025525325000071.tif224170TIFF2025525325000072.tif241170TIFF2025525325000073.tif237170TIFF2025525325000074.tif243170TIFF2025525325000075.tif230170TIFF2025525325000076.tif235170TIFF2025525325000077.tif211170TIFF2025525325000078.tif226170TIFF2025525325000079.tif234170TIFF2025525325000080.tif232170TIFF2025525325000081.tif246170TIFF2025525325000082.tif244170TIFF2025525325000083.tif216170TIFF2025525325000084.tif237170TIFF2025525325000085.tif244170TIFF2025525325000086.tif219170TIFF2025525325000087.tif214170TIFF2025525325000088.tif243170TIFF2025525325000089.tif227170TIFF2025525325000090.tif125170

[0150] In certain compounds of Table C1, one or more stereocenters are designated by a "V3000 enhanced stereochemical designation" (see support.collaborativedrug.com / hc / en-us / articles / 360020872171-Advanced-Stereochemistry-Registration-Atropisomers-Mixtures-Unknowns-and-Non-Tetrahedral-Chirality, accessed on December 23, 2022, and Accelrys Chemical Representation Guide, Accelrys Software Inc., 2014, each of which is incorporated by reference in its entirety). Using this stereochemical designation, a particular stereocenter is designated by "abs," "&x," or "orx," where x is an integer (e.g., 1 or 2). For the avoidance of doubt, the stereochemical designations in Table C1 have the following meanings:

[0151] (1) When a stereocenter (e.g., an asymmetric carbon) is depicted in a structural formula with a "flat" bond (i.e., none of the chemical bonds at the stereocenter are depicted with a wedge or dash), each of said stereocenters can independently have either the (R)- or (S)-configuration. For example, the structure TIFF2025525325000091.tif18170 represents (S)-(1-methylpyrrolidin-2-yl)methanol, (R)-(1-methylpyrrolidin-2-yl)methanol, or a mixture thereof.

[0152] As another example, the structure TIFF2025525325000092.tif21170 represents (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 a mixture thereof.

[0153] When a stereocenter or centers are indicated by a wedge and a dash, the following notation is used:

[0154] (2) If a stereocenter is designated by "abs" or if the stereocenter is not designated by an augmented stereochemical designation (e.g., "abs," "&x," or "orx"), the stereocenter has the absolute configuration as shown by the structural formula. For example, the structure TIFF2025525325000093.tif16170 both refer to (S)-(1-methylpyrrolidin-2-yl)methanol.

[0155] (3) When a stereocenter in a structural formula is written as "orx," the stereocenter is resolved, but the configuration of the stereocenter is not determined. For example, in the structure TIFF2025525325000094.tif13170 refers to one stereoisomer selected from the group consisting of (S)-(1-methylpyrrolidin-2-yl)methanol and (R)-(1-methylpyrrolidin-2-yl)methanol.

[0156] (4) When two or more stereocenters are represented by "orx" in a structural formula, each of these stereocenters is resolved, but the configuration at said stereocenters is not determined. Specifically, For any pair of stereocenters designated "orx" in a structural formula, when the numerical moieties in the designation are different (e.g., two stereocenters designated "or1" and "or2," respectively), each stereocenter is independently defined according to (3) (see above). For example, in the structure TIFF2025525325000095.tif20170 is TIFF2025525325000096.tif22170. b. For any pair of stereocenters designated "orx" in a structural formula, when the numerical moieties in the designation are identical (e.g., two stereocenters designated "or1" respectively), the structural formula refers to one stereoisomer having the relative stereochemistry at those stereocenters shown in the structural formula, but the absolute configuration of those stereocenters has not been determined. For example, the structure TIFF2025525325000097.tif23170 contains two "syn" stereoisomers: TIFF2025525325000098.tif22128. Another example is the structure TIFF2025525325000099.tif22170 is the "anti" stereoisomer It points to one of the files: TIFF2025525325000100.tif24170.

[0157] (5) When two or more stereocenters are designated by "&x" in a structural formula, the structural formula refers to a mixture of stereoisomers differing in configuration at said stereocenters, specifically: a. When the numerical moieties in the designation for any pair of stereocenters designated "&x" in a structural formula are different (e.g., two stereocenters designated "&1" and "&2", respectively), the structural formula refers to a mixture of stereoisomers at these two stereocenters, and the configuration at each stereocenter can vary independently of each other. For example, in the structure TIFF2025525325000101.tif21170 contains four stereoisomers: Refers to a mixture of TIFF2025525325000102.tif21136. b. For any pair of stereocenters designated by "&x" in a structural formula, when the numerical moieties in the designation are identical (e.g., two stereocenters each designated by "&1"), the structural formula refers to a mixture of stereoisomers at those two or more stereocenters, with the relative configurations as shown in the structural formula. For example, the structure TIFF2025525325000103.tif23170 is the "syn" stereoisomer: TIFF2025525325000104.tif23170. Another example is the structure TIFF2025525325000105.tif23170 is the "anti" stereoisomer: Refers to a mixture of TIFF2025525325000106.tif25170.

[0158] Exemplary compounds of Formula (I-aa) (e.g., Formula (Ia)) include compounds as shown in Table C1: 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, or a pharmaceutically acceptable salt thereof.

[0159] Exemplary compounds of Formula (I-aa-1) (e.g., Formula (Ia-1)) include compounds as shown in Table C1: 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, or a pharmaceutically acceptable salt thereof.

[0160] Exemplary compounds of Formula (I-aa-2) (e.g., Formula (Ia-2)) include compounds as shown in Table C1: 101, 102, 107, 108, 281, 288, 307, 307a, 307b, 308, 308a, 308b, 309, 309a, 309b, 333, 334, 336, 336a, 337, 340, and 346, or a pharmaceutically acceptable salt thereof.

[0161] Exemplary compounds of Formula (I-aa-3) (e.g., Formula (Ia-3)) include compounds 103, 104, 298, 311, and 325, as shown in Table C1, or a pharmaceutically acceptable salt thereof.

[0162] Exemplary compounds of Formula (I-aa-4) (e.g., Formula (Ia-4)) include compounds 327, 328, and 345, as shown in Table C1, or a pharmaceutically acceptable salt thereof.

[0163] Exemplary compounds of Formula (I-bb) (e.g., Formula (Ib)) include 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.

[0164] 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.

[0165] Exemplary compounds of Formula (I-bb-2) (e.g., Formula (Ib-2)) include compounds 341 and 342, as shown in Table C1, or pharmaceutically acceptable salts thereof.

[0166] In some embodiments, the compound is selected from the group consisting of the compounds of Table C2 or a pharmaceutically acceptable salt thereof.

[0167] [Table C2] TIFF2025525325000108.tif244170TIFF2025525325000109.tif234170TIFF202 5525325000110.tif234170TIFF2025525325000111.tif237170TIFF20255253250 00112.tif232170TIFF2025525325000113.tif222170TIFF2025525325000114.t if221170TIFF2025525325000115.tif223170TIFF2025525325000116.tif115170

[0168] Certain examples of compounds of Formula (I) were synthesized using methods involving resolution of stereoisomeric mixtures (e.g., SFC separation of stereoisomers). In Table C1, the resolved stereocenters of these compounds are labeled with the enhanced stereochemical designation "or1" and / or "or2." In some cases, stereoisomeric resolution was performed during the final step of the synthesis, thereby providing individual stereoisomers of the compounds of Formula (I). Alternatively, in some other examples, resolution was performed on intermediates or starting materials, and each of the constituent stereoisomers of the intermediate or starting material was subjected separately to subsequent steps of the synthesis to provide each compound of Formula (I) as a separate stereoisomer. Methods for resolution and correlation between resolved intermediates and compounds of Formula (I) are disclosed in the Examples and Examples 28, 39, or 83 herein. One skilled in the art will understand that either approach to stereoisomeric resolution provides stereoisomers with both (R)- and (S)-configurations at the resolved stereocenter. See Table C3 (in Table C1, compounds whose stereoisomers contain the or1 and / or or2 stereochemical designations are provided in the unstereoformed form, followed by the respective stereoisomers having the (R)- and (S)-configuration).

[0169] [Table C3] TIFF2025525325000118.tif139170

[0170] Exemplary compounds of Formula (I) also include those set forth in Table C1 of U.S. Provisional Patent Application No. 63 / 420,411, filed October 28, 2022; Table C1 of U.S. Provisional Patent Application No. 63 / 444,778, filed February 10, 2023; Table C1 of U.S. Provisional Patent Application No. 63 / 497,063, filed April 19, 2023; and Table C1 of U.S. Provisional Patent Application No. 63 / 501,082, filed May 9, 2023; or a pharmaceutically acceptable salt thereof, each Table C1 being incorporated herein by reference in its entirety.

[0171] Formula (II): TIFF2025525325000119.tif29170 or a pharmaceutically acceptable salt thereof, During the ceremony, TBMs are (T1), (T2), and (T3): TIFF2025525325000120.tif76170; X 1 and X 2 N and CR 2 are independently selected from the group consisting of Each R 2 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 are independently selected from the group consisting of m3 is 0, 1, 2, or 3; each X 3 -O-, -NR f -, -C(=O)-, and 1 to 3 R c C optionally substituted with 1~3 alkylene; R 1 is H, halo, cyano and R b1 is selected from the group consisting of However, N-(X 3 ) m3 -R 1 The moiety does not contain any O-O, N-O or N-halo bonds; R 3 -A 1 -C(R 4 R 4 )-A 2 and -CH=CH-A 2 wherein A is selected from the group consisting of 1 is -O- or -S-, Each R 4 is H, C 1~6 Alkyl, and C 1~6 haloalkyl; R 4The pair of carbon atoms, together with the carbon atoms to which they are bonded, form C 3~6 Forms a cycloalkyl ring or a 4- to 8-membered heterocyclyl ring, wherein C 3~6 The cycloalkyl ring or the 4- to 8-membered heterocyclyl ring may have 1 to 3 R g may be substituted with A 2 is -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)NH; R 3A is R a and -(C 0~3 alkylene)-R b1 C, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of 1~6 Alkyl, C 3~6 Alkenyl, C 3~6 Alkynyl, C 3~6 selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; X a and X c are independently selected from the group consisting of N, CH, and CF, with the proviso that X a and X c one or both of are N; X b N and CR x1 is selected from the group consisting of R 6 and R x1 H, halo, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 are each independently selected from the group consisting of alkoxy, CN, and —C≡CH; R 5 teeth, (a)H; (b) halo; (c) cyano; (d) NO2; (e) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 Alkynyl; (f) 1 to 6 R c C optionally substituted with 1~6 Alkoxy; and (g)-L 51 -R 51 is selected from the group consisting of L 51 is a 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 0~2 alkylene)-*, where * is R 51 represents the point of attachment to -N(R d )-(C 0~2 (Alkylene)-*C 0~2 The alkylene portion is C 1~3 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl and halo; R 51 teeth, (a)H; (b) Each contains 1 to 6 R c and may be further substituted with R b1 optionally substituted with C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 alkynyl; and (c)R a and R b and each of the groups may be substituted with 1 to 6 substituents selected from the group consisting of —C(O)N(Rf )(CH2CH2O) 1-4 -R a may be further substituted with C 3~10 Cycloalkyl, 4-12 membered heterocyclyl, C 6~10 Aryl or 5-15 membered heteroaryl is selected from the group consisting of L is -(L A ) n1 - and L A and n1 is defined according to (AA) or (BB): (AA) n1 is an integer from 1 to 15, Each L A L A1 , L A3 , and L A4 independently selected from the group consisting of: A 1 to 3 occurrences of L A4 and (BB) n1 is an integer from 0 to 20, Each L A L A1 and L A3 are independently selected from the group consisting of Each L A1 -CH2-, -CHR L - and -C(R L )2-, Each L A3 is -N(R d )-, -N(R b )-, -O-, -S(O) 0~2 -, and C(=O), Each L A4 teeth, (a)R a and R b C3-15 cycloalkylene or 3-15 membered heterocyclylene, each of which may be substituted by 1 to 6 substituents independently selected from the group consisting of: (b)R a and R bC, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of 6~15 Arylene or 5- to 15-membered heteroarylene are independently selected from the group consisting of However, L is not a NO bond, an NN bond, an NS(O)0 bond, or an OS(O) 0~2 Does not include bonds, Each R L are 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 1 to 6 R c C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Ring C is TIFF2025525325000121.tif25128; c1 is 0, 1, 2, or 3; Each R Y is R a and R b are independently selected from the group consisting of R aN is H or 1 to 3 R c C optionally substituted with 1~6 is alkyl, Y 1 and Y 2 are independently N, CH or CR Y and yy represents the point of attachment to L; X is CH, C or N; TIFF2025525325000122.tif5170 is a single or double bond, L C is a bond, -CH2-, -CHRa -, -C(R a )2-, -C(=O)-, -N(R d )-, and O, provided that when X is N, then L C is other than O, Further, provided that ring C is -L c -, X is CH, and L C is a bond, Each R a teeth, (a) Halo; (b) cyano; (c) -OH; (d) oxo; (e) 1 to 6 R c C optionally substituted with 1~6 Alkoxy; (f)-NR d R e ; (g) 1 to 6 R c C(=O)C optionally substituted with 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) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl or C 2~6 Alkynyl are independently selected from the group consisting of Each R b is -(L b ) b -Rb1 and -R b1 are independently selected from the group consisting of each b is independently 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O) and C 1~3 alkylene; Each R b1 is 1 to 3 R g each of which may be substituted with C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 independently selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; Each R c are 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 independently selected from the group consisting of: Each R d and R e is 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) 1~2N(R f )2 and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R g is R h , Oxo, C 1~3 Alkyl and C 1~3 haloalkyl; Each R h are 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; However, if TBM is (T1), X 1 and X 2 are independently selected CRs 2 and X is N and ring C is TIFF2025525325000123.tif23170, Also provided herein is a compound of formula (II) or a pharmaceutically acceptable salt thereof.

[0172] In formula (II), L, ring C, L C and X may be as defined herein for formula (I).

[0173] Exemplary compounds of Formula (II) include those shown in Table C1 of U.S. Provisional Patent Application No. 63 / 351,715, filed June 13, 2022; Table C1 of U.S. Provisional Patent Application No. 63 / 351,697, filed June 13, 2022; Table C1 of U.S. Provisional Patent Application No. 63 / 395,630, filed August 5, 2022; Table C1 of U.S. Provisional Patent Application No. 63 / 395,638, filed August 5, 2022; Table C1 of U.S. Provisional Patent Application No. 63 / 420,421, filed October 28, 2022; and Table C1 of U.S. Provisional Patent Application No. 63 / 444,801, filed February 10, 2023; or a pharmaceutically acceptable salt thereof, each of which is incorporated herein by reference in its entirety.

[0174] 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, has an EC 50 (e.g., less than 750 nM, less than 500 nM, or less than 200 nM) reduce cell viability in a cell line expressing BCL6 protein. In some embodiments, the compound reduces cell viability in a cell line expressing BCL6 protein at an EC 50 (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 may reduce the EC 50 The cell viability in a cell line expressing BCL6 protein can be reduced at a concentration of about 0.1 nM to about 100 nM, about 0.1 nM to about 50 nM, about 1 nM to about 50 nM, about 1 nM to about 20 nM, or about 0.1 nM to about 1 nM.

[0175] 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, has a DC of less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 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, induces degradation of BCL6 protein in a cell line expressing a BCL6 protein having the following structure: 50 For example, the compound induces degradation of BCL6 protein in a cell line expressing a BCL6 protein having the formula: 50 can induce degradation of BCL6 protein in cell lines that express BCL6 protein.

[0176] 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, has less than 70% (e.g., less than 50%, less than 30%, less than 20%, or less than 10%) of the 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, has less than 50% (e.g., less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%) of 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, has less than 30% (e.g., less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%) of Y minFor example, the compound induces degradation of the BCL6 protein in a cell line expressing the BCL6 protein, with a Y of about 1% to about 70%. min (For example, about 5% to about 50% or about 10% to about 30%), the degradation of the BCL6 protein can be induced.

[0177] Also provided herein is a BCL6 protein non-covalently bound 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.

[0178] Also provided herein is a ternary complex comprising a BCL6 protein, 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 or a portion thereof.

[0179] chemical definition The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0180] The term "oxo" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl.

[0181] The term "alkyl" refers to a saturated acyclic hydrocarbon radical, which may be straight or branched, containing the indicated number of carbon atoms. For example, C 1~10 indicates that the group may have from 1 to 10 carbon atoms in it. Alkyl groups can be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. The term "saturated," as used in this context, means that only single bonds exist between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0182] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms have been replaced with an independently selected halo (e.g., -CF3, -CHF2, or -CH2F).

[0183] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0184] The term "alkylene" refers to a divalent alkyl (e.g., -CH2-). Similarly, terms such as "cycloalkylene" and "heterocyclylene" refer to divalent cycloalkyl and heterocyclyl, respectively. For the avoidance of doubt, in "cycloalkylene" and "heterocyclylene", the two radicals are attached to the same ring carbon atom (e.g., geminal diradicals such as TIFF2025525325000124.tif18128), or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., adjacent ring carbon and / or nitrogen atoms)) (e.g., TIFF2025525325000125.tif20170).

[0185] 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 2~6indicates that the group may have at least 2 but no more than 6 carbon atoms in it. An alkenyl group can be unsubstituted or substituted with one or more substituents.

[0186] 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 may have at least 2 but no more than 6 carbon atoms in it. Alkynyl groups can be unsubstituted or substituted with one or more substituents.

[0187] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbons in which 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), where 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0188] The term "cycloalkyl" as used herein refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated hydrocarbon group, e.g., having 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons, 3 to 10 ring carbons, or 3 to 6 ring carbons, and the cycloalkyl group may be substituted. As used in this context, the term "saturated" refers to only single bonds present between 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, so long as one or more double bonds are present in the cycloalkyl, none of the rings in the ring system are aromatic, and the partially unsaturated cycloalkyl group as a whole is not fully saturated. Examples of partially unsaturated cycloalkyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkyls can contain multiple fused 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. Cycloalkyl also includes spirocycles (e.g., spirocyclic bicycles in which the two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls 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.

[0189] The term "heteroaryl" as used herein means a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10, or 15 ring atoms, wherein at least one ring in the system contains N, O, S (in oxidized form, e.g., TIFF2025525325000126.tif14170), and P (oxidized forms, e.g. TIFF2025525325000127.tif13170) (e.g., N, O, and S (oxidized forms, e.g., TIFF2025525325000128.tif14170)), and at least one ring in the system is aromatic (although it is not necessary for the ring to contain a heteroatom (e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl)). In some embodiments, heteroaryl groups are selected from the group consisting of N, O, and S (oxidized forms, e.g., TIFF2025525325000129.tif14170). Heteroaryl groups can be unsubstituted or substituted with one or more substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d] and the like. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinyl analogs thereof, in which each ring nitrogen adjacent to the carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), e.g., pyridone. TIFF2025525325000130.tif23170, pyrimidon TIFF2025525325000131.tif21170, Pyridazinone TIFF2025525325000132.tif21170, Pyrazinone TIFF2025525325000133.tif23170 and imidazolone TIFF2025525325000134.tif17170, where each ring nitrogen adjacent to the carbonyl is tertiary (i.e., an oxo group (i.e., "=O") herein is part of a heteroaryl ring).

[0190] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system having 3 to 15 ring atoms (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 15-membered tricyclic ring system) having 1 to 3 heteroatoms in the monocyclic, 1 to 6 heteroatoms in the bicyclic, or 1 to 9 heteroatoms in the tricyclic or polycyclic ring systems, wherein the heteroatoms are O, N, S (in oxidized form, e.g., TIFF2025525325000135.tif14170) and P (oxidized forms, e.g. TIFF2025525325000136.tif14170) (e.g., N, O, and S (oxidized forms, e.g., TIFF2025525325000137.tif12128)) (e.g., selected from carbon atoms and 1 to 3, 1 to 6, or 1 to 9 heteroatoms of N, O, S, or P (in the case of monocyclic, bicyclic, or tricyclic rings, respectively), where 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. The term "saturated" as used in this context means that only single bonds exist between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclyl groups include: Examples of partially unsaturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Partially unsaturated heterocyclyl groups can have any degree of unsaturation, so long as one or more double bonds are present in the heterocyclyl, none of the rings in the ring system are aromatic, and the partially unsaturated heterocyclyl group as a whole is not fully saturated. Examples of partially unsaturated heterocyclyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl.

[0191] Heterocyclyls can contain multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls 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]oct ...4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[4.1.0]octyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[4.1.0]heptyl, 2-azabicyclo[4.1.0]octyl, 2-azabicyclo[4.1.0]heptyl, 2-azabicyclo[4.1.0]octyl, 2-azabicyclo[4.1.0]octyl, 2-azabicyclo[4.1 Heterocyclyl includes 2-oxabicyclo[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 spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are connected through only one atom).Non-limiting examples of spirocyclic heterocyclyls 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[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.

[0192] As used herein, a nitrogen-containing heterocyclyl is a heterocyclic group containing 1-2 ring nitrogen atoms and 0 and S (oxidized, e.g., and 0 to 2 additional ring heteroatoms selected from the group consisting of (including TIFF2025525325000138.tif15170). Nitrogen-containing heterocyclyls can be monocyclic, bicyclic, or polycyclic as defined elsewhere herein. Examples of monocyclic nitrogen-containing heterocyclyls include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like. Examples of bicyclic nitrogen-containing heterocyclyls 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.

[0193] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (e.g., one or more double or triple bonds between constituent ring atoms in addition to the unsaturation due to the ring itself), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc.

[0194] For the avoidance of doubt, unless otherwise stated, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form a bicyclic or higher ring system (e.g., tricyclic, polycyclic ring system), such rings and cyclic groups are defined as rings in which the point of fusion is between (i) adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a 0 atom bridge). (ii) a single ring atom (spiro-fused ring system) on TIFF2025525325000140.tif23170, or (iii) an arrangement of consecutive ring atoms (bridged ring systems with all bridge lengths > 0). It should be understood that this encompasses those with fused rings, including those located on TIFF2025525325000141.tif18170.

[0195] Furthermore, atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 114, 115, 120, 121, 122, 12 13 C and 14 Contains C.

[0196] Additionally, compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: The compound containing TIFF2025525325000142.tif15170 is the moiety: TIFF2025525325000143.tif18170. Similarly, pyridinyl or pyrimidinyl moieties described as being optionally substituted with hydroxyl encompass the pyridone or pyrimidone tautomeric forms.

[0197] The compounds provided herein can include various stereochemical forms.Compounds also include diastereomers and optical isomers, for example, mixtures of enantiomers, including racemic mixtures, and individual enantiomers and diastereomers resulting from the structural asymmetry of a particular compound.Unless otherwise indicated, when the disclosed compounds are named or depicted by structure without specifying stereochemistry, and have one or more chiral centers, it is understood that they represent all possible stereoisomers of the compound.

[0198] Treatment method Indications Methods for inducing degradation of BCL6 protein are provided herein. For example, compounds capable of inducing degradation of BCL6 protein are provided herein, which are useful for treating or preventing cancer. Exemplary compounds that bind to BCL6 include, for example, 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;McCoull,William,et al.,ACS Chemical Biology 13.11(2018):3131-3141;Guo,Weikai,et al.Journal of Medicinal Chemistry 63.2(2020):676-695;Teng,Mingxing,et al.,ACS Medicinal Chemistry Letters 11.6(2020):1269-1273;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;Xing,Y.et al.,Cancer Letters(2022), doi:10.1016 / j.canlet.2021.12.035;Huckvale, R. et al., Journal of Medicinal Chemistry(2022),doi:10.1021 / acs.jmedchem.1c02175;Davis,O.et al.,Journal of Medicinal Chemistry(2022),doi:10.1021 / acs.jmedchem.1c02174;International Publication No. 2008 / 066887;International Publication No. 2010 / 008436;International Publication No. 2014 / 204859;International Publication No. 2018 / 215798;International Publication No. 2018 / 215801;International Publication No. 2018 / 219281;International Publication No. 2019 / 11913 No. 8; 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.

[0199] The efficacy of degradation by 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, is determined by DC 50 As used herein, DC 50The method comprises transfecting cells with a gene encoding 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 (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 of the protein in a cell that is 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). A lower DC determined under substantially similar conditions 50 Compounds with higher DC 50 In some embodiments, DC 50The level can be determined in vitro or in vivo (e.g., using HiBiT detection) 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) that express BCL6 protein. Cardenas, Mariano G., et al. Clinical Cancer Research 23.4(2017):885-893, and those disclosed in WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673. In some embodiments, a cell line that is BCL6-independent and / or does not have significant expression of BCL6 can be used as a control (e.g., Toledo, H929, MM.1S, or OPM2).

[0200] The efficacy of degradation by 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, is measured by the EC 50 As used herein, EC 50The method comprises transfecting the cells with a gene encoding 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 (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), Formula (I-bb) (e.g., Formula (I-aa-1), (Ia-2), (Ia-3), or (Ia-4)), or Formula (I-aa-2) (e.g., Formula (I-aa-1), (Ia-2), (Ia-3), or (Ia-4)), or Formula (I-aa-1 ... "BCL6" refers to the 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) that results in a 50% decrease in the concentration of a protein (e.g., a BCL6 protein) compared to the trough concentration of the protein in a cell when compared to the concentration of the protein in a cell that is not contacted with 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 (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). A lower EC when determined under substantially similar conditions 50 Compounds with higher EC 50 In some embodiments, the EC 50The level can be determined in vitro or in vivo (e.g., using HiBiT detection) 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) that express BCL6 protein. Cardenas, Mariano G., et al. Clinical Cancer Research 23.4(2017):885-893, and those disclosed in WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673. In some embodiments, a cell line that is BCL6-independent and / or does not have significant expression of BCL6 can be used as a control (e.g., Toledo, H929, MM.1S, or OPM2).

[0201] The efficacy of degradation by 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, provided herein, is determined by the following: Y min As used herein, Y minis compared to the concentration of the protein before the cell is 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 after 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), expressed as a percentage. As used herein, D refers to the ratio of the trough concentration of a protein (e.g., BCL6 protein) in a cell compared to the concentration of the protein in a cell not contacted 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)), or Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)). max is 1-Y min Y min can be measured by the HiBiT assay described in Example B1. A lower Y min Compounds with higher Y min In some embodiments, Y is a more potent inducer of degradation than a compound having a Y minThe level can be determined in vitro or in vivo (e.g., using HiBiT detection) 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) that express BCL6 protein. Cardenas, Mariano G., et al. Clinical Cancer Research 23.4(2017):885-893, and those disclosed in WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673. In some embodiments, a cell line that is BCL6-independent and / or does not have significant expression of BCL6 can be used as a control (e.g., Toledo, H929, MM.1S, or OPM2).

[0202] 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 less than 70% (e.g., less than 50%, or less than 30%) Y degradation in a HiBiT-based degradation assay (e.g., the assay described in Example B1). 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 less than 50% (e.g., less than 30%) Y degradation 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 degradation of less than 30% in a HiBiT-based degradation assay. min Shows.

[0203] 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, has a Y δ of less than 70% (e.g., less than 50% or less than 30%) in the assay described in Example B1. 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, has a 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, exhibits a Y min Shows.

[0204] 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 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%) of Y in a HiBiT-based degradation assay (e.g., the assay described in Example B1). 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 degradation 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 degradation of about 0% to about 30% in a HiBiT-based degradation assay. min Shows.

[0205] 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 about 0% to about 70% (e.g., about 0% to about 50%, about 30% to about 50%, or about 0% to about 30%) of Y in the assay described in Example B1. 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 activity 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 min Shows.

[0206] The appearance of degradation (e.g., the rate of degradation compared to the control, or the parameter Y min , D.C. 50 , and / or D max It will be understood that the degradation rate (represented by ) is affected by the rate of protein resynthesis, but the effects of protein degradation typically increase over time. It is common in the art to examine degradation after a specific period of time, such as 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 5 days, 10 days or more. For example, degradation can be expressed as percent degradation after 24 hours.

[0207] Exemplary assays for verifying the mechanism of decomposition induction of the compounds provided herein are known in the art, see, for example, Wu, et al. Nature Structural & Molecular Biology 27.7(2020):605-614.

[0208] Degradation assays can be used to quantify both on-target and off-target degradation-inducing effects of compounds such as those provided herein. Exemplary assays include quantitative immunoblotting, other immunoassays (e.g., MesoScale Discovery (MSD) immunoassays), homogeneous time-resolved fluorescence (HTRF), and HiBiT. In some embodiments, cells are 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, and incubated, and then lysates are 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 a HiBiT-tagged BCL6 protein, and the amount of fluorescence observed upon addition of the 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, off-target degradation induction effects can be assessed for the proteins eukaryotic peptide chain release factor GTP-binding subunit ERF3A (GSPT1), Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and / or casein kinase I isoform alpha (CK1α).See, for example, WO 2018 / 215798; WO 2018 / 215801; WO 2020 / 104820; McCoull, 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.

[0209] 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 provided herein for BCL6 can be measured, for example, by the binding IC 50 Or K i value (e.g., using a competitive assay) or K D A lower binding IC when determined under substantially similar conditions can be determined by a biophysical assay (e.g., using a biophysical assay). 50 Compounds with higher binding IC 50 A compound having a lower binding K when determined under substantially similar conditions is a stronger binder than a compound having a lower binding K i Compounds with higher binding K i Similarly, a compound having a lower K value when determined under substantially similar conditions is a stronger binder than a compound having a lower K value. D Compounds with higher K D It is a stronger binder compared to compounds with a K value. DThe value can be determined by surface plasmon resonance (SPR) or biolayer interferometry. See, for example, Guo, Weikai, et al., Journal of Medicinal Chemistry 63.2(2020):676-695; Lloyd, Matthew G., et al., Journal of Medicinal Chemistry 64.23(2021):17079-17097 and WO 2019 / 153080; WO 2019 / 119144; and WO 2019 / 119145.

[0210] 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 provided herein to inhibit BCL6 is measured by IC 50 A lower IC when determined under substantially similar conditions can be determined using the IC value. 50 Compounds with higher IC 50For example, a tagged (e.g., His-tagged) BCL6 protein and a tagged (e.g., fluorophore-tagged (e.g., Alexa-Fluor 633)) corepressor peptide (e.g., BCOR) are incubated 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) and an IC 50 A value can be calculated, and then the FRET ratio (relative to an appropriate control) can be measured using an appropriate FRET pair (e.g., using an antibody that recognizes the tagged BCL6 protein (e.g., anti-His-terbium cryptate)). See, for example, WO 2018 / 108704; WO 2018 / 215798; WO 2019 / 197842; WO 2020 / 104820; WO 2021 / 074620. As another example, IC 50The value can be calculated using an enzyme-linked immunosorbent assay (ELISA) using a tagged (e.g., biotinylated) corepressor peptide (e.g., BCOR) and a tagged (e.g., FLAG-tagged) BCL6 (e.g., a domain such as the BTB domain thereof) immobilized on a substrate, and the ... protein represented by 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), Compounds of formula (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 a corepressor peptide and BCL6, and the interaction between a corepressor peptide and BCL6 can be measured using an antibody against a BCL6 construct (e.g., an anti-FLAG antibody). See, for example, Kamada, Yusuke, et al., Journal of Medicinal Chemistry 60.10(2017):4358-4368. As yet another example, IC 50 The IC value can be calculated using a fluorescence polarization assay with a fluorescently tagged corepressor peptide (e.g., SMRT), 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) can be used to prevent the interaction between the corepressor peptide and BCL6. See, e.g., WO 2019 / 119144. As another example, a BRET (bioluminescence resonance energy transfer) assay can be used to determine the cellular IC 50A value can be calculated, where a vector encoding BCL6 and a corepressor peptide (e.g., SMRT) complementarily fused to NanoLuc or HaloTag can be inserted into cells. To determine the effect of a compound on inhibiting BCL6-corepressor interaction, cells 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. See, e.g., WO 2018 / 215798 and WO 2019 / 197842. In another example, IC for inhibition of BCL6 repressor function 50 The value 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 are 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), or a pharmaceutically acceptable salt thereof, to determine the effect of the compound on BCL6 repressor function. See, e.g., WO 2019 / 119144; WO 2019 / 119145; WO 2019 / 153080.

[0211] Another exemplary method of assessing 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 a method such as RT-PCR. See, for example, Guo, Weikai, et al., Journal of Medicinal Chemistry 63.2 (2020): 676-695.

[0212] An exemplary assay for determining the 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, is a cell proliferation assay. and / or viability 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. Cell proliferation assays can be performed in a number of formats, including 2D and 3D. Similarly, cell proliferation assays can be performed using any suitable cell line, including, for example, A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2. In some embodiments, a cell line that is BCL6-independent and / or does not have significant expression of BCL6 can be used as a control (e.g., Toledo, H929, MM.1S, or OPM2).As an illustrative example, a 3D cell proliferation assay involves growing cells in a 3D medium, dissolving the cells in a 3D medium containing 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 is contacted with a compound of Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)) or Formula (II) or a pharmaceutically acceptable salt thereof, cell proliferation is measured using an appropriate reagent (e.g., CELLTITERGLO® 3D), and the signal from the experiment is then converted to a signal of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-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, and a signal from a control experiment (e.g., 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).As another illustrative example, a 2D cell proliferation assay involves plating cells on a growth surface, optionally allowing the cells to grow for a period of time, and detecting 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 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 measuring cell proliferation using an appropriate reagent (e.g., CELLTITERGLO®), and then comparing the signal from 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)). a compound of formula (I) (e.g., formula (I-aa) (e.g., formula (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 signal from a control experiment (e.g., a compound of formula (I) (e.g., formula (I-aa) (e.g., formula (I-aa (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). Additional cell viability assays include the MTT assay, 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 known in the art. See, e.g., Example B2.For example, Guo,Weikai,et al.,Journal of Medicinal Chemistry 63.2(2020):676-695;McCoull,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 WO 2018 / 215798; WO 2018 / 215801; WO 2018 / 219281; WO 2019 / 119145; WO 2019 / 153080; and WO 2020 / 104820.

[0213] A cell viability assay 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, on cell death. For example, a BCL6 protein (e.g., A3 / KAW, A4 / FUK, DB, DOHH2, Faraj, HT, Karpas Cells expressing Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)) were cultured in a 500-well platelet-free, 500-well platelet-free, or ... )), 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 then exposed to a detection reagent (e.g., using a CELLTITER-GLO® Cell Viability Assay Kit) to determine cell viability. In some embodiments, the effect on cell viability can be compared to a cell line that is BCL6-independent and / or does not have significant expression of BCL6 and can be used as a control (e.g., Toledo, H929, MM.1S, or OPM2).

[0214] 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, on cell death in combination with an additional therapeutic agent. For example, BCL6 protein (e.g., A3 / KAW, A4 / FUK, DB, DOHH2, Faraj, HT, Karpas Cells expressing a polypeptide of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), or (I-aa-4)), a polypeptide of Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), a polypeptide of Formula (Ia-2), a polypeptide of Formula (Ia-3), or a polypeptide of Formula (Ia-4)), a polypeptide of Formula (Ia-5), a polypeptide of Formula (Ia-6), a polypeptide of Formula (Ia-7), a polypeptide of Formula (Ia-8), a polypeptide of Formula (Ia-9), a polypeptide of Formula (Ia-10), a polypeptide of Formula (Ia-11), a polypeptide of Formula (Ia-12), a polypeptide of Formula (Ia-13), a polypeptide of Formula (Ia-14), a polypeptide of Formula (Ia-15), a polypeptide of Formula (Ia-16), a polypeptide of Formula (Ia-17), a polypeptide of Formula (Ia-18), a polypeptide of Formula (Ia-19), a polypeptide of Formula (Ia-20), a polypeptide of Formula (Ia-21), a polypeptide of Formula (Ia-22), a polypeptide of Formula (Ia-23), a polypeptide of Formula (Ia-24), a polypeptide of Formula (Ia-25), a polypeptide of Formula (Ia-26), a polypeptide of Formula (Ia-27), a polypeptide of Formula (Ia-28), a polypeptide of Formula (Ia-29), a polypeptide of Formula (Ia-29), a polypeptide of Formula (Ia-29), a polypeptide of Formula (Ia-29), a polypeptide of Formula (Ia-21), a polypeptide of Formula (Ia-22), a polypeptide of Formula (Ia-23), a polypeptide of Formula (Ia-24), a polypeptide of Formula (Ia-25), a polypeptide of Formula (Ia-26), a polypeptide of Formula A compound of 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 of the additional therapeutic agents described herein) (e.g., half-log diluted from 316 nM to 1 nM) can be incubated (e.g., for 72 or 120 hours) in a 7x7 dose matrix, followed by exposure to a detection reagent (e.g., using a CELLTITER-GLO® Cell Viability Assay Kit) to determine cell viability. Combination activity can be assessed by a Bliss-independent model: a negative value indicating antagonism, a positive value indicating synergism, and a value of 0 indicating additive activity.The Bliss scores in the dose matrix can be summed to obtain a "Bliss sum" value reflecting 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 an additional therapeutic agent in each cell line. In some embodiments, a cell line that is BCL6-independent and / or does not have significant expression of BCL6 can be used as a control (e.g., Toledo, H929, MM.1S, or OPM2).

[0215] 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 evaluated in an animal model, for example, a cell line-derived (CDX) xenograft model (e.g., DB, DoHH2, OCI-Ly1, OCI-Ly7, RL, Pfe The tumors can be evaluated using established cancer cell lines, such as OCI-Ly1, OCI-Ly7, 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 immunodeficient mice (e.g., athymic nude, outbred homozygous (e.g., Crl:NU(NCr)-Foxn1) nu ) or Fox Chase SCID (CB17 / Icr-Prkdc scid The tumors can be measured weekly and measured when the tumor volume reaches 150-300 mm. 3Once the IL-16 receptor agonist (IL-16) is reached, the mice can be randomized into treatment and control groups. In some embodiments, one or more experimental arms can be added to evaluate pharmacokinetics and / or pharmacodynamics. The 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., via IP or PO administration), and optionally an additional therapy or therapeutic agent (e.g., any of the additional therapies or therapeutic agents described herein). Mice's health, weight, and tumor volume can be recorded weekly throughout the study. Mice are removed at day 28 or when tumors reach 1 cm 3 When t > 10 days, the animals can be sacrificed and tumors can be assessed (e.g., by tumor weight, by tumor volume). At the end of each study, the best response can be calculated for each treatment group. The best response is the Δ volume for t > 10 days. tThe best effect between the control and treatment groups can be compared to determine whether the treatment works better than the control group. In some embodiments, tumor samples can also be taken at the end of each study and relevant proteins (e.g., BCL6) can be measured to determine whether the treatment has a better protein modulation profile compared to the control. In some embodiments, tumor and / or blood samples are taken at the end of each study to measure altered gene expression activity (e.g., altered ARID3A, ARID3B, ATR, B2M, BANK1, BATF, BCL11A, BCL2, BCL2A1, BLIMP1, BM11, CASP8, CCND1, CCND2, CCR6, CCR7, CD38, CD44, CD69, CDKN1A, CDKN1B, CFLAR / FLIP, CHEK1, CXCR4, CXCR5, DR5, EBI2, ETV6, FCMR, FGD4, ID2, IFITM1, IFITM2, IFITM3, IFITM4, IFITM5, IFITM6, IFITM7, IFITM8, IFITM9, IFITM10, IFITM11, IFITM12, IFITM13, IFITM14, IFITM15, IFITM16, IFITM17, IFITM18, IFITM19, IFITM19, IFITM16, IFITM19, IFITM19, IFITM19, IFITM11, IFITM12, IFITM15, IFITM16, IFITM17, IFITM18, IFITM19 ... The tumors may also be analyzed for tumor and / or blood expression levels (e.g., FNAR2, 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 expression levels). For pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples from the mice can be obtained at the same or different time points as efficacy studies. For example, for pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples from mice can be taken at 6, 12, and / or 24 hours post-dose to obtain on days 1, 3, and / or 5, relevant proteins can be measured in the tumor samples, and pharmacokinetic studies can be performed on the blood samples or portions 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 an MLL-Af4, MLL-Af6, MLL-Af9, MLL-ENL, or MLL-PTD fusion), DLBCL, FL, MCL, Burkitt's lymphoma, or peripheral T-cell lymphoma (PTCL) (e.g., PTCL with a follicular helper T 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.

[0216] 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 autoimmune disease. Exemplary assays can be found, for example, in WO 2020 / 014599 and WO 2021 / 074620.

[0217] 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., decrease) IgG antibody production and / or modulate (e.g., decrease) germinal center formation in an animal (e.g., a mouse) following antigenic stimulation 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). After sacrifice, serum samples from the mice can be analyzed for IgG specific to KLH, for example, by ELISA. Similarly, germinal centers can be detected using immunohistochemical staining, for example, using peanut agglutinin (PNA). See, for example, Example 1 of WO 2020 / 014599.

[0218] 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) the number of germinal center B cells in an animal (e.g., a mouse) after immunization with an antigen. For example, an animal (e.g., a mouse) can be immunized with Freund's complete adjuvant (CFA), and after a period of time (e.g., 8 days), the animal can be sacrificed and the spleen can be 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 the lineage markers GL7 and CD95). See, e.g., WO 2021 / 074620.

[0219] 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 ameliorate one or more symptoms, biomarkers, or other indicia of an autoimmune disease in an animal model of the autoimmune disease.

[0220] Experimental autoimmune encephalitis (EAE) can be used as an animal model for inflammatory diseases of the CNS, including multiple sclerosis (MS) and neuromyelitis optica. In some cases, EAE can be induced by, for example, recombinant human myelin oligodendrocyte glycoprotein (MOG) or a fragment thereof (e.g., MOG 1-125 EAE can be induced in animals (e.g., mice) via immunization with EAE, myelin basic protein, and / or proteolipid protein. After induction of EAE, the 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. The animals can be evaluated, for example, 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.

[0221] In some embodiments, the autoimmune disease is antisynthetase syndrome. For example, a model of antisynthetase 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 begin at the time of immunization and continue for a period of time (e.g., short-term (e.g., 10-14 days) or long-term (e.g., 8-16 weeks)), and then the mice can be sacrificed. Mice can be evaluated, for example, 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.

[0222] In some embodiments, the autoimmune disease is arthritis (e.g., rheumatoid arthritis or inflammatory arthritis). For example, collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis, can be induced in susceptible mice (e.g., DBA / 1 or HLA-DR) by immunization with type II collagen (CII). 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 begin at the time of immunization and continue for a period of time (e.g., 6 weeks). Mice can be evaluated, for example, for clinical scores (e.g., inflammation of the arthritic paw, paw thickness, paw volume (e.g., using a plethysmometer), or a combination thereof), production of CII-specific antibodies, B cell depletion, or a combination thereof. See, for example, Example 2 of International Publication No. WO 2020 / 014599; Brand, David D., et al. Nature Protocols 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, e.g., in a manner similar to that of CII-immunized mice, or further evaluated by titration for autoantibodies, such as those against 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.

[0223] 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 an animal (e.g., a mouse) pretreated with high-dose cyclophosphamide and lethal total body irradiation (TBI), optionally rescued with allogeneic splenocytes or bone marrow containing purified T cells. 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, can continue for a period of time. The animals can be evaluated, for example, by pulmonary function tests, by immunohistochemistry to assess the presence of autoantibodies, or by examining sections of the spleen for germinal centers, including, for example, examining for B cell depletion (e.g., germinal center B cell depletion). See, e.g., 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, e.g., Dubovsky, Jason A., et al., The Journal of Clinical Investigation 124.11 (2014): 4867-4876.

[0224] In some embodiments, the autoimmune disease is IgG4-related disease (IgG4-RD). Optionally, an animal model of IgG4-RD can be generated by injecting mice with IgG (e.g., IgG1 and / or IgG4) from a human IgG4-RD patient. 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 evaluated, for example, by measuring pancreatic and / or salivary tissue damage, B cell depletion, or both. See, e.g., Shiokawa, Masahiro, et al. Gut 65.8(2016):1322-1332.

[0225] In some embodiments, the autoimmune disease is lupus (e.g., lupus erythematosus). In some cases, an animal model of lupus is the MRL / lpr mouse, which exhibits high expression of Tfh-associated molecules such as ICOS, PD-1, BCL-6, and IL-21, produces autoantibodies against nuclear components, and can develop 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 evaluated, for example, by measuring B cell depletion (e.g., germinal center B cell depletion), identifying the presence and / or severity of glomerulonephritis, autoantibody titers (e.g., anti-RNA antibody titers, anti-nuclear antibody titers, and / or anti-dsDNA antibody titers), IL-21 expression, and / or the amount of activated CD4+ T cells. See, e.g., Ahuja, Anupama, et al. The Journal of Immunology 179.5(2007):3351-3361; Shen, Chunxiu, et al. Journal of Cellular and Molecular Medicine 25.17(2021):8329-8337; and Marinov, Anthony D., et al. Arthritis & 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 MRL / lpr mice. See, for example, 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.

[0226] In some embodiments, the autoimmune disease is myasthenia gravis (e.g., muscle-specific tyrosine kinase (MuSK)-positive myasthenia gravis). For example, an animal model of myasthenia gravis (e.g., a rat model, a mouse model, or a rabbit model) can be generated by immunizing an animal with an acetylcholine receptor from the electric organ of an electric ray (e.g., Torpedo californica) or an electric eel (e.g., Electrophorus electricus), or a recombinant acetylcholine receptor protein or 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 example, for clinical scores (e.g., tremors, hunched posture, muscle strength, and grasping and / or lifting weights while looking for 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.

[0227] In some embodiments, the autoimmune disease is multiple sclerosis (MS). In some embodiments, the MS is clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), or secondary progressive MS (SPMS). In some embodiments, the animal model of MS is EAE, e.g., relapsing-remitting EAE in SJL / J mice (e.g., proteolipid protein (PLP) expression). 139~151 via immunization with ), chronic EAE in C57BL / 6J mice (e.g., MOG 35-55 via immunization with ), or EAE in transgenic mice (e.g., MOG 35-55 In some embodiments, the animal (e.g., mouse) model is generated via infection with a picornavirus, such as Theiler's murine encephalitis virus. In some embodiments, the animal (e.g., mouse) model is generated by feeding C57BL / 6 mice cuprizone (e.g., 0.2% for 6 weeks). In some embodiments, the animal (e.g., mouse) model is generated by lysolecithin injection (e.g., in SJL / J mice). 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 can be analyzed for, for example, levels of myelin-specific T cells, B cell depletion, reduction in inflammatory lesions, axonal degeneration, protection or reversal of cuprizone- or lysolecithin-induced demyelination, or a combination thereof. See, e.g., Procaccini, Claudio, et al. European Journal of Pharmacology 759(2015):182-191.

[0228] In some embodiments, the autoimmune disease is neuromyelitis optica (NMO). In some cases, animal models of NMO involve administering an antibody against the astrocyte water channel aquaporin-4 (AQP4), referred to as AQP4-IgG or NMO-IgG, to various CNS tissues, such as the brain. In some embodiments, the antibody is administered to an animal with EAE. The AQP4-IgG may be recombinant or derived from a human NMO patient. 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 followed by analysis of sacrificed animals for, for example, delay or reversal of astrocytic demyelination, macrophage counts, activated microglia counts, activated neutrophil counts, 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.

[0229] 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 but Desmoglein 3-expressing recipient mouse to create 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 with an MHC class II null background that expresses the pemphigus-associated HLA-DRB1*0402 allele and produces anti-human DSG3 antibodies after immunization with recombinant human DSG3. 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, can be followed by analysis of the animal's B cell repertoire for, for example, anti-desmoglein B cell clones, B cell depletion, or both. See, e.g., Kasperkiewicz, Michael, et al. Nature Reviews Disease Primers 3.1 (2017): 1-18.

[0230] In some embodiments, the autoimmune disease is Sjogren's syndrome. In some cases, the animal model for Sjogren's syndrome is the NOD mouse, which sometimes has additional genetic manipulations or is bred to reproduce symptoms of the syndrome (e.g., NOD.B10.H2 bor C57BL / 6.NOTDc3.NODc1t. 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 evaluated, for example, for salivary and lacrimal gland secretion flow, 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, including, for example, NFS / sld mice, IQI / Jic mice, Aly / aly mice, and mice immunized with M3R peptides, which can optionally 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.

[0231] 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, for example, a mouse model, a rat model, a dog model, or a non-human primate (e.g., a cynomolgus monkey) model. Pharmacokinetic (PK) studies can be conducted in animal models (e.g., male CD-1 mice) using two exemplary delivery routes: intravenous (IV) injection and oral (PO), e.g., by oral gavage. Animals in the IV group (e.g., n = 3) have free access to food and water, while animals in the PO group are allowed free access to food or are fasted for 6–8 h prior to administration. 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, can be formulated into a solution for IV administration and a solution or suspension for PO administration.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 by intravenous injection (e.g., at 1 mg / kg) for the IV route, or by oral gavage (e.g., 3 to 90 mg / kg, or 3 to 10 mg / kg, e.g., 10 mg / kg) for the PO route. In some cases, the animal can be orally pre-administered with 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 by serial blood sampling (e.g., at eight time points from 0.83 to 24 hours post-dose). At each time point, blood (e.g., approximately 30 μL to approximately 125 μL, or approximately 75 μL to approximately 125 μL) can be collected (e.g., via the saphenous vein) into tubes containing an anticoagulant (e.g., K2EDTA). The blood sample can be placed on wet ice and centrifuged (e.g., at 2000 x g for 4 to 10 minutes) to obtain a plasma sample. The plasma sample can then 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 subjected to LC-MS / MS for sample analysis. Clearance (CL), volume of distribution (V), etc. can be analyzed. d ), maximum plasma concentration (C max ), time to maximum plasma concentration (t max ), half-life (t 1 / 2Pharmacokinetic parameters including the %F, area under the curve (AUC), and oral bioavailability (%F) can be calculated using a non-compartmental model.

[0232] In some embodiments, the %F of 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, is at least 4%. In some embodiments, the %F of 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, is at least 10%. In some embodiments, the %F of 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, is at least 20%. In some embodiments, the %F of 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, is at least 30%.In some embodiments, the %F of 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, is at least 40%. In some embodiments, the %F of 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, is at least 60%. In some embodiments, the %F of 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, is at least 80%.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 a compound of Formula (II) or a pharmaceutically acceptable salt thereof, the %F 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 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 20%. 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 20% to about 40%.In some embodiments, the %F of 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, is about 40% to about 60%. In some embodiments, the %F of 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, is about 50% to about 80%.

[0233] 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 of a human cytochrome P450 enzyme. 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 human cytochrome P450 enzymes for which 25% or more of the clearance is attributable. 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.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, and has an IC of one or more human cytochrome P450 enzymes. 50 and / or EC 50 are concentrations significantly higher than the estimated free fraction 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, at a clinically relevant dose, respectively.

[0234] Exemplary human cytochrome P450 enzymes include those of the CYP1, CYP2, and CYP3 families, such as any of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2J2, CYP2S1, CYP2E1, CYP3A4, and CYP3A5. In some embodiments, no single cytochrome P450 enzyme accounts for 25% or more of the excretion 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. Cytochrome P450 inhibition and / or induction activity can be determined using any suitable assay, such as those described in the guidance document "In Vitro Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions" provided by the U.S. FDA in January 2020. For example, assessment of cytochrome P450 inhibition can be performed in in vitro studies in both a reversible and a time-dependent manner. In vitro inhibition tests can be performed to calculate the ratio of the intrinsic clearance values of the probe substrate to 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, where this ratio is referred to as R1 for reversible inhibition, and R1 = 1 + (I max,u / K i,u) and I max,u is 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; i,u is the unbound inhibition constant determined in vivo. Specifically, for CYP3A, R 1、gut can be calculated, where R 1,gut =1+(I gut +K i,u ) and I gut is the intestinal 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 ratio R2 can be calculated similarly, where R2=(k obs +k deg ) / k deg and kobs is k obs =(k inact *50*I max,u ) / (K I,u +50*I max,u ), where k is the observed (apparent first-order) inactivation rate of the affected cytochrome P450, calculated by deg is the apparent first-order degradation rate constant of the affected cytochrome P450, and K I、uis 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 causes half-maximal inactivation; k inact is the maximum inactivation rate constant. R1 ≥ 1.02, R2 ≥ 1.25, and / or R 1、gutIf ≥ 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 potential drug-drug interactions (DDIs) may be further investigated using mechanistic models and / or by conducting clinical DDI studies using sensitivity index substrates. For example, assessment of cytochrome P450 induction can be performed by the fold change method, measuring the fold change in cytochrome P450 enzyme mRNA levels upon incubation 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, using cutoffs determined from known positive and negative controls to calibrate the system. For 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, is interpreted as an inducer if: (1) it increased mRNA expression of a cytochrome P450 enzyme in a concentration-dependent manner; or (2) the fold change in cytochrome P450 mRNA expression compared to a vehicle control is ≧2-fold at the expected liver concentration of the drug.As another example, assessment of cytochrome P450 induction can be performed by correlation methods, where the correlation method is the relative induction score (RIS) or I relative to a set of known inducers of the same cytochrome P450. max,u / EC 50 The calibration curve is used to predict the magnitude of the clinical induction effect (e.g., the AUC ratio of the indicator substrate in the presence and absence of an 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 exceeds a predetermined cutoff (e.g., AUC ratio ≦0.8), 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, is considered to have in vivo induction ability.

[0235] 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 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, has 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 For 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, has an IC of greater than 500 nM (e.g., 1 μM, 3 μM, 5 μM, 10 μM, 20 μM, or 30 μM). 50In 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, has 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, 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, has an IC of greater than 10 μM (e.g., greater than 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, has an IC of greater than 30 μM. 50 inhibits hERG.

[0236] Heterobifunctional degraders can, in some cases, induce degradation of off-target proteins. In the case of heterobifunctional degraders that utilize CRBN, common off-target proteins that can be degraded include GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α. This degradation is generally attributed to the E3 binding portion of the heterobifunctional degrader, which promotes ternary complex formation between the off-target protein and CRBN. GSPT1 is a translation termination factor, and CK1α is a kinase involved in many important cellular processes, including cell cycle progression and chromosome segregation. Because both are generally essential genes, undesired degradation of either or both can result in nonspecific cytotoxicity. IKZF proteins are zinc finger transcription factors involved in cell fate during hematopoiesis, and degradation of these proteins is associated with hematotoxicity. See, for example, Moreau, Kevin, et al. British Journal of Pharmacology 177.8(2020):1709-1718.

[0237] 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, may exhibit potent and selective 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, is administered to a second protein (e.g., a For example, BCL6 protein can be selectively targeted for degradation by GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP (cathelicidin antimicrobial peptide), CCNA2 (cyclin-A2), FSP1 (ferroptosis inhibitory protein 1, also known as AIFM2), JCHAIN (immunoglobulin J chain), NLRP7 (NACHT, LRR, PYD domain-containing protein 7), PTTG1 (securin), and / or TPX2 (targeting protein for Xklp2). CAMP is an antimicrobial protein that is an integral part of the innate immune system and binds to bacterial lipopolysaccharide. CCNA2 regulates both the G1 / S and G2 / M transitions of the cell cycle. FSP1 is an oxidoreductase that is an inhibitor of ferroptosis. JCHAIN links two monomeric units of either IgM or IgA, and the J chain-linked dimer is the nucleating unit of the IgM pentamer, while the IgA J chain-linked dimer induces dimers or larger polymers. NLRP7 inhibits CASP1 / caspase-1-dependent IL1B secretion.PTTG1 is key to chromosome stability and negatively regulates TP53, while TPX2 is required for normal assembly of the mitotic spindle.

[0238] As used herein, when referring 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 in a proteolysis assay, "selective" or "selectively" refers to at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) superior performance in a proteolysis assay for a particular protein with reference to a comparison protein in the assay.

[0239] In some embodiments, the compounds provided herein can exhibit potency against a BCL6 protein (e.g., nanomolar potency) with minimal activity against a second protein (e.g., single-digit micromolar potency, e.g., potency greater than 1 μM (e.g., greater than 3 μM, 5 μM, 10 μM, 20 μM, or 30 μM)). In some embodiments, the compounds provided herein can exhibit potency against a BCL6 protein (e.g., nanomolar potency) with minimal activity against a second protein (e.g., single-digit micromolar potency, e.g., potency greater than 1 μM (e.g., greater than 3 μM, 5 μM, 10 μM, 20 μM, or 30 μM ... Ib-1) or (Ib-2)), or a compound of formula (II), or a pharmaceutically acceptable salt thereof, exhibits potent degradation of BCL6 protein and inhibits degradation (e.g., Y) of a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1 and / or TPX2).min , D.C. 50 , and / or D max may have minimal efficacy in (as measured by α-values). 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 induce degradation (e.g., Y) of a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2). min , D.C. 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, may exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater induction of degradation of BCL6 protein compared to the induction of degradation of a second 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, may exhibit up to 1000-fold greater induction of degradation of BCL6 protein compared to induction of degradation of a second protein. 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, is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that is capable of binding to a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., Y min , D.C. 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, may exhibit about 10 to about 100-fold greater induction of BCL6 protein degradation compared to the induction of degradation of a second 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, may exhibit about 100 to about 1000 times greater induction of degradation of BCL6 protein compared to induction of degradation of a second 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, may exhibit about 1,000 to about 10,000 times greater induction of degradation of BCL6 protein compared 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.

[0240] In some embodiments, the compounds provided herein may exhibit potency against a BCL6 protein with similar activity against a second protein (i.e., less than 2-fold activity against the BCL6 protein than against the second protein, and no more than 2-fold activity against the second protein than against the BCL6 protein). In some embodiments, the compounds provided herein may be 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 salts selected from the group consisting of GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1 and / or TPX2) induce degradation (e.g., Y) of a second protein (i.e., induce degradation of the BCL6 protein by less than 2-fold more than induce degradation of the second protein, and have no more than 2-fold activity against the second protein than against the BCL6 protein). min , D.C. 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, may exhibit less than a two-fold induction of BCL6 protein degradation compared to the 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.

[0241] In some embodiments, the compounds provided herein may exhibit potency against a BCL6 protein with minimal activity against a second protein (e.g., as measured by a proteomic assay, e.g., less than a 20% decrease in protein abundance as measured in a proteomic assay described herein). In some embodiments, the compounds provided herein are selected from the group consisting 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 resulting salts may exhibit potent degradation of BCL6 protein and have minimal potency 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) (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 (I The compound of formula I) or a pharmaceutically acceptable salt thereof may exhibit greater induction of degradation of BCL6 protein compared 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. Acceptable salts may exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater induction of degradation of BCL6 protein (e.g., as measured by abundance in a proteomic assay, e.g., a proteomic assay as described herein) compared 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 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) The compound, or a pharmaceutically acceptable salt thereof, may exhibit up to 1000-fold greater induction of degradation of BCL6 protein compared 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) The compound, or a pharmaceutically acceptable salt thereof, may exhibit about a 2-fold to about a 10-fold greater induction of degradation of BCL6 protein compared to the 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 a compound of Formula (II) The compound or a pharmaceutically acceptable salt thereof may exhibit about 10-fold to about 100-fold greater induction of degradation of BCL6 protein compared 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) The compound or a pharmaceutically acceptable salt thereof may exhibit about 100-fold to about 1000-fold greater induction of BCL6 protein degradation compared 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.

[0242] In some embodiments, the compounds provided herein may exhibit potency against BCL6 protein with minimal activity against any other detectable protein (e.g., as measured by a proteomic assay, e.g., less than a 20% reduction in protein abundance 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, exhibits potent degradation of BCL6 protein and may have minimal potency in the 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, may exhibit greater induction of BCL6 protein degradation compared to the induction of any other detectable protein degradation (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 a compound of formula (II) or a pharmaceutically acceptable salt thereof may exhibit at least a 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater induction of degradation of BCL6 protein compared to the 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, may exhibit up to a 1000-fold greater induction of degradation of BCL6 protein compared to the 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, may exhibit about a 2-fold to about 10-fold greater induction of degradation of BCL6 protein compared to the 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, may exhibit about a 10-fold to about a 100-fold greater induction of degradation of BCL6 protein compared to the 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).

[0243] 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, may exhibit potent degradation of BCL6 protein and may have minimal efficacy in degrading one or more additional proteins, as measured by abundance in a proteomic assay. An exemplary proteomic experiment is shown below. OCI-Ly1 (DSMZ:ACC722) cells are 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 6 hours. The cells are then washed twice with phosphate-buffered saline and harvested. The cells are lysed to extract total protein, and EASYPEP (商標)Total protein was prepared for mass spectrometry analysis according to the protocol of the MS Sample Prep Kit (Fisher Scientific). Briefly, proteins were reduced with dithiothreitol, alkylated with iodoacetamide, and digested with trypsin and LysC enzyme. The resulting peptides were labeled with TMTPRO™ 18plex reagent (Fisher Scientific) according to the manufacturer's protocol. Equal amounts of labeled peptides from each sample were mixed together, and the peptide mixture was separated by basic reverse-phase chromatography. A total of 85 fractions were combined into 18 pooled fractions. The pooled fractions were dried on a centrifugal pump and resuspended in 5% acetonitrile, 0.1% formic acid for mass spectrometry analysis. Peptide abundance was quantified by tandem mass spectrometry using a Vanquish Neo chromatography system (Fisher Scientific) and an Orbitrap FUSION™ LUMOS™ mass spectrometer (Fisher Scientific). Briefly, 2 micrograms of total peptides are loaded onto a 2-centimeter C8 trap column, followed by a 50-centimeter C18 column. Data-dependent acquisition is performed to obtain peptide sequence and abundance information. Peptide and protein abundances are determined using PROTEOME DISCOVERER™ software and the Homo sapiens proteome database (TaxID 9606), and results are filtered to an FDR of <0.01. The significance threshold is a p-value of <0.001 and an abundance fold change of <50%.

[0244] 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, Provided herein are methods comprising administering to a subject 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 is untreated for cancer. In some embodiments, the subject has received one or more lines of prior treatment for cancer.

[0245] A method of treating cancer in a subject in need thereof, comprising administering, as monotherapy, 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. Also provided herein are methods comprising administering to a subject a salt or 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 is untreated for cancer. In some embodiments, the subject has received one or more lines of prior treatment for cancer.

[0246] Also provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject, as monotherapy, 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. In some embodiments, the subject is treatment-naive for cancer. In some embodiments, the subject has received one or more lines of prior treatment for cancer.

[0247] Provided herein is the use 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 cancer, e.g., any of the cancers provided herein.

[0248] Provided herein is the use 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.

[0249] Provided herein is the use 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 cancer, e.g., any of the cancers provided herein.

[0250] Provided herein is 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 use as a pharmaceutical. Also provided herein is 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 use as a medicament for treating cancer, e.g., any of the cancers provided herein.

[0251] Provided herein is 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 use in treating cancer, e.g., any of the cancers provided herein.

[0252] As used herein, cancer treatment can include treatment of a primary tumor (i.e., a non-metastatic cancer) (e.g., as a first, second, third or subsequent line of treatment, including but not limited to, in the relapsed / refractory setting), treatment of a metastatic (or secondary) tumor, neoadjuvant therapy (e.g., prior to treatment with an additional treatment or therapeutic agent, such as surgery, radiation, chemotherapy, or a course of treatment), adjuvant therapy (e.g., after treatment with an additional treatment or therapeutic agent, such as surgery, radiation, chemotherapy, or a course of treatment), or maintenance therapy (e.g., treatment after response to an additional treatment or therapeutic agent, such as surgery, radiation, chemotherapy, or a course of treatment).

[0253] 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 in the treatment of a primary tumor. In some embodiments, the subject is untreated for cancer. In some embodiments, the subject has received one or more lines of therapy for cancer. In some embodiments, the patient has received chemotherapy, cell 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-arm cell therapy), or both. In some embodiments, the patient has received chemotherapy, cell 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-arm cell therapy), or both. 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 rituximab-containing regimen. In some embodiments, the patient has received an obinutuzumab-containing regimen. In some embodiments, the patient has received a mosunetuzumab-containing regimen. In some embodiments, the patient has received an epcolitamab-containing regimen. 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 systemic therapies 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 systemic therapies for cancer.

[0254] 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 in the treatment of a metastatic tumor. In some embodiments, the subject is treatment-naive for the metastatic tumor. In some embodiments, the subject has received one or more lines of therapy for a secondary tumor. In some embodiments, the patient has received chemotherapy, cell 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-arm cell therapy), or both. In some embodiments, the patient has received chemotherapy, cell 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-arm cell therapy), or both. 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 rituximab-containing regimen. In some embodiments, the patient has received an obinutuzumab-containing regimen. In some embodiments, the patient has received a mosunetuzumab-containing regimen. In some embodiments, the patient has received an epcolitamab-containing regimen. 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 systemic therapies 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 systemic therapies for cancer.

[0255] 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 neoadjuvant therapy. In some embodiments, the neoadjuvant therapy precedes surgery (e.g., surgical resection, such as partial surgical resection or complete, total, or total surgical resection). In some embodiments, the neoadjuvant therapy precedes radiation therapy. In some embodiments, neoadjuvant therapy precedes chemotherapy.

[0256] 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, is adjuvant therapy. In some embodiments, the patient has received chemotherapy, cell 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-arm cell therapy), or both. In some embodiments, patients are treated with 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 rituximab-containing regimen. In some embodiments, the patient has received an obinutuzumab-containing regimen. In some embodiments, the patient has received a mosunetuzumab-containing regimen. In some embodiments, the patient has received an epcolitamab-containing regimen. 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 systemic therapies 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 systemic therapies for cancer. In some embodiments, the adjuvant therapy is administered after surgery (e.g., surgical resection, such as partial surgical resection or complete, total, or total surgical resection). In some embodiments, the adjuvant therapy follows radiation therapy. In some embodiments, the adjuvant therapy follows chemotherapy.

[0257] 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, is maintenance therapy. In some embodiments, the patient has received chemotherapy, cell 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-arm cell therapy), stem cell transplant, or a combination thereof. In some embodiments, patients are treated with 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 rituximab-containing regimen. In some embodiments, the patient has received an obinutuzumab-containing regimen. In some embodiments, the patient has received a mosunetuzumab-containing regimen. In some embodiments, the patient has received an epcolitamab-containing regimen. In some embodiments, the patient has received a stem cell transplant. In some embodiments, the patient has received cell 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 systemic therapies 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 systemic therapies for cancer.

[0258] As used herein, "monotherapy," when referring 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, means a compound of Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I (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, is the only therapeutic substance or therapy (e.g., anti-cancer agent or treatment) administered to the subject during a treatment cycle (e.g., no additional targeted therapeutic, anti-cancer agent, chemotherapeutic agent, or checkpoint inhibitor is administered to the subject during a treatment cycle). As will be understood by one of skill in the art, monotherapy does not preclude the co-administration of a medication for the treatment of cancer- or treatment-related side effects or general symptoms such as pain, rash, edema, photosensitivity, pruritus, skin discoloration, brittle hair, hair loss, brittle, cracked, or discolored nails, swollen cuticles, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms (including nausea, diarrhea, and loss of appetite).

[0259] As used herein, "the subject has previously received one or more therapeutic agents or therapies for cancer" means that the subject has previously been administered one or more therapeutic agents or therapies (e.g., anti-cancer agents or therapies) for cancer other than 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, during a previous treatment cycle. In some embodiments, the subject is unable to tolerate one or more previously administered therapeutic agents or treatments for cancer. In some embodiments, the subject has failed to respond to one or more previously administered therapeutic substances or therapies for the cancer. In some embodiments, the subject has not adequately responded to one or more previously administered therapeutic substances or therapies for the cancer. In some embodiments, the subject has stopped responding to one or more previously administered therapeutic substances or therapies for the cancer. In some embodiments, the lack of response, inadequate response, or aborted response can be determined by objective criteria (e.g., by criteria such as tumor volume or RECIST 1.1). In some embodiments, the lack of response, inadequate response, or aborted response can be determined by the subject's physician.

[0260] As used herein, "a subject is untreated for cancer" means that the subject has not previously been administered or administered one or more therapeutic substances or therapies for cancer.

[0261] 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 began to grow (i.e., where it originated). As used herein, a "metastatic" (or "secondary") tumor is a tumor that has spread from the original tumor site to other parts of the body. In some embodiments, the metastatic or secondary tumor is the same type of cancer as the primary tumor. In some embodiments, the metastatic or secondary tumor is not genetically identical to the primary tumor.

[0262] In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal carcinoma of the breast), cancer of a central or peripheral nervous system tissue (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligoastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal gland cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple neuroendocrine tumors type I and type II, parathyroid cancer, pituitary tumor, thyroid cancer (e.g., papillary thyroid cancer)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma), )), gastrointestinal cancer (e.g., anal cancer, bile duct cancer (e.g., cholangiocarcinoma), colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), 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 pigment epithelial cell carcinoma) cancer), prostate cancer (e.g., prostatic 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., ovarian serous carcinoma, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinoma, endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, endometrial carcinoma of the corpus uteri), 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, Head cancer, oropharyngeal cancer), blood 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 (e.g., Hodgkin's lymphoma (e.g., nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL))), non-Hodgkin's lymphoma (e.g., Burkitt's 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 follicular helper T 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) ), Li-Fraumeni tumor, mesenteric cancer (e.g., omental carcinoma, peritoneal carcinoma), pleural cancer, respiratory cancer (e.g., laryngeal cancer, lung cancer (e.g., lung squamous cell carcinoma, lung 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.

[0263] In some embodiments, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal 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 gland cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), thyroid cancer (e.g., papillary thyroid carcinoma)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., bile duct cancer (e.g., cholangiocarcinoma), 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 (e.g., pancreatic adenocarcinoma), or gastric 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), 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., ovarian serous carcinoma) , ovarian serous cystadenocarcinoma) or uterine cancer (e.g., uterine carcinoma, 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), blood cancer (e.g., leukemia (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) myeloid leukemia (AML), chronic myeloid leukemia (CML)) or lymphoma (e.g., Hodgkin's lymphoma (e.g., nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL)), non-Hodgkin's lymphoma (e.g., Burkitt's 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 follicular helper T 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., lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, non-small cell lung cancer (NSCLC)), sarcoma (e.g., leiomyosarcoma, myxofibrosarcoma), skin cancer (e.g., melanoma), thymic carcinoma (e.g., thymoma), or a combination thereof.

[0264] In some embodiments, the cancer is a hematological 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 a follicular helper T phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (PTCL-NOS)), small lymphocytic lymphoma (SMLL), or PTCL (e.g., PTCL with a follicular helper T phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (PTCL-NOS)). lymphoma (SLL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL)) or leukemia (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)), 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).For example, 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 23.4(2017):885-893;Walker,Sarah R.,et al.,Oncogene 34.9(2015):1073-1082; see WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673.

[0265] In some embodiments, the cancer is non-Hodgkin's lymphoma (e.g., Burkitt's 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 a follicular helper T phenotype (PTPCL-TFH)), or small lymphocytic lymphoma (SLL)). In some embodiments, the non-Hodgkin's lymphoma is a B-cell non-Hodgkin's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is CD20 positive. In some embodiments, the non-Hodgkin's lymphoma is a CD20-positive B-cell non-Hodgkin's lymphoma. In some embodiments, the patient has not been previously treated for the non-Hodgkin's lymphoma. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has been previously treated with rituximab or obinutuzumab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with rituximab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with obinutuzumab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with R-CHOP (RITUXAN® (rituximab), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) or G-CHOP (GAZYVA® (obinutuzumab), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone). Optionally, the patient has been previously treated with etoposide and R-CHOP (referred to as R-EPOCH). In some cases, patients have been previously treated with R-CHOP in combination with lenalidomide, venetoclax, ibrutinib, acalabrutinib, obinutuzumab, polatuzumab, pembrolizumab, durvalumab, or mosunetuzumab.In some embodiments, the patient has been previously treated with cyclophosphamide, vincristine, and prednisone (CVP), with or without rituximab or obinutuzumab. In some embodiments, the patient has received one or more systemic therapies. In some embodiments, the patient has received two or more systemic therapies. In some embodiments, the patient has been previously treated with cell 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-arm 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 or is refractory to a rituximab-containing regimen. In some embodiments, the patient is a patient who has relapsed or is refractory to an obinutuzumab-containing regimen. In some such embodiments, therapeutic efficacy may be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, the cancer is non-Hodgkin's lymphoma, and 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, is administered as monotherapy.

[0266] In some embodiments, the cancer is DLBCL. In some embodiments, the DLBCL is characterized by a BCL2 translocation, a BCL6 translocation, a CD79B mutation (e.g., H225Y, A205D, Y196del, Y196F, Y196D, Y207X, Y196N, A205fs, Y196S, Y196H, A205fs, T206fs, H194_E197delinsQ, E197G, K219T, E192fs, or Y196C), an EZH2 mutation (e.g., a Y646F, Y646N, A682G, or A692V mutation), a MYC translocation, a MYD88 mutation (e.g., a L265P mutation), a NOTCH1 mutation (e.g., a for example, Q2394X, Q2501X, Q2459X, Y2490X, 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, A161T, D148fs, M246I, Y126C, H179R, A159P, C238G, L93fs, Y220C, R283fs, G244D, G245S, E171X, R209X, T155_R156dup, E271K, R306X, G105D, L93fs, G262 V, W53X, G244V, H214Y, R282W, R337C, Q331fs, R273G, R273C, C176Y, S215R , R213Q, I195T, G245R, I232T, R175H, Y126D, R273H, R196X, Y205C, C141Y, C229X, Y126N, P278S, P151S, Y236H, R282G, Y103X, V216M, G244S, G266E, V 173A, V173fs, I254S, T125M, R342X, P152fs, 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, the DLBCL is a DLBCL having a germinal center B cell (GCB) cell of origin. In some embodiments, the DLBCL is a BN2-type DLBCL (e.g., having a BCL6 rearrangement and / or a NOTCH2 mutation). In some embodiments, the DLBCL is an EZB-type DLBCL (e.g., having an EZH2 mutation and / or a BCL2 translocation). In some embodiments, the DLBCL is a C1 gene cluster DLBCL (e.g., having a BCL6 rearrangement and / or a NOTCH2 mutation). For further description of these classifications, see, e.g., 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.

[0267] In some embodiments, the cancer is FL. In some embodiments, the FL has a BCL2 translocation (e.g., a t(14;18) translocation). In some embodiments, the 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 monotherapy.

[0268] In some embodiments, the cancer is B-ALL. In some embodiments, the B-ALL has an MLL rearrangement (e.g., an MLL-Af4 fusion, an MLL-Af6 fusion, an MLL-Af9 fusion, an MLL-ENL fusion, or an 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 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, is administered as 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 in the treatment of patients with B-ALL. In some embodiments, the B-ALL is relapsed or refractory B-ALL after two or more systemic therapies.

[0269] In some embodiments, the patient has been previously treated with another anti-cancer agent, a chemotherapeutic agent, surgery, radiation, a multikinase inhibitor, or a combination thereof.

[0270] In some embodiments, the cancer is DLBCL. In some embodiments, the patient has not been previously treated for DLBCL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has been previously treated with rituximab or obinutuzumab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with rituximab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with obinutuzumab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with lenalidomide in combination with rituximab or obinutuzumab. In some embodiments, the patient has been previously treated with cyclophosphamide, vincristine, and prednisone (CVP), optionally in combination with rituximab or obinutuzumab. In some embodiments, the patient has been previously treated with R-CHOP (RITUXAN® (rituximab), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) or G-CHOP (GAZYVA® (obinutuzumab), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone). Optionally, the patient has been previously treated with etoposide and R-CHOP (referred to as R-EPOCH). Optionally, the patient has been previously treated with R-CHOP in combination with lenalidomide, venetoclax, ibrutinib, acalabrutinib, obinutuzumab, polatuzumab, pembrolizumab, durvalumab, or mosunetuzumab. In some embodiments, the patient has been previously treated with a rituximab-containing regimen. In some embodiments, the patient has been previously treated with an obinutuzumab-containing regimen. In some embodiments, the patient has previously been treated with a mosunetuzumab-containing regimen. In some embodiments, the patient has previously been treated with an epcolitamab-containing regimen. In some embodiments, the patient has received one or more systemic therapies. In some embodiments, the patient has received two or more systemic therapies.In some embodiments, the patient has been previously treated with cell 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-arm cell therapy). In some embodiments, the DLBCL is non-progressing (including stable disease) DLBCL. In some embodiments, the DLBCL is relapsed or refractory DLBCL. In some embodiments, the patient is a patient who has relapsed or is refractory after a rituximab-containing regimen. In some embodiments, the patient is a patient who has relapsed or is refractory after 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, 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 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, is administered as 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 in the treatment of patients with DLBCL. In some embodiments, the DLBCL is relapsed or refractory DLBCL after two or more systemic therapies.

[0271] In some embodiments, the cancer is FL. In some embodiments, the patient has not been previously treated for FL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has been previously treated with rituximab or obinutuzumab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with rituximab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with obinutuzumab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with rituximab or obinutuzumab monotherapy. In some embodiments, the patient has been previously treated with bendamustine in combination with rituximab or obinutuzumab. In some embodiments, the patient has been previously treated with lenalidomide in combination with rituximab or obinutuzumab (the combination with rituximab is 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. 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 systemic therapies. In some embodiments, the patient has received two or more systemic therapies. In some embodiments, the patient has been previously treated with cell 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-arm cell therapy). In some embodiments, the non-Hodgkin's lymphoma is non-progressive (including stable disease) FL. In some embodiments, the FL is relapsed or refractory FL. In some embodiments, the patient is a patient who has relapsed or is refractory to a rituximab-containing regimen. In some embodiments, the patient is a patient who has relapsed or is refractory to an obinutuzumab-containing regimen. In some such embodiments, therapeutic efficacy may be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, the cancer is FL and 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 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 in the treatment of patients with FL. In some embodiments, the FL is relapsed or refractory FL after two or more systemic therapies.

[0272] In some embodiments, the cancer is BL. In some embodiments, the patient has not been previously treated for BL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has been previously treated with rituximab or obinutuzumab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with rituximab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with obinutuzumab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with rituximab or obinutuzumab monotherapy. In some embodiments, the patient has been previously treated with bendamustine in combination with rituximab or obinutuzumab. In some embodiments, the patient has been previously treated with R-CHOP or G-CHOP. In some embodiments, the patient has been previously treated with rituximab, cyclophosphamide, vincristine, doxorubicin, and methotrexate (R-CODOX-M). In some embodiments, the patient has been previously treated with rituximab, ifosfamide, etoposide, and cytarabine (R-IVAC). In some embodiments, the patient has been previously treated with rituximab with dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH-R). In some embodiments, the patient has received one or more systemic therapies. In some embodiments, the patient has received two or more systemic therapies. In some embodiments, the patient has been previously treated with cell 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-arm cell therapy). In some embodiments, the BL is BL that has not progressed (including stable disease). In some embodiments, the BL is relapsed or refractory BL. In some embodiments, the patient is a patient who has relapsed or is refractory to a rituximab-containing regimen.In some embodiments, the patient is a patient who has relapsed after 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, 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 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 in the treatment of patients with BL. In some embodiments, the BL is relapsed or refractory BL after two or more systemic therapies.

[0273] In some embodiments, the cancer is PTCL (e.g., PTCL with a follicular helper T phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified (PTCL-NOS)). In some embodiments, the patient has not been previously treated for PTCL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has been previously treated with rituximab or obinutuzumab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with rituximab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with obinutuzumab, either as monotherapy or in combination with an additional therapy or therapeutic. In some embodiments, the patient has been previously treated with rituximab or obinutuzumab monotherapy. In some embodiments, the patient has been previously treated with bendamustine in combination with rituximab or obinutuzumab. In some embodiments, the patient has been previously treated with lenalidomide in combination with rituximab or obinutuzumab (the combination with rituximab is 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 systemic therapies. In some embodiments, the patient has received two or more systemic therapies. In some embodiments, the patient has been previously treated with cell 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-arm cell therapy). In some embodiments, the PTCL is a PTCL that has not progressed (including stable disease). In some embodiments, the PTCL is a relapsed or refractory PTCL. In some embodiments, the patient is a patient that has relapsed or is refractory to a rituximab-containing regimen. In some embodiments, the patient is a patient that has relapsed or is refractory to an obinutuzumab-containing regimen. In some such embodiments, therapeutic efficacy may be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, the cancer is PTCL and 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, is administered as 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 in the treatment of patients with PTCL. In some embodiments, the PTCL is relapsed or refractory PTCL after two or more systemic therapies.

[0274] In some embodiments, the cancer is B-ALL. In some embodiments, the B-ALL is Philadelphia chromosome-positive B-ALL. In some embodiments, the B-ALL is Philadelphia chromosome-negative B-ALL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously been treated with at least one cycle of induction, intensification, boost, and optional maintenance. In some cases, the induction therapy may include an anthracycline, vincristine, a corticosteroid, and cyclophosphamide. In some embodiments, the anthracycline is doxorubicin. In some embodiments, the corticosteroid is dexamethasone. In some cases, the combination of doxorubicin, vincristine, dexamethasone, and cyclophosphamide is known as CVAD. In some embodiments, the induction therapy may further include a tyrosine kinase inhibitor (e.g., a BCR-ABL inhibitor for patients with this fusion). In some embodiments, the induction therapy may further include asparaginase (e.g., for pediatric patients). In some embodiments, consolidation therapy may 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., a BCR-ABL inhibitor for patients with this fusion). In some embodiments, consolidation therapy may further include asparaginase (e.g., for pediatric patients). In some embodiments, augmentation therapy may include an anthracycline, vincristine, a corticosteroid, and cyclophosphamide. In some embodiments, augmentation therapy may further include a tyrosine kinase inhibitor (e.g., a BCR-ABL inhibitor for patients with this fusion). In some embodiments, augmentation therapy may further include asparaginase (e.g., for pediatric patients). Typically, pediatric and young adult regimens contain higher cumulative doses of asparaginase and vincristine, but may have lower cumulative doses of anthracycline and cyclophosphamide compared to adult regimens.At any of these cycle stages, anti-CD20 immunotherapy (e.g., rituximab) can be added for patients who express CD20 protein on their 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 systemic therapies. In some embodiments, the patient has received two or more systemic therapies. 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 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, is administered as 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 in the treatment of patients with B-ALL. In some embodiments, the B-ALL is relapsed or refractory B-ALL after two or more systemic therapies.

[0275] Also provided herein are methods of treating a subject having cancer, the methods 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, as monotherapy or in combination with a first anti-cancer agent, to a subject who has been administered one or more doses of the first anti-cancer agent to the subject for a period of time.

[0276] Also provided herein are methods of treating a subject having cancer, the methods comprising: (a) administering to the subject one or more doses of a first anticancer agent for a period of time; (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 monotherapy or in combination with a first anticancer agent; Includes.

[0277] Also provided herein are methods of treating a subject having cancer, the methods comprising: (a) administering to the subject one or more doses of a first anticancer agent for a period of time; (b) after (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 monotherapy or in combination with a second anticancer agent; Includes.

[0278] 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 qd (once daily) to the 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 bid (twice daily) to the 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 tid (three times daily) to the 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 qid (four times a day) to the 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 qod (every other day) to the 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 the subject once a 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 weekly) to the 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 tiw (three times a week) to the subject.

[0279] BCL6 activity has also been implicated in 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. Accordingly, there is provided a method of treating an autoimmune condition 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. Also provided herein are methods, the methods comprising administering to a subject 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.

[0280] Provided herein is the use 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 the treatment of an autoimmune condition, e.g., any of the autoimmune conditions provided herein.

[0281] Provided herein is the use 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 the treatment of an autoimmune condition, such as any of the autoimmune conditions provided herein.

[0282] Provided herein is the use 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 condition, such as any of the autoimmune conditions provided herein.

[0283] Provided herein is 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 use as a medicament for the treatment of an autoimmune condition, e.g., any of the autoimmune conditions provided herein.

[0284] Provided herein is 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 use in treating an autoimmune condition, such as any of the autoimmune conditions provided herein.

[0285] In some embodiments, the autoimmune condition 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, Hashimoto's thyroiditis, or the like. In some embodiments, the autoimmune condition is rheumatoid arthritis, Hughes' syndrome, IgG4-related disease, immune thrombocytopenic purpura (ITP), inflammatory bowel disease, localized scleroderma, multiple sclerosis, myasthenia gravis (MG), neuromyelitis optica spectrum disorder (NMOSD) (e.g., neuromyelitis optica (NMO)), pemphigus, pemphigus folliculorum, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, seronegative spondyloarthropathy, Sjogren's syndrome, systemic lupus erythematosus, thrombocytopenic purpura, type 1 diabetes, ulcerative colitis, vitiligo, or a combination thereof. In some embodiments, the autoimmune condition is rheumatoid arthritis, systemic lupus erythematosus, or a combination thereof. In some embodiments, the autoimmune condition is ANCA vasculitis, GVHD (e.g., cGVHD), myasthenia gravis, NMO, or a combination thereof. In some embodiments, the autoimmune condition is ANCA vasculitis, antisynthetase 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), Sjogren's syndrome, or a combination thereof. In some embodiments, the autoimmune condition is ANCA vasculitis, antisynthetase 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 condition 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), Sjogren'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 WO 2020 / 014599; WO 2021 / 074620.

[0286] In some embodiments of any of the methods of treating an autoimmune condition 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). In some embodiments of any of the methods of treating an autoimmune condition 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 bid (twice daily). In some embodiments of any of the methods of treating an autoimmune condition 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 tid (three times a day).In some embodiments of any of the methods of treating an autoimmune condition 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 qid (four times a day). In some embodiments of any of the methods of treating an autoimmune condition 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). In some embodiments of any of the methods of treating an autoimmune condition 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 once a week (once a week).In some embodiments of any of the methods of treating an autoimmune condition 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 the subject. In some embodiments of any of the methods of treating an autoimmune condition 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 the subject.

[0287] A method of treating a lymphoproliferative disorder 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 Formula (II), 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.

[0288] Provided herein is the use 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.

[0289] Provided herein is the use 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.

[0290] Provided herein is the use 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 a lymphoproliferative disorder, such as any of the lymphoproliferative disorders provided herein.

[0291] Provided herein is 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 use as a medicament for treating a lymphoproliferative disorder, e.g., any of the lymphoproliferative disorders provided herein.

[0292] Provided herein is 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 use in treating a lymphoproliferative disorder, e.g., any of the lymphoproliferative disorders provided herein.

[0293] In some embodiments, the lymphoproliferative disorder is Epstein-Barr virus-associated lymphoproliferative disorder.

[0294] Also provided are methods of modulating (e.g., decreasing) BCL6 protein activity in a cell, 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 in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo and the method comprises administering to the subject 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), 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 described herein. As used herein, the term " contact " refers to bringing together the indicated parts in vitro or in vivo.For example, " contact " cell with provided herein compound comprises the in vitro or in vivo administration of provided herein compound to cell, for example, comprises introducing provided herein compound into the sample comprising cell (for example, grown in culture or derived from patient), organoid, or organism (for example, animal (for example, tumor-bearing animal) or human).

[0295] Also provided is a method for modulating (e.g., decreasing) the level of BCL6 protein in a cell, 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 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 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), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo and the method comprises administering 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), or a pharmaceutically acceptable salt thereof, to a subject having cells having a BCL6 protein. In some embodiments, the cells are cancer cells.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 described herein.

[0296] Also provided are methods of inducing ubiquitination of BCL6 protein in a cell, 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 in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo and the method comprises administering 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), or a pharmaceutically acceptable salt thereof, to a subject having cells having a BCL6 protein. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer described herein.

[0297] a ternary complex comprising a BCL6 protein, 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)), a compound of Formula (Ia) (e.g., Formula (Ia-1), (Ia-2), (Ia-3), or (Ia-4)), a compound of Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2)), or a compound of Formula (Ib) (e.g., Formula (Ib-1) or (Ib-2)), or a compound of Formula (II) or a pharmaceutically acceptable salt thereof, and a CRBN protein or a fragment thereof, in a cell; Also provided are methods of forming a coalescence, the methods comprising contacting a 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 in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo and the method comprises administering 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), or a pharmaceutically acceptable salt thereof, to a subject having cells having a BCL6 protein. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer described herein.

[0298] Also provided herein is a method for inducing degradation of BCL6 protein in a mammalian cell, comprising contacting the mammalian 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), or a pharmaceutically acceptable salt thereof.

[0299] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a 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.

[0300] Further provided herein is a method of increasing cell death in vitro or in vivo, comprising contacting a 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 includes administering to the subject 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 an amount effective to increase tumor cell death.

[0301] When used as a pharmaceutical, 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 in the form of a pharmaceutical composition as described herein.

[0302] combination 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, may be used as 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 the administration or administration of an additional therapeutic substance or treatment. For example, a subject in need thereof can be administered 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, 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.

[0303] In some embodiments, a subject in need thereof may be administered 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, over a period of time, and may be subjected to one or more radiation therapies. 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 radiation therapy treatments.

[0304] In some embodiments of any of the methods 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, is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent (e.g., a chemotherapeutic agent).

[0305] Non-limiting examples of additional therapeutic agents include RAS pathway-targeted therapeutic agents (e.g., Ras / RAF / MEK / PI3K pathway inhibitors (e.g., Ras inhibitors, KRas-targeted therapeutic agents, SOS1 inhibitors, SOS1 / Ras protein-protein interaction inhibitors, SHP2 inhibitors, PI3K-AKT-mTOR pathway inhibitors)), kinase-targeted therapeutic agents (e.g., MEK inhibitors, ERK inhibitors, Raf inhibitors (e.g., BRaf inhibitors), PI3K inhibitors, AKT inhibitors, BTK inhibitors, mTOR inhibitors, CDK4 / 5 inhibitors, CDK4 / 6 inhibitors, MET inhibitors, JAK inhibitors, and the like). inhibitors (e.g., JAK2 inhibitors), FAK inhibitors, ErbB family inhibitors (e.g., EGFR inhibitors, Her2 inhibitors), Src inhibitors), menin inhibitors, mTORC1 inhibitors, YAP inhibitors, proteasome inhibitors, farnesyltransferase inhibitors, HSP90 inhibitors, PTEN inhibitors, inhibitors of polycomb repressive complex 2 (PRC2) (e.g., EZH1 / 2 or EZH2 inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, regulators of apoptosis pathways (e.g., BCL-2 inhibitors, BCL-X inhibitors), Linhibitors), 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 antibodies (e.g., single-targeted antibodies targeting one or more of PD1, PD-L1, CD19, CD20, CD22, CD3, CD30, CD79B, or CD47, or antibodies targeting one or more of PD1, PD-L1, CD19, CD47, or CD47); bispecific antibodies targeting one or more of CD20, CD22, CD3, CD30, CD79B, or CD47 (including bispecific T-cell engagers (BiTEs)), and antibody-drug conjugates (ADCs) incorporating one or more of PD1, PD-L1, CD19, CD20, CD22, CD3, CD30, CD79B, or CD47 antibodies or antigen-binding fragments thereof, anti-CD47 therapies including PD-1 inhibitors, or PD-L1 inhibitors), cell-based therapies (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-arm cell therapy), and radiation therapy.

[0306] 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 may optionally have detectable differences in post-translational modifications (e.g., glycosylation and / or phosphorylation) as compared to the reference antibody (e.g., different glycoforms).

[0307] 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 PI3K inhibitor. L inhibitors, MCL-1 inhibitors, XPO1 inhibitors, inhibitors of polycomb repressive 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.

[0308] Without being bound to any particular theory, it is believed that targeting BCL6 can induce genes that BCL6 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).

[0309] In some embodiments, the PI3K inhibitor is alpelisib (BYL719), amdizalisib, apitolisib (GDC-0980), bimiralisib, buparlisib (BKM120), copanlisib (ALIQOPA™, BAY80-6946) (e.g., copanlisib dihydrochloride or copanlisib dihydrochloride hydrate), dactolisib (NVP-BEZ235, BEZ-235), dezapelisib, daldabiprone, duvelisib (e.g., duvelisib hydrate), egafenib, galf ... Nelisib, fimepinostat, gedatolisib (PF-05212384, PKI-587), idelalisib, inavolisib, leniolisib (e.g., leniolisib phosphate), linpelisib, omipalisib (GSK2126458, GSK458), palsalisib, pitilisib (GDC-0941), pilalisib (XL147, SAR245408), paxalisib, ridizertib, rizovalisib, seravelisib, seretalisib, selavelisib (TAK-117, MLN1117, INK 1117), sonolisib (PX-866), taselisib (GDC-0032, RG7604), ambralisib (ambralisib tosylate), voxalisib (XL756, SAR245409), wortmannin, zandelisib, AMG511, AMG319, ASN003, AZD8835, BGT-226 (NVP-BGT226), CH5132799, CUDC-907, GDC-0077, GDC-0084 (RG76 66), 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 alpelisib, amzizalisib, apitolisib, bimiralisib, buparlisib, copanlisib (e.g., copanlisib dihydrochloride or copanlisib dihydrochloride hydrate), dactolisib, dezapelisib, daldabiprone, duvelisib (e.g., duvelisib hydrate), eganelisib, fimepinostat, gedatrisib, idela lisib, inavolisib, leniolisib (e.g., leniolisib phosphate), linpelisib, parsalisib, paxalisib, rizovalisib, seravalisib, seretalisib, selavelisib, sonolisib, tenalisib, umbralisib (e.g., umbralisib tosylate), zandelisib, PF-04691502, SHC-014748-M, TQ-B-3525, or a combination thereof.

[0310] In some embodiments, the Abl inhibitor (e.g., a BCR-Abl inhibitor) is selected from the group consisting of asintinib (e.g., asintinib hydrochloride), bafetinib, bosutinib (e.g., bosutinib monohydrate), dansertib, dasatinib (e.g., dasatinib monohydrate), flumatinib (e.g., flumatinib mesylate), imatinib (e.g., imatinib mesylate), nilotinib (e.g., nilotinib), nivolumab (e.g., nivolumab ... tinib (e.g., nilotinib monochloride monohydrate), orveremvatinib (e.g., orveremvatinium mesylate), ponatinib (e.g., ponatinib hydrochloride), radotinib (e.g., radotinib dihydrochloride), luselontinib, vandetanib, AN-019, AT-9283, IkT-148009, NPB-001-056, or a combination thereof.

[0311] In some embodiments, the cancer is B-ALL and the additional therapy or therapeutic is an Abl inhibitor. In some embodiments, the cancer is Philadelphia chromosome-positive B-ALL and the additional therapy or therapeutic is an Abl inhibitor. In some embodiments, the cancer is Philadelphia chromosome-like B-ALL and the additional therapy or therapeutic is an Abl inhibitor. In some embodiments, the Abl inhibitor is selected from the group consisting of imatinib, dasatinib, ponatinib, or a combination thereof.

[0312] In some embodiments, the BTK inhibitor is selected from the group consisting of abivertinib, acalabrutinib, atasavrutinib, brambrutinib, dasatinib (e.g., dasatinib monohydrate), edralbrutinib (SHR-1459), ersbrutinib, evobrutinib, fenebrutinib, ibrutinib, luxeptinib, nemtabrutinib, orafeltinib, nemtabrutinib, orelabrutinib, and pirtobrutinib. , repbrutinib, rilzabrutinib, spebrutinib, sambocertinib, tirabrutinib (e.g., tirabrutinib hydrochloride), trebrutinib, becabrutinib, 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 abivertinib, acalabrutinib, atusabrutinib, brambrutinib, dasatinib (e.g., dasatinib monohydrate), edralbrutinib, ersbrutinib, evobrutinib, fenebrutinib, ibrutinib, nemtabrutinib, orelbrutinib, pirtobrutinib, remibrutinib, rilzabrutinib, sambocertinib, tirabrutinib (e.g., tirabrutinib hydrochloride), trebrutinib, zanubrutinib, AC-0058, BMS-986142, DTRMWXHS-12, LY-3337641, TAS-5315, or a combination thereof.

[0313] In some embodiments, the cancer is B-ALL and the additional therapy or therapeutic is a BTK inhibitor. In some embodiments, the cancer is pre-BCR+ B-ALL and the additional therapy or therapeutic is a BTK inhibitor. In some embodiments, the cancer is Ras signaling dependent B-ALL and the additional therapy or therapeutic is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or acalabrutinib.

[0314] In some embodiments, the JAK inhibitor is selected from the group consisting of abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, deurxolitinib, ersbrutinib, fedratinib (e.g., fedratinib dihydrochloride monohydrate), filgotinib (e.g., filgotinib maleate), gandotinib, gusatinib, irginatinib, itacitinib, ivarmacitinib, isencitinib, jactinib, momelotinib, nedulcitinib, pacritinib (e.g., pacritinib citrate), peficitinib (e.g., peficitinib hydrobromide), and the like. ), povolicitinib (INCB-54707), lopsatinib, ruxolitinib (e.g., ruxolitinib phosphate), solcitinib, tasocitinib (e.g., tofacitinib citrate), tingotinib, upadacitinib (e.g., upadatinib hydrate), zasocitinib, AGA-201, ATI-1777, ATI-501, ESK-001, GLPG-3667, INCB-52793, LNK-01001, LNK-01003, R-348, TD-8236, TLL-018, TQ-05105, VTX-958, or a combination thereof. In some embodiments, the JAK inhibitor is abrocitinib, baricitinib, brepositinib, decernotinib, delgocitinib, deurxolitinib, fedratinib (e.g., fedratinib dihydrochloride monohydrate), filgotinib (e.g., filgotinib maleate), gandotinib, gusatinib, irginatinib, itacitinib, ivarmacitinib, isencitinib, jactinib, momelotinib, nedulcitinib, pacritinib (e.g., pacritinib citrate), peficitinib (e.g., peficitinib hydrobromide), or rivaroxaban (e.g., rivaroxaban). salt), povolicitinib (INCB-54707), lopsatinib, ruxolitinib (e.g., ruxolitinib phosphate), solcitinib, tasocitinib (e.g., tofacitinib citrate), tingotinib, upadacitinib (e.g., upadatinib hydrate), zasocitinib, AGA-201, ATI-1777, ATI-501, ESK-001, GLPG-3667, LNK-01001, LNK-01003, R-348, TD-8236, TLL-018, TQ-05105, VTX-958, or a combination thereof.

[0315] In some embodiments, the cancer is B-ALL and the additional therapy or therapeutic agent is a JAK inhibitor. In some embodiments, the cancer is a JAK2 (e.g., JAK2 R683G or JAK2 I682F ) mutant B-ALL, and the addit...

Claims

1. Formula (I): or a pharmaceutically acceptable salt thereof, During the ceremony, R １ is H, halo, cyano and R ｂ１ is selected from the group consisting of m3 is 0, 1, 2, or 3; Each X ３ is -O-, -NR ｆ -, -C(=O)-, and 1 to 3 R ｃ C optionally substituted with １～３ alkylene; However, N-(X ３ ) ｍ３ -R １ the moiety does not contain O—O, N—O, N—N, O-halo or N-halo bonds; Each R ２ is 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 are independently selected from the group consisting of R ３ Is, -A １ -C(R ４ R ４ )-A ２ and -CH=CH-A ２ wherein A is selected from the group consisting of １ is —O— or —S—, Each R ４ is H, C １～６ Alkyl, and C １～６ haloalkyl; R ４ The pair of carbon atoms, together with the carbon atoms to which they are attached, form C ３～６ Forms a cycloalkyl ring or a 4- to 8-membered heterocyclyl ring, wherein said C ３～６ The cycloalkyl ring or the 4- to 8-membered heterocyclyl ring may be one to three R ｇ may be substituted with A ２ is -C(O)OH, -C(O)NH ２ , -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 alkyl) ２ , and -C(=NH)NH ２ is selected from the group consisting of R ３Ａ is R ａ and -(C ０～３ alkylene)-R ｂ１ C, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of １～６ Alkyl, C ３～６ Alkenyl, C ３～６ Alkynyl, C ３～６ selected from the group consisting of cycloalkyl, and 3- to 8-membered heterocyclyl; X ａ and X ｃ are independently selected from the group consisting of N, CH, and CF, with the proviso that X ａ and X ｃ one or both of are N; X ｂ is N and CR ｘ１ is selected from the group consisting of R ６ and R ｘ１ is H, halo, C １～２ Alkyl, C １～２ Haloalkyl, C １～２ are each independently selected from the group consisting of alkoxy, CN, and —C≡CH; L is - (L Ａ ) ｎ１ - and L Ａ and n1 is defined according to (AA) or (BB): (AA) n1 is an integer from 1 to 15, Each L Ａ Is, L Ａ１ , L Ａ３ , and L Ａ４ and independently selected from the group consisting of: Ａ 1 to 3 occurrences of L Ａ４ and (BB) n1 is an integer from 0 to 20, Each L Ａ Is, L Ａ１ and L Ａ３ are independently selected from the group consisting of Each L Ａ１ is -CH ２ --, --CHR Ｌ - and -C(R Ｌ ) ２ - independently selected from the group consisting of Each L Ａ３ is -N(R ｄ ) -, -N(R ｂ )-, -O-, -S(O) ０～２ -, and C(=O); Each L Ａ４ teeth, (a) R ａ and R ｂ C, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of ３～１５ cycloalkylene or 3- to 15-membered heterocyclylene, and (b) R ａ and R ｂ C, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of ６～１５ Arylene or 5- to 15-membered heteroarylene are independently selected from the group consisting of However, L is not an N-O bond, an O-O bond, an N-N bond, or an N-S(O) ０ The bond is also O-S(O) ０～２ Does not include bonds, Each R Ｌ is 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 1 to 6 R ｃ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Ring C is is selected from the group consisting of c1 is 0, 1, 2, or 3; Each R Ｙ is R ａ and R ｂ are independently selected from the group consisting of R ａＮ is H or 1 to 3 R ｃ C optionally substituted with １～６ is alkyl, Y １ and Y ２ are independently Ns, CH or CR Ｙ and yy represents the point of attachment to L; X is CH, C or N; is a single or double bond, L Ｃ is a bond, -CH ２ --, --CHR ａ -, -C(R ａ ) ２ -, -C(=O)-, -N(R ｄ )- and O, provided that when X is N, L Ｃ is other than O, Further, provided that ring C is connected to -L via the ring nitrogen Ｃ When bonded to -, X is CH, and L Ｃ is a bond, Each R ａ teeth, (a) halo; (b) cyano; (c) —OH; (d) oxo; (e) 1 to 6 R ｃ C optionally substituted with １～６ Alkoxy; (f)-NR ｄ R ｅ ; (g) 1 to 6 R ｃ C(═O)C optionally substituted with 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) 1 to 6 R ｃ each of which may be substituted with １～６ Alkyl, C ２－６ Alkenyl or C ２－６ Alkynyl are independently selected from the group consisting of Each R ｂ Is -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ are independently selected from the group consisting of each b is independently 1, 2, or 3; Each -L ｂ is -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O) and C １～３ alkylene; Each R ｂ１ is 1 to 3 R ｇ each of which may be substituted with ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ independently selected from the group consisting of aryl, and 5- to 10-membered heteroaryl; Each R ｃ is 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 are independently selected from the group consisting of Each R ｄ and R ｅ is 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 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｆ is H and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｇ is R ｈ , oxo, C １～３ Alkyl and C １～３ haloalkyl; Each R ｈ is halo, cyano, -OH, -(C ０～３ alkylene)-C １～６ Alkoxy, -(C ０～３ alkylene)-C １～６ Haloalkoxy, -(C ０～３ (alkylene)-NH ２ , -(C ０～３ alkylene)-N(H)(C １～３ alkyl) and -(C ０～３ alkylene)-N(C １～３ alkyl) ２ are independently selected from the group consisting of However, when X is N, ring C is That is, A compound of the formula (I) or a pharmaceutically acceptable salt thereof.

2. R ３ Ga-A １ -C(R ４ R ４ )-A ２ 2. The compound of claim 1, wherein:

3. A １ The compound according to claim 1 or 2, wherein is —O—.

4. Each R ４ The compound of any one of claims 1 to 3, wherein is H.

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

6. R ３Ａ But 1 to 6 R ｃ C optionally substituted with １～３ The compound of claim 5, wherein the compound is alkyl.

7. A ２ is -C(O)NH ２ , —C(O)NHMe, or —C(O)NMe ２ The compound according to any one of claims 1 to 5,

8. R ３ but, 2. The compound of claim 1, wherein:

9. X ａ is N and X ｃ is N and X ｂ is CR ｘ１ (e.g., CH), or X ａ is CH and X ｃ is N and X ｂ is CR ｘ１ (e.g., CH), The compound according to any one of claims 1 to 8.

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

11. Each R ２ The compound of any one of claims 1 to 10, wherein is H.

12. m3 is 0, or m3 is 1, and X ３ is C １～３ is alkylene, The compound according to any one of claims 1 to 11.

13. R １ The compound of any one of claims 1 to 12, wherein is H.

14. m3 is 1, and X ３ is methylene, ethylene or isopropylene, and R １ The compound of any one of claims 1 to 11, wherein is H.

15. R ３ But, -A １ -C(R ４ R ４ )-A ２ where A １ is O, and each R ４ is H and A ２ is -C(O)NH ２ or -C(O)NR ３Ａ R ｆ where R ３Ａ But 1 to 6 R ｃ C optionally substituted with １～３ is alkyl, Each R ２ is H, X ａ is N or CH; X ｃ is N, X ｂ is CH, R ６ is —F or —Cl; The compound of claim 1.

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

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

18. A ２ The compound of any one of claims 15 to 17, wherein is C(O)NHMe.

19. Ring C is or Ring C or Ring C is That is, A compound according to any one of claims 1 to 18.

20. c1 is 0, or c1 is 1, and R Ｙ is halo (e.g., —F); A compound according to any one of claims 1 to 19.

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

22. R ａＮ is C １～３ 22. The compound of any one of claims 1 to 21, which is alkyl (e.g. methyl).

23. L Ｃ The compound of any one of claims 1 to 22, wherein is a bond.

24. The aforementioned The part is, or The aforementioned The part is, selected from the group consisting of A compound according to any one of claims 1 to 18.

25. The aforementioned The part is, and where: m3 is 1, X ３ is C １～３ is alkylene, R １ is H, X ａ is CH or N, X ｃ is N, R ６ is —F or —Cl, and The aforementioned The part is, selected from the group consisting of The compound of claim 1.

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

27. X ａ is CH, or X ａ is N, 27. A compound according to claim 25 or 26.

28. L is - (L Ａ ) ｎ１ - and L Ａ and n1 is defined according to (AA).

29. n1 is an integer from 1 to 5, or n1 is an integer of 2 to 4 (e.g., 2 or 3); A compound according to any one of claims 1 to 28.

30. L, -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 is selected from the group consisting of bb represents the attachment point to ring C; 30. The compound according to any one of claims 1 to 29.

31. Each L Ａ４ are independently 1 to 6 R ａ C, each of which may be substituted with ３～１０ cycloalkylene or 4- to 12-membered heterocyclylene; Each L Ａ４ are independently 1 to 3 R ａ or a 4-12 (e.g., 4-10) membered nitrogen-containing heterocyclylene optionally substituted with Each L Ａ４ are independently 1 to 3 R ａ or a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by One L Ａ４ But 1 to 3 R ａ and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by Ａ４ is 1 to 3 R ａ or a bicyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with One L Ａ４ But 1 to 3 R ａ and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by Ａ４ is 1 to 3 R ａ or a bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with One L Ａ４ But 1 to 3 R ａ and the other L is a monocyclic 4- to 6-membered nitrogen-containing heterocyclylene optionally substituted by Ａ４ But 1 to 3 R ａ a bicyclic bridged 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with 31. The compound of claim 30.

32. Each L Ａ４ 32. The compound of claim 31, wherein R<1> contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms.

33. L Ａ４ Each R on ａ But -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ 33. The compound of claim 31 or 32, independently selected from the group consisting of alkyl.

34. L is -L Ａ４ -L Ａ１ -L Ａ４ - ｂｂ The compound according to any one of claims 30 to 33, wherein

35. L Ａ１ Ga-CH ２ -, -CHMe- or -CMe ２ The compound of claim 34, wherein

36. L is -L Ａ４ -L Ａ３ -L Ａ４ - ｂｂ The compound according to any one of claims 30 to 33, wherein

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

38. L is -L Ａ４ -L Ａ１ -L Ａ４ -L Ａ３ - ｂｂ and L Ａ３ The compound of any one of claims 30 to 33, wherein is C(=O).

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

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

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

42. L Ａ４ But 1 to 6 R ａ or a 4- to 12-membered heterocyclylene optionally substituted by L Ａ４ But 1 to 3 R ａ or a 4- to 12- (e.g., 6- to 10-) membered nitrogen-containing heterocyclylene optionally substituted with L Ａ４ But 1 to 3 R ａ or a bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with L Ａ４ contains 1 to 2 ring nitrogen atoms and no further ring heteroatoms; The compound according to any one of claims 39 to 41.

43. L Ａ４ Each R on ａ But -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ 43. The compound of claim 42, wherein each of the groups is independently selected from the group consisting of alkyl.

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

45. Formula (I-aa): or a pharmaceutically acceptable salt thereof, During the ceremony, X ａ is N or CH, R ６ is —F or —Cl, m3 is 1, and X ３ is C １～３ alkylene, and R １ is H, Ring C is wherein c1 is 0 or 1; and R Ｙ is halo (e.g., —F), and C optionally substituted with 1 to 3 F. １～３ alkyl; R ａＮ is C １～３ is alkyl, L is, -L Ａ４ -L Ａ１ -L Ａ４ - ｂｂ ; -L Ａ４ -O-L Ａ４ - ｂｂ ; -L Ａ４ -C(=O)-L Ａ４ - ｂｂ and -L Ａ４ -L Ａ１ -L Ａ４ -C(=O)- ｂｂ is selected from the group consisting of bb represents the point of attachment to ring C; L Ａ１ is CH ２ , CHMe, or CMe ２ and Each L Ａ４ are independently 1 to 3 R ａ a 4- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L Ａ４ Each R on ａ is -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ independently selected from the group consisting of alkyl, The compound of the formula (I-aa) or a pharmaceutically acceptable salt thereof or Formula (I-a): or a pharmaceutically acceptable salt thereof, During the ceremony, X ａ is N or CH, R ６ is —F or —Cl, m3 is 1, and X ３ is C １～３ alkylene, and R １ is H, Ring C is is selected from the group consisting of L is, -L Ａ４ -L Ａ１ -L Ａ４ - ｂｂ ; -L Ａ４ -O-L Ａ４ - ｂｂ ; -L Ａ４ -C(=O)-L Ａ４ - ｂｂ and -L Ａ４ -L Ａ１ -L Ａ４ -C(=O)- ｂｂ is selected from the group consisting of bb represents the point of attachment to ring C; L Ａ１ is CH ２ , CHMe, or CMe ２ and Each L Ａ４ are independently 1 to 3 R ａ a 4- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L Ａ４ Each R on ａ is -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ independently selected from the group consisting of alkyl, The compound of the formula (Ia) or a pharmaceutically acceptable salt thereof or Formula (I-aa-1): or a pharmaceutically acceptable salt thereof, During the ceremony, X ａ is N or CH, R ６ is —F or —Cl, m3 is 1, and X ３ is C １～３ alkylene, and R １ is H, Ring C is where c1 is 0 or 1, and R Ｙ is halo (e.g., —F), and C optionally substituted with 1 to 3 F. １～３ alkyl; R ａＮ is C １～３ is alkyl, L Ａ１ is CH ２ , CHMe, or CMe ２ and Each L Ａ４ are independently 1 to 3 R ａ is a monocyclic 4-6 membered nitrogen-containing heterocyclylene optionally substituted by Each L Ａ４ contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms; L Ａ４ Each R on ａ is -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ independently selected from the group consisting of alkyl, The compound of the formula (I-aa-1) or a pharmaceutically acceptable salt thereof or Formula (I-a-1): or a pharmaceutically acceptable salt thereof, During the ceremony, X ａ is N or CH, R ６ is —F or —Cl, m3 is 1, and X ３ is C １～３ alkylene, and R １ is H, Ring C is is selected from the group consisting of L Ａ１ is CH ２ , CHMe, or CMe ２ and Each L Ａ４ are independently 1 to 3 R ａ is a monocyclic 4-6 membered nitrogen-containing heterocyclylene optionally substituted by Each L Ａ４ contains 1 to 2 ring nitrogen atoms and no additional ring heteroatoms; L Ａ４ Each R on ａ is -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ independently selected from the group consisting of alkyl, The compound of the formula (I-a-1) or a pharmaceutically acceptable salt thereof or Formula (I-aa-2): or a pharmaceutically acceptable salt thereof, During the ceremony, X ａ is N or CH, R ６ is —F or —Cl, m3 is 1, and X ３ is C １～３ alkylene, and R １ is H, Ring C is is selected from the group consisting of c1 is 0 or 1, and R Ｙ is halo (e.g., —F), and C optionally substituted with 1 to 3 F. １～３ alkyl; R ａＮ is C １～３ is alkyl, L Ａ１ is CH ２ , CHMe, or CMe ２ and Z １ and Z ２ , CH, CR ａ４ and N, Z ３ and Z ４ , CH, CR ａ５ and N, However, Z １ and Z ２ At least one of is N, and Z ３ and Z ４ At least one of is N, and Z ２ If N, then Z ３ is CH or CR ａ５ and m4 and m5 are independently selected from the group consisting of 0, 1, and 2; Each R ａ４ and R ａ５ is -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ independently selected from the group consisting of alkyl, The compound of the formula (I-aa-2) or a pharmaceutically acceptable salt thereof or Formula (I-a-2): or a pharmaceutically acceptable salt thereof, During the ceremony, X ａ is N or CH, R ６ is —F or —Cl, m3 is 1, and X ３ is C １～３ alkylene, and R １ is H, Ring C is is selected from the group consisting of L Ａ１ is CH ２ , CHMe, or CMe ２ and Z １ and Z ２ , CH, CR ａ４ and N, Z ３ and Z ４ , CH, CR ａ５ and N, However, Z １ and Z ２ At least one of is N, and Z ３ and Z ４ At least one of is N, and Z ２ If N, then Z ３ is CH or CR ａ５ and m4 and m5 are independently selected from the group consisting of 0, 1, and 2; Each R ａ４ and R ａ５ is -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ independently selected from the group consisting of alkyl, The compound of the formula (I-a-2) or a pharmaceutically acceptable salt thereof or Formula (I-aa-3): or a pharmaceutically acceptable salt thereof, During the ceremony, X ａ is N or CH, R ６ is —F or —Cl, m3 is 1, and X ３ is C １～３ alkylene, and R １ is H, Ring C is where c1 is 0 or 1, and R Ｙ is halo (e.g., —F), and C optionally substituted with 1 to 3 F. １～３ alkyl; R ａＮ is C １～３ is alkyl, L Ａ１ is CH ２ , CHMe, or CMe ２ and One L Ａ４ is 1 to 3 R ａ and The other L Ａ４ is 1 to 3 R ａ a bicyclic 6- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L Ａ４ Each R on ａ is -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ independently selected from the group consisting of alkyl, A compound of the formula (I-aa-3) or a pharmaceutically acceptable salt thereof or Formula (I-a-3): or a pharmaceutically acceptable salt thereof, During the ceremony, X ａ is N or CH, R ６ is —F or —Cl, m3 is 1, and X ３ is C １～３ alkylene, and R １ is H, Ring C is is selected from the group consisting of L Ａ１ is CH ２ , CHMe, or CMe ２ and One L Ａ４ is 1 to 3 R ａ and The other L Ａ４ is 1 to 3 R ａ a bicyclic 6- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L Ａ４ Each R on ａ is -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ independently selected from the group consisting of alkyl, The compound of the formula (I-a-3) or a pharmaceutically acceptable salt thereof or Formula (I-bb): or a pharmaceutically acceptable salt thereof, During the ceremony, X ａ is N or CH, R ６ is —F or —Cl, m3 is 1, and X ３ is C １～３ alkylene, and R １ is H, Ring C is where c1 is 0 or 1, and R Ｙ is halo (e.g., —F), and C optionally substituted with 1 to 3 F. １～３ alkyl; R ａＮ is C １～３ is alkyl, L is -L Ａ４ -L Ａ３ - ｂｂ or -L Ａ４ -L Ａ１ -L Ａ３ - ｂｂ and bb represents the point of attachment to ring C. L Ａ４ is 1 to 3 R ａ a 4- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L Ａ４ Each R on ａ is -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ independently selected from the group consisting of alkyl, The compound of the formula (I-bb) or a pharmaceutically acceptable salt thereof or Formula (Ib): or a pharmaceutically acceptable salt thereof, During the ceremony, X ａ is N or CH, R ６ is —F or —Cl, m3 is 1, and X ３ is C １～３ alkylene, and R １ is H, Ring C is is selected from the group consisting of L is -L Ａ４ -L Ａ３ - ｂｂ or -L Ａ４ -L Ａ１ -L Ａ３ - ｂｂ and bb represents the point of attachment to ring C. L Ａ４ is 1 to 3 R ａ a 4- to 12-membered nitrogen-containing heterocyclylene optionally substituted by L Ａ４ Each R on ａ is -F, CN, C １～３ C optionally substituted with alkoxy, OH, and 1 to 3 F １～３ independently selected from the group consisting of alkyl, The compound of the formula (Ib) or a pharmaceutically acceptable salt thereof 2. The compound of claim 1, wherein:

46. 10. The compound of claim 1 selected from the group consisting of the compounds of Table C1 or a pharmaceutically acceptable salt thereof.

47. 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. 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 to 46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

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

50. the hematological cancer is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), nodular lymphocyte-predominant Hodgkin's 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 hematological cancer is DLBCL; or the hematological cancer is FL; or the hematological cancer is BL, or the hematological cancer is PTCL; or the blood cancer is ALL (e.g., B-ALL); 50. The method of claim 49.

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

52. 51. The method of any one of claims 48 to 50, comprising administering to the subject a further therapy or a further therapeutic substance.

53. The additional therapy or additional therapeutic agent may be 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 53. The method of claim 52, wherein the therapeutic agent is an inhibitor, an XPO1 inhibitor, an inhibitor of polycomb repressive complex 2 (PRC2), an immunomodulatory imide drug, an anti-CD19 therapy, an anti-CD20 therapy, an anti-CD3 therapy, chemotherapy, or a combination thereof.

54. 48. A method for treating an autoimmune condition 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 to 46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

55. 48. A method for treating a lymphoproliferative disorder 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 to 46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

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

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