1, 8-naphthyridine-2-ketone isodifunctional BCL6 degradation agent

Abstract

The present disclosure provides a compound having formula (I) (e.g., formula (I-1), formula (I-a) (e.g., formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5), or (I-a-6)), or formula (I-b) (e.g., formula (I-b-1), or (I-b-2)), or a pharmaceutically acceptable salt thereof that induces degradation of a BCL6 protein. These compounds are useful, for example, in the treatment of cancer in a subject (e.g., a human). The disclosure also provides compositions containing the same and methods of use and manufacture thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims U.S. Provisional Application No. 63 / 351,715, filed June 13, 2022; U.S. Provisional Application No. 63 / 351,697, filed June 13, 2022; U.S. Provisional Application No. 63 / 395,630, filed August 5, 2022; U.S. Provisional Application No. 63 / 395,638, filed August 5, 2022; and U.S. Provisional Application No. 63 / 407,006, filed September 15, 2022. Priority claims to U.S. Provisional Application No. 63 / 420,421, filed October 28, 2022; U.S. Provisional Application No. 63 / 436,009, filed December 29, 2022; U.S. Provisional Application No. 63 / 444,801, filed February 10, 2023; U.S. Provisional Application No. 63 / 497,054, filed April 19, 2023; and U.S. Provisional Application No. 63 / 501,077, filed May 9, 2023, are hereby incorporated in their entirety by reference.

[0003] Description of the text file submitted electronically

[0004] This application contains a sequence list submitted electronically in XML format. The sequence list XML is incorporated herein by reference. The XML file, created on May 26, 2023, is named TLS-037WO_SL.xml and is 2,663 bytes in size. Technical Field

[0005] This disclosure provides compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) that induce the degradation of BCL6 protein, or pharmaceutically acceptable salts thereof. These compounds can be used, for example, to treat cancer in a subject (e.g., a human). This disclosure also provides compositions containing the same, and methods of using and manufacturing them. Background Technology

[0006] 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 coordinates the activity of signaling mediators during GC B-cell maturation. More than 1000 BCL6 target genes are known or presumed, including MYC, BCL2, genes associated with DNA damage responses (e.g., ATR, TP53), and cell cycle checkpoint regulators (e.g., CDKN1A, CDKN1B). BCL6 is expressed in the darker cells of GCs, where somatic hypermutation is permitted to produce high-affinity B-cell receptors. Overexpression or loss of control of BCL6 (e.g., through translocation) can allow for maintenance of hypermutagenic function and deactivation of BCL6's antitumor function. Summary of the Invention

[0007] This article provides compounds having formula (I):

[0008]

[0009] Or its pharmaceutically acceptable salt, wherein:

[0010] R 1 Choose from the following groups: H, halogen, cyano, and R. b1 ;

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

[0012] Each X 3 Choose independently from the following groups: -O-, -NR f -, -C(=O)- and optionally by 1-3 R c Replacement C 1-3 Alkylene;

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

[0014] Each R 2 Choose independently from the following groups: H, halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, -OH, and -NR d R e ;

[0015] R 3 Choose from the following groups:

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

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

[0018] Each R 4 Choose independently from the following groups: H, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or

[0019] The R 4 Together with the carbon atoms attached to them, they form C 3-6 Cycloalkyl ring or 4-8 membered heterocyclic ring, wherein the C 3-6 Cycloalkyl rings or 4-8 membered heterocyclic rings are optionally surrounded by 1-3 R groups. g replace;

[0020] A 2 Choose from the following groups: -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 alkyl)2 and -C(=NH)NH2, wherein:

[0021] R 3A Choose from the following groups: C 1-6 Alkyl, C 3-6 alkenyl, C 3-6 alkynyl group, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, each optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and -(C 0-3 (alkylene)-R b1 ;

[0022] X a and X c Independently select the following groups: N, CH, and CF, provided that X a and X c One or both of them are N;

[0023] X b Choose from the following groups: N and CR x1 ;

[0024] R6 and R x1 Each can independently choose from the following groups: H, halogenated, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, CN, and -C≡CH;

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

[0026] (AA)

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

[0028] Each L A Choose independently from the following groups: L A1 L A3 and L A4 The condition is that 1-3 L appear A It is L A4 ;

[0029] (BB)

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

[0031] Each L A Choose independently from the following groups: L A1 and L A3 ;

[0032] Each L A1 Independently select from the following groups: -CH2-, -CHR L -、and-C(R) L )2-;

[0033] Each L A3 Independently select from the following groups: -N(R) d )-、-N(R b -、-O-、-S(O) 0-2 - and C (=O);

[0034] Each L A4 Choose independently from the following groups:

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

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

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

[0038] Each R L Choose independently from the following groups: halogenated, 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 groups), S(O) 0-2 (C 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f )2、-R b , and optionally by 1-6 R c Replacement C 1-6 alkyl;

[0039] Ring C can be selected from the following groups:

[0040] c1 is 0, 1, 2, or 3;

[0041] Each R Y Independently select from the following groups: R a and R b ;

[0042] R aN It is H or optionally 1-3 R c Replacement C 1-6 alkyl;

[0043] Y 1 and Y 2 Independently N, CH, or CR Y ;

[0044] yy represents the attachment point to L;

[0045] X is CH, C, or N;

[0046] Is it a single bond or a double bond?

[0047] L C Choose from the following groups: bond, -CH2-, -CHR a -、-C(R a )2-、-C(=O)-、-N(R d - and O, the condition is that when X is N, L C Not O; and

[0048] A further condition is that the ring C is attached to -L via a ring nitrogen. C - When X is CH, and L C It is a key;

[0049] Each R a Choose independently from the following groups:

[0050] (a) Halogenation;

[0051] (b) Cyano group;

[0052] (c)-OH;

[0053] (d) Oxidation;

[0054] (e) Optional land area is 1-6 R c Replacement C 1-6 Alkoxy;

[0055] (f)-NR d R e ;

[0056] (g) Optional land area is covered by 1-6 R c Replacement C (=O)C 1-6 alkyl;

[0057] (h)C(=O)OH;

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

[0059] (j)C(=O)OC 1-6 Halogenated alkyl groups;

[0060] (k)C(=O)N(R f )2;

[0061] (l)S(O) 0-2 (C 1-6 alkyl);

[0062] (m)S(O) 0-2 (C 1-6 (Halogenated alkyl);

[0063] (n)S(O)1-2 N(R f )2; and

[0064] (o)C 1-6 Alkyl, C 2-6 alkenyl, or C 2-6 Alkyne groups, each optionally surrounded by 1-6 R groups c replace;

[0065] Each R b Independently select from the following groups: -(L b ) b -R b1 and -R b1 ,in:

[0066] Each b is independently 1, 2, or 3;

[0067] Each -L b Choose independently from the following groups: -O-, -N(H)-, -N(C)-. 1-3 Alkyl)-, -S(O) 0-2 -, C (=O), and C 1-3 Alkylene; and

[0068] Each R b1 Choose independently from the following groups: C 3-10 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, each optionally bounded by 1-3 R groups g replace;

[0069] Each R c Choose independently from the following groups: halogenated, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e C(=O)C 1-6 Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Halogenated alkyl groups, C(=O)OH, C(=O)N(R) f 2. S(O) 0-2 (C 1-6 Alkyl groups), S(O) 0-2 (C 1-6 Halogenated alkyl groups), and S(O) 1-2 N(R f )2;

[0070] Each R d and Re Independently select from the following groups: H, C (=O)C 1-6 Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Haloalkyl, C(=O)N(R) f 2. S(O) 1-2 (C 1-6 Alkyl groups), S(O) 1-2 (C 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f 2. and optionally by 1-3 R h Replacement C 1-6 alkyl;

[0071] Each R f Independently select from the following groups: H and optionally 1-3 Rs. h Replacement C 1-6 alkyl;

[0072] Each R g Independently select from the following groups: R h Oxygen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0073] Each R h Independently select from the following groups: halogenated, cyano, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl), and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

[0074] This article also provides pharmaceutical compositions comprising a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5) or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0075] This article provides methods for treating cancer in a subject in need, including administering to the subject a therapeutically effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0076] This article also provides BCL6 proteins that are non-covalently bound to compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof.

[0077] This article also provides ternary complexes comprising BCL6 protein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))), or a pharmaceutically acceptable salt thereof, and CRBN protein or a portion thereof.

[0078] To facilitate understanding of the disclosures set forth herein, several additional terms are provided. Generally, the nomenclature used herein and the laboratory procedures described in organic chemistry, medicinal chemistry, and pharmacology are those well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Every patent, application, published application, and other publication mentioned throughout this specification and its appendices is incorporated herein by reference in its entirety. In the event of any conflict between this disclosure and any content incorporated herein by reference, this disclosure shall prevail.

[0079] Details of one or more embodiments of the present invention are set forth in the accompanying drawings and the description below. Further features and advantages of the invention will become apparent from the specification, the drawings, and the claims. Detailed Implementation

[0080] This disclosure provides compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) that induce the degradation of BCL6 protein, or pharmaceutically acceptable salts thereof. These compounds can be used, for example, to treat cancer. This disclosure also provides compositions containing the compounds provided herein, as well as methods of using and manufacturing them.

[0081] Under antigen attack, germinal centers (GCs) form in lymphoid follicles, and B cells in the GC dark zone undergo rapid proliferation and somatic hypermutation. Their immunoglobulin variable genes all produce high-affinity B cell receptors, as well as other genes (including BCL6). BCL6 is generally considered a "master regulator" of the GC response. In some cancers, BCL6 can be mutated, translocated, and / or its expression can be upregulated. See, for example, Leeman-Neill and Bhagat, Expert Opinion on Therapeutic Targets 22.2(2018):143-152; Mlynarczyk and Melnick. Immunological Reviews 288.1(2019):214-239.

[0082] The BCL6 protein possesses multiple domains, including the BTB domain, the RD2 domain, and a DNA-binding domain. The N-terminal BTB domain is the homodimerization site of BCL6, and the monomer interface forms a "side groove," which is the binding site for endogenous co-repressors of BCL6 (such as SMRT, NCOR, and BCOR). See, for example, Cardenas, Mariano G. et al., Clinical Cancer Research 23.4 (2017):885-893.

[0083] Compounds that induce the degradation of target proteins are sometimes referred to as heterobifunctional compounds, PROTACs, or degrading agents. Such compounds typically consist of a portion that binds to the target protein and a portion that binds to a ubiquitin E3 ligase (sometimes called E3 ligase or simply E3), these two portions optionally separated by a linker. To induce degradation, heterobifunctional compounds are thought to induce the formation of a ternary complex between the target protein, the compound, and the E3 ligase. Once the ternary complex is formed, the target protein is ubiquitinated, and the ubiquitinated target protein is degraded by the proteasome. Several E3 ligases have been used as companion E3 ligases for heterobifunctional degrading agents. This article uses the cereblon (CRBN) E3 ligase (also referred to herein as CRBN protein).

[0084] Degradation of target proteins may have potential advantages over small-molecule inhibition, such as the inhibition of the target protein itself. One potential advantage is that the duration of action of heterobifunctional compounds is often based on the rate of resynthesis of the target protein. Another potential advantage is that many heterobifunctional compounds are thought to be released from ubiquitinated target protein-E3 ligase complexes and can be used to form additional ternary complexes; this is sometimes referred to as the “catalytic” turnover of heterobifunctional compounds. In some cases, degradation of the target protein may also be more advantageous than small-molecule inhibition because degradation may impair the scaffold function of the target protein, while small molecules may not. It is also generally accepted that a high affinity for the target protein is not always required for the formation of ternary complexes.

[0085] Heterobifunctional compounds are further described, for example, in the following: International Publications WO 2021 / 077010 and WO2022 / 221673; McCoulll, 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.

[0086] Compound Examples

[0087] This article provides compounds having formula (I):

[0088]

[0089] Or its pharmaceutically acceptable salt, wherein:

[0090] R 1 Choose from the following groups: H, halogen, cyano, and R. b1 ;

[0091] m3 is 0, 1, 2, or 3;

[0092] Each X 3 Choose independently from the following groups: -O-, -NR f -, -C(=O)- and optionally by 1-3 R c Replacement C 1-3 Alkylene;

[0093] The condition is N-(X) 3 ) m3 -R 1 Some of them do not contain any OO, NO, NN, O-halogenated or N-halogenated bonds;

[0094] Each R 2 Choose independently from the following groups: H, halogen, cyano, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups, -OH, and -NR d R e ;

[0095] R 3 Choose from the following groups:

[0096] -A 1 -C(R 4 R 4 )-A 2 and -CH=CH-A 2 ,in:

[0097] A 1 It is -O- or -S-;

[0098] Each R 4 Choose independently from the following groups: H, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or

[0099] The R 4 Together with the carbon atoms attached to them, they form C 3-6 Cycloalkyl ring or 4-8 membered heterocyclic ring, wherein the C 3-6 Cycloalkyl rings or 4-8 membered heterocyclic rings are optionally surrounded by 1-3 R groups. g replace;

[0100] A 2 Choose from the following groups: -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 alkyl)2 and -C(=NH)NH2, wherein:

[0101] R 3A Choose from the following groups: C 1-6 Alkyl, C 3-6 alkenyl, C 3-6 alkynyl group, C 3-6 Cycloalkyl and 3-8 membered heterocyclic groups, each optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and -(C 0-3 (alkylene)-R b1 ;

[0102] X a and X c Independently select the following groups: N, CH, and CF, provided that X a and X c One or both of them are N;

[0103] X b Choose from the following groups: N and CR x1 ;

[0104] R 6 and R x1 Each can independently choose from the following groups: H, halogenated, C. 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, CN, and -C≡CH;

[0105] L is -(L) A ) n1 -, where L A and n1 are defined according to (AA) or (BB):

[0106] (AA)

[0107] n1 is an integer from 1 to 15; and

[0108] Each L A Choose independently from the following groups: L A1 L A3 and L A4 The condition is that 1-3 L appear A It is L A4 ;

[0109] (BB)

[0110] n1 is an integer from 0 to 20; and

[0111] Each L A Choose independently from the following groups: L A1 and L A3 ;

[0112] Each L A1 Independently select from the following groups: -CH2-, -CHR L -、and-C(R) L )2-;

[0113] Each L A3 Independently select from the following groups: -N(R) d )-、-N(R b -、-O-、-S(O) 0-2 - and C (=O);

[0114] Each L A4 Choose independently from the following groups:

[0115] (a)C 3-15 Cycloalkyl or 3-15 membered heterocyclic groups, each optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and R b ;as well as

[0116] (b)C 6-15 arylene or 5-15 heteroarylene, each optionally substituted by 1-6 substituents independently selected from the group consisting of: R a and R b ;

[0117] The condition is that L does not contain any NO, OO, NN, NS(O)0, or OS(O). 0-2 key;

[0118] Each R L Choose independently from the following groups: halogenated, 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 groups), S(O) 0-2 (C 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f )2、-R b , and optionally by 1-6 R c Replacement C1-6 alkyl;

[0119] Ring C can be selected from the following groups:

[0120] c1 is 0, 1, 2, or 3;

[0121] Each R Y Independently select from the following groups: R a and R b ;

[0122] R aN It is H or optionally 1-3 R c Replacement C 1-6 alkyl;

[0123] Y 1 and Y 2 Independently N, CH, or CR Y ;

[0124] yy represents the attachment point to L;

[0125] X is CH, C, or N;

[0126] Is it a single bond or a double bond?

[0127] L C Choose from the following groups: bond, -CH2-, -CHR a -、-C(R a )2-、-C(=O)-、-N(R d - and O, the condition is that when X is N, L C Not O; and

[0128] A further condition is that the ring C is attached to -L via a ring nitrogen. C - When X is CH, and L C It is a key;

[0129] Each R a Choose independently from the following groups:

[0130] (a) Halogenation;

[0131] (b) Cyano group;

[0132] (c)-OH;

[0133] (d) Oxidation;

[0134] (e) Optional land area is 1-6 R c Replacement C 1-6 Alkoxy;

[0135] (f)-NR d R e ;

[0136] (g) Optional land area is covered by 1-6 R c Replacement C (=O)C 1-6 alkyl;

[0137] (h)C(=O)OH;

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

[0139] (j)C(=O)OC 1-6 Halogenated alkyl groups;

[0140] (k)C(=O)N(R f )2;

[0141] (l)S(O) 0-2 (C 1-6 alkyl);

[0142] (m)S(O) 0-2 (C 1-6 (Halogenated alkyl);

[0143] (n)S(O) 1-2 N(R f )2; and

[0144] (o)C 1-6 Alkyl, C 2-6 alkenyl, or C 2-6 Alkyne groups, each optionally surrounded by 1-6 R groups c replace;

[0145] Each R b Independently select from the following groups: -(L b ) b -R b1 and -R b1 ,in:

[0146] Each b is independently 1, 2, or 3;

[0147] Each -L b Choose independently from the following groups: -O-, -N(H)-, -N(C)-. 1-3 Alkyl)-, -S(O) 0-2 -, C (=O), and C 1-3 Alkylene; and

[0148] Each R b1 Choose independently from the following groups: C 3-10Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl groups, each optionally bounded by 1-3 R groups g replace;

[0149] Each R c Choose independently from the following groups: halogenated, cyano, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e C(=O)C 1-6 Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Halogenated alkyl groups, C(=O)OH, C(=O)N(R) f 2. S(O) 0-2 (C 1-6 Alkyl groups), S(O) 0-2 (C 1-6 Halogenated alkyl groups), and S(O) 1-2 N(R f )2;

[0150] Each R d and R e Independently select from the following groups: H, C (=O)C 1-6 Alkyl, C(=O)C 1-6 Haloalkyl, C(=O)OC 1-6 Alkyl, C(=O)OC 1-6 Haloalkyl, C(=O)N(R) f 2. S(O) 1-2 (C 1-6 Alkyl groups), S(O) 1-2 (C 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f 2. and optionally by 1-3 R h Replacement C 1-6 alkyl;

[0151] Each R f Independently select from the following groups: H and optionally 1-3 Rs. h Replacement C 1-6 alkyl;

[0152] Each R g Independently select from the following groups: R h Oxygen, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0153] Each R h Independently select from the following groups: halogenated, cyano, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl), and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

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

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

[0156] In some embodiments, each R 4 It is H. In some embodiments, an R 4 It is C 1-3 Alkyl (e.g., methyl); and another R 4 It is H.

[0157] In some embodiments, R 3 It is -CH=CH-A 2 .

[0158] In some embodiments, A 2 It is -C(O)NH2 or -C(O)NR 3A R f In some embodiments, R 3A It can be arbitrarily divided by 1-6 Rs c Replacement C 1-3 Alkyl group. In some embodiments, A 2 It is -C(O)NH2, -C(O)NHMe, or -C(O)NMe2. For example, A 2 It can be -C(O)NHMe.

[0159] In some embodiments, R 3 Yes - A 1 -C(R 4 R 4 )-A 2 A 1 It is O; each R 4It is H; and A 2 It is -C(O)NH2 or -C(O)NR 3A R f , where R 3A It can be arbitrarily divided by 1-6 Rs c Replacement C 1-3 Alkyl group. In some embodiments, A 2 It is -C(O)NH2, -C(O)NHMe or -C(O)NMe2.

[0160] In some embodiments, R 3 yes

[0161] In some embodiments, the compound having formula (I) is a compound having formula (I-1):

[0162]

[0163] Or its pharmaceutically acceptable salt, wherein:

[0164] A 2 It is -C(O)NH2 or -C(O)NR 3A R f ;as well as

[0165] Each R 4 Independently, it is H or C 1-3 alkyl.

[0166] In some embodiments of equation (I-1), each R 4 It is H.

[0167] In some embodiments of equation (I-1), A 2 It is -C(O)NH2, -C(O)NHMe, or -C(O)NMe2. For example, A 2 It can be -C(O)NHMe.

[0168] In some embodiments of equation (I-1), each R 4 It is H; and A 2 It is -C(O)NH2, -C(O)NHMe, or -C(O)NMe2. For example, A 2 It can be -C(O)NHMe.

[0169] In some embodiments, X a It is N; X c It is N; and X b It is CR x1 For example, X a It can be N; X c It can be N; and X b It can be CH.

[0170] In some embodiments, X a It is CH; X c It is N; and X b It is CR x1 (For example, CH). For example, X a It can be CH; X c It can be N; and X b It can be CH.

[0171] In some embodiments, R 6 It is halogenated (e.g., -F, -Cl, -Br) or CN. For example, R 6 It can be -Cl, -F, or CN.

[0172] In some embodiments, R 6 It is -Cl or -F.

[0173] In some embodiments, each R 2 It is H.

[0174] In some embodiments, m3 is 0.

[0175] In some embodiments, m3 is 1; and X 3 It is C 1-3 Alkylene (e.g., methylene, ethylene, or isopropylene).

[0176] In some embodiments, R 1 It is H.

[0177] In some embodiments, R 1 It is R b1 In some embodiments, R 1 It is C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, each optionally surrounded by 1-3 R groups. g Replacement. For example, R 1 You can choose from the following groups:

[0178] In some embodiments, m3 is 1; X 3 It is methylene, ethylene, or isopropylene; and R 1 It is H.

[0179] In some embodiments, R 3 Yes - A 1 -C(R 4 R 4 )-A 2 A 1 It is O; each R 4 It is H; and A2 It is -C(O)NH2 or -C(O)NR 3A R f , where R 3A It can be arbitrarily divided by 1-6 Rs c Replacement C 1-3 alkyl;

[0180] Each R 2 It is H; X a Is it N or CH; X c It is N; X b It is CH; and R 6 It is -F or -Cl. In some embodiments, m3 is 1; X 3 It is methylene, ethylene, or isopropylene; and R 1 It is H. In some embodiments, X a It's N.

[0181] In some embodiments, Part of it is in:

[0182] X a It is N or CH; R 6 It is -F or -Cl;

[0183] m3 is 1; X 3 It is C 1-3 Alkylene; and

[0184] R 1 It is H, for example, X 3 It can be isopropylidene.

[0185] In some embodiments, ring C is In some embodiments, ring C is (For example, In some embodiments, ring C is... (For example, In some embodiments, c1 is 0. In some embodiments, c1 is 1; and R Y It is halogenated (e.g., -F). In some embodiments, R aN It is C 1-3 Alkyl (e.g., methyl).

[0186] In some embodiments, ring C is In some embodiments, c1 is 0. In some embodiments, c1 is 1; and R Y It is halogenated (e.g., -F).

[0187] In some embodiments, ring C is selected from the group consisting of: and In some embodiments, c1 is 0. In some embodiments, c1 is 1; and R Y It is halogenated (e.g., -F).

[0188] In some embodiments, c1 is 0. In some embodiments, c1 is 1; and R Y It is halogenated (e.g., -F). In some embodiments, R aN It is C 1-3 Alkyl (e.g., methyl).

[0189] In some embodiments, X is CH. In some embodiments, X is N.

[0190] In some embodiments, L C It is a key.

[0191] In some embodiments, Some selections are made from the following groups:

[0192]

[0193] In some embodiments, Some selections are made from the following groups:

[0194]

[0195] In some embodiments, Some selections are made from the following groups:

[0196]

[0197] In some embodiments, Some selections are made from the following groups:

[0198] In some embodiments, Some selections are made from the following groups:

[0199] In some embodiments, Part of it is

[0200] In some embodiments, L is -(L A ) n1 -, where L A n1 is defined according to (AA). In some embodiments, n1 is an integer from 1 to 5. In some embodiments, n1 is an integer from 2 to 5 (e.g., 2 or 3).

[0201] In some embodiments, L is selected from the group consisting of:

[0202] -L A4 -L A1 -L A4 - bb ;

[0203] -L A4 -L A1 -L A1 -L A4 - bb ;as well as

[0204] -L A4 -L A3 -L A4 - bb ,

[0205] Where bb represents the attachment point to ring C.

[0206] In some embodiments, each L A4 C is independent 3-10 Cycloalkyl or 4-12 membered heterocyclic groups, each optionally surrounded by 1-6 R groups. a replace.

[0207] In some embodiments, each L A4 Independently, it is optional to be 1-6 Rs a Substituted 4-12-membered heterocyclic group.

[0208] In some embodiments, each L A4 Independently, it is optional to be 1-3 Rs a Substituted 4-10-membered heterocyclic groups.

[0209] In some embodiments, each L A4 Independently, it is optional to be 1-3 Rs a Substituted monocyclic 4-6 member nitrogen-containing subheterocyclic groups.

[0210] In some embodiments, an L A4 It is optional to be 1-3 R a Substituted monocyclic 4-6-membered monocyclic nitrogen-containing heterocyclic group; and another L A4 It is optional to be 1-3 R a Substituted bicyclic 6-12 membered nitrogen-containing heterocyclic group. In some embodiments, another L A4 It is optional to be 1-3 R a Substituted spirocyclic bicyclic 6-10 member nitrogen-containing heterocyclic sub-groups. In some embodiments, another L... A4 It is optional to be 1-3 R a Substituted bridging bicyclic 6-10 nucleotide nitrogen-containing subheterocyclic groups.

[0211] In some embodiments, L A4 Each R existing on a Choose independently from the following groups: -F; CN; C 1-3 Alkyl group; OH group; C group optionally substituted with 1-3 F groups 1-3 Alkyl groups; and C groups substituted with -OH 1-3 alkyl.

[0212] In some embodiments, L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0213] In some embodiments, L A4 Each R existing on a The following groups are selected independently: F, methyl, CF3, CHF2 and CH2F.

[0214] In some embodiments, each L A4 It contains 1-2 cyclic nitrogen atoms and no other cyclic heteroatoms.

[0215] In some embodiments, L is -L A4 -L A1 -L A4 - bb , where bb represents the attachment point to ring C. In some embodiments, L A1 It is -CH2-. In some embodiments, L A1 Yes -CHMe-. In some embodiments, L A1 It is -C(Me)2-.

[0216] In some embodiments, L is -L A4 -L A3 -L A4 - bb , where bb represents the attachment point to ring C. In some embodiments, L A3 It is -O-, -NH-, or -N(C) 1-3 alkyl)-.

[0217] In some embodiments, L is -L A4 -L A1 -L A1 -L A4 - bb , where bb represents the attachment point to ring C. In some embodiments, each L A1 It is CH2.

[0218] In some embodiments, L is -L A4 -L A1 -(L A3 ) 1-2-bb , where bb represents the attachment point to ring C. In some embodiments, L is -L A4 -L A1 -L A3 - bb , where bb represents the attachment point to ring C. In some embodiments, L A1 It is -CH2-. In some embodiments, L A3 Is it NH or N(C)? 1-3 Alkyl groups (e.g., NH). In some embodiments, L is -L A4 -CH2-NH- bb , where bb represents the attachment point to ring C. In some embodiments, L A4 It is optional to be 1-3 R a Replaced 4-10 membered heterocyclic groups. In some embodiments, L A4 It is optional to be 1-3 R a Substituted monocyclic 4-6 member nitrogen-containing subheterocyclic groups.

[0219] In some embodiments, L is -L A4 -L A3 - bb , where bb represents the attachment point to ring C. In some embodiments, L A3 It is NH. In some embodiments, L A3 Yes -O-. In some embodiments, L A4 It is optional to be 1-3 R a Substituted monocyclic 4-8 (e.g., 4-6) nitrogen-containing heterocyclic groups. In some embodiments, L A4 It is optional to be 1-3 R a Substituted spirocyclic bicyclic 6-12 (e.g., 8-12) nitrogen-containing subheterocyclic groups.

[0220] In some embodiments, L is -L A4 -L A4 -L A3 -L A4 - bb or -L A4 -L A3 -L A4 -L A4 - bb , where bb represents the attachment point to ring C.

[0221] In some embodiments, L is -L A4 -(C 3-6 (cycloalkylene)-OLA4 - bb or -L A4 -O-(C 3-6 (cycloalkylene)-L A4 - bb , of which C 3-6 The cyclohexene alkyl group is optionally surrounded by 1-2 Rs. a Replace; and each L A4 Independently, it is optional to be controlled by 1-2 Rs. a Substituted 4-12-membered heterocyclic groups (e.g., 5-6-membered groups (e.g., 6-membered groups)).

[0222] In some embodiments, L is Each L A4 It is optional to be 1-2 R a Substituted monocyclic 4-6 membered subheterocyclic groups.

[0223] In some embodiments, L is selected from the group consisting of the portions depicted in Table L, where bb represents the attachment point to ring C.

[0224] Table L

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231] In some embodiments, L is selected from the group consisting of the portions depicted in Table L1a: Table L1a

[0232]

[0233] Where bb represents the attachment point to ring C.

[0234] In some embodiments, L is selected from the group consisting of the portions depicted in Table L3a:

[0235] Table L3a

[0236]

[0237] Where bb represents the attachment point to ring C.

[0238] In some embodiments, L is selected from the group consisting of the portions depicted in Table L4a:

[0239] Table L4a

[0240]

[0241] Where bb represents the attachment point to ring C.

[0242] In some embodiments, L is selected from the group consisting of:

[0243] -L A4 -L A1 -L A4 - bb ;

[0244] -L A4 -L A4 - bb ;

[0245] -L A4 -L A1 -L A1 -L A4 - bb ;as well as

[0246] -L A4 -L A3 -L A4 - bb ;

[0247] Where bb represents the attachment point to ring C; and

[0248] L A1 It is -CH2-, -CHMe-, -CMe2-, or -CH(OH)-;

[0249] Each L A4 Independently, it is optional to be 1-3 Rs a Substituted 4-12 nitrogen-containing heterocyclic groups, wherein:

[0250] L A4 Each R existing on a Choose independently from the following groups: -F; CN; C 1-3 Alkyl group; OH; C substituted with -OH 1-3 Alkyl groups; and C groups optionally substituted with 1-3 F atoms. 1-3 alkyl.

[0251] In some embodiments, L is selected from the group consisting of:

[0252] -L A4 -L A1 -L A4 -bb ;

[0253] -L A4 -L A4 - bb ;

[0254] -L A4 -L A1 -L A1 -L A4 - bb ;as well as

[0255] -L A4 -L A3 -L A4 - bb ;

[0256] Where bb represents the attachment point to ring C; and

[0257] L A1 It is CH2, CHMe, or CMe2;

[0258] Each L A4 Independently, it is optional to be 1-3 Rs a Substituted 4-12 nitrogen-containing heterocyclic groups, wherein:

[0259] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0260] In some embodiments, L is L A4 -L A1 -L A4 - bb ,in:

[0261] bb represents the attachment point with ring C;

[0262] L A1 It is -CH2-, -CHMe-, -CMe2-, or -CH(OH)-;

[0263] Each L A4 Independently, they are 4-12 subheterocyclic groups, each optionally separated by 1-3 R groups. a Replace; and

[0264] L A4 Each R existing on a Choose independently from the following groups: -F; CN; C 1-3 Alkyl group; OH; C substituted with -OH 1-3Alkyl groups; and C groups optionally substituted with 1-3 F atoms. 1-3 alkyl.

[0265] In some embodiments, L is L A4 -L A1 -L A4 - bb ,in:

[0266] bb represents the attachment point with ring C;

[0267] L A1 It is CH2, CHMe, or CMe2;

[0268] Each L A4 Independently, it is optional to be 1-3 Rs a Substituted 4-12 nitrogen-containing heterocyclic groups, wherein:

[0269] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0270] In some embodiments, Part of it is:

[0271] in:

[0272] R 6 It is -F or -Cl;

[0273] X a It is N or CH;

[0274] L can choose from the following groups:

[0275] -L A4 -L A1 -L A4 - bb ;

[0276] -L A4 -L A1 -L A1 -L A4 - bb ;as well as

[0277] -L A4 -L A3 -L A4 - bb ,

[0278] Where bb represents the attachment point to ring C, and:

[0279] Each L A4 Independently, it is optional to be 1-3 Rs a Substituted monocyclic 4-6 member nitrogen-containing heterocyclic groups; and

[0280] Some selections are made from the following groups:

[0281] In some embodiments, m3 is 1; X 3 It is methylene, ethylene, or isopropylene; and R 1 It is H. In some embodiments, X a It is N. In some embodiments, X a It is N. In some embodiments, Some selections are made from the following groups:

[0282] In some embodiments, Part of it is:

[0283] in:

[0284] R 6 It is -F or -Cl;

[0285] X a It is N or CH;

[0286] L can choose from the following groups:

[0287] -L A4 -L A1 -L A4 - bb ;

[0288] -L A4 -L A1 -L A1 -L A4 - bb ;as well as

[0289] -L A4 -L A3 -L A4 - bb ,

[0290] Where bb represents the attachment point to ring C, and:

[0291] An L A4 It is optional to be 1-3 R a Substituted monocyclic 4-6 membered nitrogen-containing heterocyclic groups; and another L A4 It is optional to be 1-3 Ra Substituted bicyclic 6-12 member nitrogen-containing heterocyclic groups; and

[0292] Some selections are made from the following groups: In some embodiments, m3 is 1; X 3 It is methylene, ethylene, or isopropylene; and R 1 It is H. In some embodiments, X a It is N. In some embodiments, Some selections are made from the following groups:

[0293] In some embodiments, Part of it is:

[0294] in:

[0295] R 6 It is -F or -Cl;

[0296] X a It is N or CH;

[0297] L is selected from the following groups: portions depicted in Table L, Table L1a, or Table L3a (e.g., Table L1a or Table L3a); and

[0298] Some selections are made from the following groups:

[0299] In some embodiments, m3 is 1; X 3 It is methylene, ethylene, or isopropylene; and R 1 It is H. In some embodiments, X a It is N. In some embodiments, X a It is CH. In some embodiments, Some selections are made from the following groups:

[0300] In some embodiments, a compound having formula (I) is a compound having formula (Ia):

[0301]

[0302] Or its pharmaceutically acceptable salt, wherein:

[0303] X a It is N or CH;

[0304] R 6 It is -F or -Cl;

[0305] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0306] Ring C can be selected from the following groups: Where: c1 is 0 or 1, R Y Choose free halogenated (e.g., -F) and C that is optionally replaced by 1-3 F. 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl;

[0307] L can choose from the following groups:

[0308] -L A4 -L A1 -L A4 - bb ;

[0309] -L A4 -L A4 - bb ;

[0310] -L A4 -L A1 -L A1 -L A4 - bb ;as well as

[0311] -L A4 -L A3 -L A4 - bb ;

[0312] Where bb represents the attachment point to ring C; and

[0313] L A1 It is CH2, CHMe, or CMe2;

[0314] Each L A4 Independently, it is optional to be 1-3 Rs a Substituted 4-12 nitrogen-containing heterocyclic groups, wherein:

[0315] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0316] In some embodiments of equation (Ia), each L A4Independently, it is optional to be 1-3 Rs a Substituted monocyclic 4-6 member nitrogen-containing heterocyclic groups, wherein each L A4 It contains 1-2 cyclic nitrogen atoms and no other cyclic heteroatoms.

[0317] In some embodiments of equation (Ia), an L A4 It is optional to be 1-3 R a Substituted monocyclic 4-6 member nitrogen-containing heterocyclic groups; and

[0318] Another L A4 It is optional to be 1-3 R a Substituted bicyclic spirocyclic 6-12 (e.g., 6-10) nitrogen-containing subheterocyclic groups,

[0319] Each L A4 It contains 1-2 cyclic nitrogen atoms and no other cyclic heteroatoms.

[0320] In some embodiments of equation (Ia), L is -L A4 -L A1 -L A4 - bb ;and L A1 It is CH2 or CHMe.

[0321] In some embodiments of formula (Ia), L is selected from the group consisting of the portion depicted in table Ia, where bb represents the attachment point to ring C.

[0322] Table LIa

[0323]

[0324]

[0325]

[0326]

[0327] In some embodiments, the compound having formula (Ia) is a compound having formula (Ia-1):

[0328]

[0329] Or its pharmaceutically acceptable salt, wherein:

[0330] X a It is N or CH;

[0331] R 6 It is -F or -Cl;

[0332] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0333] Ring C can be selected from the following groups: Where: c1 is 0 or 1, R Y Choose free halogenated (e.g., -F) and C that is optionally replaced by 1-3 F. 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl;

[0334] L A1 It is CH2, CHMe, or CMe2; and

[0335] Each L A4 Independently, it is optional to be 1-3 Rs a Substituted monocyclic 4-6 member nitrogen-containing heterocyclic groups, wherein:

[0336] Each L A4 It contains 1-2 cyclic nitrogen atoms and no other cyclic heteroatoms, and

[0337] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0338] In some embodiments of formula (Ia-1), -L A4 -L A1 -L A4 - Selected from the following groups: the portions depicted in Table LIa-1, where bb represents the attachment point to ring C.

[0339] Table L1a-1

[0340]

[0341]

[0342] In some embodiments, the compound having formula (Ia) is a compound having formula (Ia-2):

[0343]

[0344] Or its pharmaceutically acceptable salt, wherein:

[0345] X a It is N or CH;

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

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

[0348] Ring C can be selected from the following groups: Where: c1 is 0 or 1, R Y Choose free halogenated (e.g., -F) and C that is optionally replaced by 1-3 F. 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl;

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

[0350] Z 1 and Z 2 Choose independently from the following groups: CH, CR a4 、 and N;

[0351] Z 3 and Z 4 Choose independently from the following groups: CH, CR a5 and N,

[0352] The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When it is N, Z 3 Is it CH or CR? a5 ;

[0353] m4 and m5 are independently selected from the following groups: 0, 1, and 2; and

[0354] Each R a4 and R a5 Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0355] In some embodiments of equation (Ia-2), Z 1 It is N. In some embodiments of equation (Ia-2), Z 1 It is N; and Z 2 Is it CH or CR? a4 In some embodiments of equation (Ia-2), Z1 It is N; Z 2 Is it CH or CR? a4 And Z 3 It is N.

[0356] In some embodiments of equation (Ia-2), Z 1 It is N; Z 2 Is it CH or CR? a4 Z 3 It is N; and Z 4 Is it CH or CR? a5 .

[0357] In some embodiments of equation (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 It is CH; and m4 and m5 are both 0. In some embodiments of equation (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 It is CH; one of m4 and m5 is 1; and the other of m4 and m5 is 0. In some embodiments of equation (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 It is CH; one of m4 and m5 is 1; the other of m4 and m5 is 0; and R a4 Or R a5 It is methyl when present. In some embodiments of formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 It is CH; m4 is 1; and m5 is 0. In some embodiments of equation (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 It is CH; m4 is 1; m5 is 0; and R a4 It is a methyl group.

[0358] In some embodiments of equation (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; and Z 4 It is CR a5 (For example, CF). In some embodiments of equation (Ia-2), Z 1 It is N; Z 2It is CH; Z 3 It is N; Z 4 It is CF; and m4 and m5 are both 0.

[0359] In some embodiments of equation (Ia-2), Z 1 It is N; Z 2 Is it CH or CR? a4 Z 3 It is N; and Z 4 It is N. In some embodiments of equation (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 It is N; and m4 and m5 are both 0. In some embodiments of equation (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 It is N; one of m4 and m5 is 1; and the other of m4 and m5 is 0. In some embodiments of equation (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 It is N; one of m4 and m5 is 1; the other of m4 and m5 is 0; and R a4 Or R a5 It is methyl when present. In some embodiments of formula (Ia-2), Z 1 It is N; Z 2 It is CH; Z 3 It is N; Z 4 It is N; m4 is 1; m5 is 0. In some embodiments, R a4 It is a methyl group.

[0360] In some embodiments of equation (Ia-2), The selection is made from the following group: the portion depicted in Table LIa-2, where bb represents the attachment point to ring C.

[0361] Table L1a-2

[0362]

[0363]

[0364]

[0365] In some embodiments, the compound having formula (Ia) is a compound having formula (Ia-3):

[0366]

[0367] Or its pharmaceutically acceptable salt, wherein:

[0368] X a It is N or CH;

[0369] R 6 It is -F or -Cl;

[0370] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0371] Ring C can be selected from the following groups: Where: c1 is 0 or 1, R Y Choose free halogenated (e.g., -F) and C that is optionally replaced by 1-3 F. 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl;

[0372] L A1 It is CH2, CHMe, or CMe2; and

[0373] An L A4 It is optional to be 1-3 R a Substituted monocyclic 4-6 member nitrogen-containing heterocyclic groups; and

[0374] Another L A4 It is optional to be 1-3 R a Substituted bicyclic 6-12 membered nitrogen-containing heterocyclic groups, wherein:

[0375] Each L A4 It contains 1-2 cyclic nitrogen atoms and no other cyclic heteroatoms, and

[0376] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0377] In some embodiments of equation (I-a3), an L A4 It is optional to be 1-3 R a Substituted monocyclic 4-6 membered nitrogen-containing heterocyclic groups; and another L A4 It is optional to be 1-3 R a Substituted bicyclic spirocyclic 6-12 (e.g., 7, 9, or 11) nitrogen-containing subheterocyclic groups.

[0378] In some embodiments of equation (I-a3), an L A4 It is optional to be 1-3 R a Substituted monocyclic 4-6 membered nitrogen-containing heterocyclic groups; and another L A4 It is optional to be 1-3 R a Substituted bicyclic bridging 6-12 (e.g., 7, 8, or 9) nitrogen-containing subheterocyclic groups.

[0379] In some embodiments of equation (I-a3), an L A4 It is optional to be 1-3 R a Substituted monocyclic 4-6 membered nitrogen-containing heterocyclic groups; and another L A4 It is optional to be 1-3 R a Substituted bicyclic fused 6-12 (e.g., 6) nitrogen-containing subheterocyclic groups.

[0380] In some embodiments of equation (Ia-3), -L A4 -L A1 -L A4 - Selected from the following groups: the portions depicted in Table LIa-3, where bb represents the attachment point to ring C.

[0381] Table L1a-3

[0382]

[0383]

[0384] In some embodiments, the compound having formula (Ia) is a compound having formula (Ia-4):

[0385]

[0386] Or its pharmaceutically acceptable salt, wherein:

[0387] X a It is N or CH;

[0388] R 6 It is -F or -Cl;

[0389] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0390] Ring C can be selected from the following groups: Where: c1 is 0 or 1, R Y Choose free halogenated (e.g., -F) and C that is optionally replaced by 1-3 F. 1-3 The group consisting of alkyl groups, and RaN It is C 1-3 alkyl;

[0391] L A1 It is CH2, CHMe, or CMe2;

[0392] Z 1 and Z 2 Choose independently from the following groups: CH, CR a4 、 and N;

[0393] Z 3 and Z 4 Choose independently from the following groups: CH, CR a5 and N,

[0394] The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When it is N, Z 3 Is it CH or CR? a5 ;

[0395] m4 and m6 are independently 0 or 1;

[0396] m5 is 0, 1, or 2; and

[0397] Each R a4 R a5 and R a6 Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0398] In some embodiments of equation (I-a4), Z 1 It is N. In some embodiments of equation (I-a4), Z 1 It is N; and Z 2 It is N. In some embodiments of equation (I-a4), Z 1 It is N; Z 2 It is N; Z 3 It is CH; and Z 4 It is N. In some embodiments of equation (I-a4), Z 1 It is N; Z 2 It is N; Z 3 It is CH; Z 4 It is N; and 2-3 (e.g., 3) of m4, m6, and m6 are 0.

[0399] In some embodiments of equation (Ia-4), The selection is made from the following group: the portion depicted in Table LIa-4, where bb represents the attachment point to ring C.

[0400] Table L1a-4

[0401]

[0402] In some embodiments, the compound having formula (Ia) is a compound having formula (Ia-5):

[0403]

[0404] Or its pharmaceutically acceptable salt, wherein:

[0405] X a It is N or CH;

[0406] R 6 It is -F or -Cl;

[0407] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0408] Ring C can be selected from the following groups: Where: c1 is 0 or 1, R Y Choose free halogenated (e.g., -F) and C that is optionally replaced by 1-3 F. 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 Alkyl groups; and

[0409] Each L A4 Independently, it is optional to be 1-3 Rs a Substituted 4-12 nitrogen-containing heterocyclic groups, wherein:

[0410] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0411] In some embodiments of equation (Ia-5), each L A4 Independently, it is optional to be 1-3 Rs a Substituted monocyclic 4-6 member nitrogen-containing heterocyclic groups, wherein each L A4 It contains 1-2 cyclic nitrogen atoms and no other cyclic heteroatoms. For example, each L A4 It can be independently selected from the group consisting of: piperazine group and piperidinyl group.

[0412] In some embodiments of equation (Ia-5), -L A4 -C(=O)L A4 - Selected from the following groups: the portions depicted in Table LIa-5, where bb represents the attachment point to ring C.

[0413] Table L1a-5

[0414]

[0415] In some embodiments, the compound having formula (Ia) is a compound having formula (Ia-6):

[0416]

[0417] Or its pharmaceutically acceptable salt, wherein:

[0418] X a It is N or CH;

[0419] R 6 It is -F or -Cl;

[0420] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0421] Ring C can be selected from the following groups: Where: c1 is 0 or 1, R Y Choose free halogenated (e.g., -F) and C that is optionally replaced by 1-3 F. 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 Alkyl groups; and

[0422] Each L A4 Independently, it is optional to be 1-3 Rs a Substituted 4-12 nitrogen-containing heterocyclic groups, wherein:

[0423] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0424] In some embodiments of equation (Ia-6), each L A4 Independently, it is optional to be 1-3 Rs a Substituted monocyclic 4-6 member nitrogen-containing heterocyclic groups, wherein each L A4It contains 1-2 cyclic nitrogen atoms and no other cyclic heteroatoms. For example, each L A4 It can be independently selected from the group consisting of: piperazine, piperidinyl, and pyrrolidine.

[0425] In some embodiments of formulas (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), ring C is selected from the group consisting of: For example, ring C could be For example, ring C could be

[0426]

[0427] In some embodiments of equations (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), X a It is N.

[0428] In some embodiments of equations (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), X a It is CH.

[0429] In some embodiments, the compound having formula (I) is a compound having formula (Ib):

[0430]

[0431] Or its pharmaceutically acceptable salt, wherein:

[0432] X a It is N or CH;

[0433] R 6 It is -F or -Cl;

[0434] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0435] Ring C can be selected from the following groups: Where: c1 is 0 or 1, R Y Choose free halogenated (e.g., -F) and C that is optionally replaced by 1-3 F. 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl;

[0436] L is -L A4 -LA3 - bb or -L A4 -L A1 -L A3 - bb , where bb represents the attachment point to ring C; and

[0437] L A4 It is optional to be 1-3 R a Substituted 4-12 nitrogen-containing heterocyclic groups, wherein:

[0438] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0439] In some embodiments of equation (Ib), L is -L A4 -L A3 - bb And L A3 It is -NH-.

[0440] In some embodiments of formula (Ib), L A4 It is optional to be 1-3 R a Substituted monocyclic 4-6 member nitrogen-containing heterocyclic groups, of which L A4 It contains 1-2 cyclic nitrogen atoms and no other cyclic heteroatoms.

[0441] In some embodiments of formula (Ib), L A4 It is optional to be 1-3 R a Substituted bicyclic spirocyclic 6-12 (e.g., 6-10) nitrogen-containing subheterocyclic groups, wherein L A4 It contains 1-2 cyclic nitrogen atoms and no other cyclic heteroatoms.

[0442] In some embodiments of formula (Ib), X a It's N.

[0443] In some embodiments of formula (Ib), X a It is CH.

[0444] In some embodiments of formula (Ib), L is selected from the group consisting of the portion depicted in table LIb, where bb represents the attachment point with ring C.

[0445] Table LIb

[0446]

[0447]

[0448] In some embodiments, the compound having formula (Ib) is the compound having formula (Ib-1):

[0449]

[0450] Or its pharmaceutically acceptable salt, wherein:

[0451] X a It is N or CH;

[0452] R 6 It is -F or -Cl;

[0453] m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H;

[0454] Ring C can be selected from the following groups: Where: c1 is 0 or 1, R Y Choose free halogenated (e.g., -F) and C that is optionally replaced by 1-3 F. 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl;

[0455] L A4 It is optional to be 1-3 R a Substituted 6-12 nitrogen-containing heterocyclic groups, wherein:

[0456] L A4 Each R existing on a Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 Alkyl groups; and

[0457] L A3 It is -NH-, -N(C 1-3 Alkyl group (-) or -O-.

[0458] In some embodiments of formula (Ib-1), L A4 It is optional to be 1-3 R a Substituted bicyclic spirocyclic 6-12 (e.g., 8-10 (e.g., 9)) nitrogen-containing heterocyclic sub-groups, wherein L A4 It contains 1-2 (e.g., 1) cyclic nitrogen atoms and no other cyclic heteroatoms.

[0459] In some embodiments of formula (Ib-1), -L A4 -L A3- Selected from the following groups: the portions depicted in Table LIb-1, where bb represents the attachment point to ring C.

[0460] Table LIb-1

[0461]

[0462] In some embodiments, the compound having formula (Ib) is a compound having formula (Ib-2):

[0463]

[0464] Or its pharmaceutically acceptable salt, wherein:

[0465] X a It is N or CH;

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

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

[0468] Ring C can be selected from the following groups: Where: c1 is 0 or 1, R Y Choose free halogenated (e.g., -F) and C that is optionally replaced by 1-3 F. 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl;

[0469] L A3 It is -NH-, -N(C 1-3 Alkyl group (-) or -O-;

[0470] m4 can be selected from the following groups: 0, 1, and 2; and

[0471] Each R a4 Choose independently from the following groups: -F, CN, C 1-3 Alkyl group, OH group, and C group optionally substituted with 1-3 F groups 1-3 alkyl.

[0472] In some embodiments of equation (Ib-2), m4 is 0 or 1; and R a4 It is a methyl group when it is present.

[0473] In some embodiments of equation (Ib-2), The selection is made from the following group: the portion depicted in Table LIb-2, where bb represents the attachment point to ring C.

[0474] Table LIb-2

[0475]

[0476]

[0477] In some embodiments, the compounds are selected from the group consisting of the compounds in Table C1 or pharmaceutically acceptable salts thereof.

[0478] Table C1

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518] In some compounds in Table C1, one or more stereoisomer centers are indicated by “V3000 enhanced stereochemistry notation” (see: support.collaborativedrug.com / hc / en-us / articles / 360020872171-Advanced-Stereochemistry-Registration-Atropisomers-Mixtures-Unknowns-and-Non-Tetrahedral-Chirality, accessed December 23, 2022, and Accelrys Chemical Representation Guide, Accelrys Software Inc., 2014, each incorporated herein by reference in its entirety). Using this stereochemistry notation, some stereoisomer centers are indicated by “abs”, “&x”, or “orx”, where x is an integer (e.g., 1 or 2). For the avoidance of doubt, the stereochemistry notations in Table C1 have the following meanings:

[0519] (1) When a stereoisomeric center (e.g., a stereoisomeric carbon) is represented by a "flat" bond in the structural formula (i.e., no chemical bond at the stereoisomeric center is represented by a wedge or dash), each of the stereoisomeric centers can independently adopt an (R)- or (S)- configuration. For example, structure Represents (S)-(1-methylpyrrolidone-2-yl)methanol, (R)-(1-methylpyrrolidone-2-yl)methanol, or mixtures thereof. As another non-limiting example, the structure... Representatives: (3S,5S)-5-methylpiperidine-3-carboxylic acid; (3R,5S)-5-methylpiperidine-3-carboxylic acid; (3S,5R)-5-methylpiperidine-3-carboxylic acid; (3R,5R)-5-methylpiperidine-3-carboxylic acid; or mixtures thereof.

[0520] When one or more solid heterogeneous centers are represented by wedges and dashes, the following symbols are used:

[0521] (2) When the stereoisomer center is represented by "abs" or not by an enhanced stereochemical symbol (e.g., "abs", "&x", or "orx"), the stereoisomer center has the absolute configuration shown in the structural formula. For example, the structure... Both refer to (S)-(1-methylpyrrolidone-2-yl)methanol.

[0522] (3) When the stereoheterogeneous center in the structural formula is represented by "orx", the stereoheterogeneous center has been split, but the configuration of the stereoheterogeneous center has not yet been determined. For example, the structure It refers to the stereoisomers selected from the group consisting of: (S)-(1-methylpyrrolidone-2-yl)methanol and (R)-(1-methylpyrrolidone-2-yl)methanol.

[0523] (4) When two or more stereoheterogeneous centers in the structural formula are denoted by "orx", each of these stereoheterogeneous centers has been split, but the configuration at the stereoheterogeneous center has not yet been determined. In particular:

[0524] a. For any pair of stereoheterogeneous centers denoted by "orx" in the structural formula, when the numerical parts in the symbols are different (e.g., the two stereoheterogeneous centers are denoted by "or1" and "or2" respectively), each stereoheterogeneous center is independently defined according to definition (3) (see above). For example, structural This refers to a stereoisomer selected from the following groups:

[0525] b. For any pair of stereoisomers denoted by "orx" in a structural formula, when the numerical parts of the symbols are the same (e.g., each stereoisomer is denoted by "or1"), the structural formula refers to a stereoisomer with relative stereochemistry at these stereoisomers, as shown in the structural formula, but the absolute configuration of these stereoisomers has not yet been determined. For example, structural... It refers to one of the following two "cis (syn)" stereoisomers: As another example, structure It refers to one of the following "anti" stereoisomers:

[0526] (5) When two or more stereoisomer centers are represented by "&x" in a structural formula, the structural formula refers to a mixture of stereoisomers with different configurations at the stereoisomer centers. Specifically:

[0527] a. For any pair of stereoisomer centers denoted by "&x" in a structural formula, when the numerical parts of the symbols differ (e.g., two stereoisomer centers are denoted by "&1" and "&2" respectively), the structural formula refers to a mixture of stereoisomers of these two stereoisomer centers, where the configuration at each stereoisomer center can vary independently from one another. For example, structural... It refers to a mixture of four stereoisomers:

[0528] b. For any pair of stereoisomers denoted by “&x” in a structural formula, when the numerical parts in the symbols are the same (e.g., each stereoisomer is denoted by “&1”), the structural formula refers to a mixture of stereoisomers of these two or more stereoisomers, where the relative configurations are as shown in the structural formula. For example, structural... This refers to a mixture of the following "cis (syn)" stereoisomers: As another example, structure This refers to a mixture of the following "anti" stereoisomers:

[0529] Exemplary compounds having formula (Ia) include compounds: 101, 103, 104, 105, 105a, 106, 106a, 107, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 124, 125, 126, 126a, 127, 127a, 128, 129, 130, 130a, 131, 131a, 132, 133, 134, 135, 1 36, 136a, 139, 140, 141, 141a, 143, 145, 149, 152, 158, 160, 161, 162, 163, 163a, 167, 168, 168a, 168b, 16 9, 169a, 169b, 171, 172, 173, 174, 174a, 174b, 175, 175a, 175b, 176, 176a, 176b, 176c, 176d, 177, 177a, 1 77b, 177c, 177d, 178, 179, 179a, 179b, 187, 188, 188a, 188b, 189, 189a, 190, 191, 192, 192a, 192b, 193, 1 93a, 195, 195a, 196, 197, 197a, 197b, 200, 203, 204, 205, 209, 210, 210a, 210b, 211, 212, 214, 215, 215a, 215b, 216, 216a, 216b, 216c, 216d, 217, 217a, 217b, 218, 218a, 218b, 219, 220, 223, 224, 225, 228, 228a, 228b, 229, 230, 235, 236, 237, 238, 238a, 238b, 239, 240, 241, 242, 242a, and 242b (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0530] Exemplary compounds having formula (Ia-1) include compounds: 101, 103, 104, 105, 105a, 106, 106a, 107, 110, 111, 126, 126a, 127, 127a, 130, 130a, 131, 131a, 132, 133, 134, 135, 139, 140, 141, 1 41a, 145, 152, 158, 160, 161, 163, 163a, 167, 168, 168a, 168b, 169, 169a, 169b ,171,172,176,176a,176b,176c,176d,177,177a,177b,177c,177d,178,179, 179a, 179b, 188, 188a, 188b, 189, 189a, 190, 192, 192a, 192b, 193, 193a, 195, 195a, 196, 197, 197a, 197b, 200, 203, 210, 210a, 210b, 212, 214, 215, 215a, 215 b, 216, 216a, 216b, 216c, 216d, 217, 217a, 217b, 218, 218a, 218b, 228, 228a, 228b, 235, 236, 238, 238a, 238b, 241, 242, 242a, and 242b (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0531] Exemplary compounds having formula (Ia-2) include compounds: 101, 103, 104, 105, 105a, 106, 106a, 107, 126, 126a, 127, 127a, 130, 130a, 131, 131a, 132, 133, 134, 135, 139, 140, 141, 141a, 145, 152, 158, 160, 161, 163, 163a, 167, 168, 168a, 168b, 169, 169a, 169b, 171, 172, 176, 176a, 176b, 176c, 176d, 177, 17 7a, 177b, 177c, 177d, 178, 179, 179a, 179b, 188, 188a, 188b, 189, 189a, 190, 192, 192a, 192b, 193, 193a, 195, 195a, 196, 197, 197a, 197b, 200, 203, 210, 210a, 210b, 212, 214, 215, 215a, 215b, 217, 217a, 217b, 238, 238a, 238b, 241, 242, 242a, and 242b (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0532] Exemplary compounds having formula (Ia-3) include compounds 112, 113, 118, 119, 120, 121, 124, 128, 136, 136a, 143, 149, 173, 174, 174a, 174b, 175, 175a, 175b, 187, 191, 204, 205, 209, 237, 239, and 240 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0533] Exemplary compounds having formula (Ia-4) include compounds 112, 113, 204, 237, 239, and 240 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0534] Exemplary compounds having formula (Ia-5) include compounds 211, 219, 220, 223, and 224 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0535] Exemplary compounds having formula (Ia-6) include compounds 229 and 230 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0536] Exemplary compounds having formula (Ib) include compounds 122, 122a, 122b, 123, 123a, 123b, 137, 138, 142, 144, 147, 148, 156, 156a, 156b, 156c, 156d, 159, 159a, 159b, 164, 180, 180a, 180b, 180c, 180d, 181, 182, 183, 184, 185, 185a, 185b, 185c, 185d, 198, 199, 202, 207, 213, 221, 221a, 221b, 221c, 221d, and 222 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0537] Exemplary compounds having formula (Ib-1) include compounds 137, 138, 142, 144, 147, 148, 156, 156a, 156b, 156c, 156d, 159, 159a, 159b, 164, 180, 180a, 180b, 180c, 180d, 181, 182, 183, 184, 185, 185a, 185b, 185c, 185d, 198, 199, 202, 207, 213, 221, 221a, 221b, 221c, 221d and 222 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0538] Exemplary compounds having formula (Ib-2) include compounds 137, 138, 142, 144, 156, 156a, 156b, 156c, 156d, 159, 159a, 159b, 180, 180a, 180b, 180c, 180d, 181, 182, 183, 184, 185, 185a, 185b, 185c, 185d, 198, 221, 221a, 221b, 221c, 221d, and 222 (as shown in Table C1) or pharmaceutically acceptable salts thereof.

[0539] In some embodiments, the compounds are selected from the group consisting of the compounds in Table C2 or pharmaceutically acceptable salts thereof.

[0540] Table C2

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566] Examples of certain formula (I) compounds are synthesized using methods involving the resolution of stereoisomer mixtures (e.g., SFC separation of stereoisomers). In Table C1, the resolved stereoisomer centers in these compounds are labeled with “or1” and / or “or2” enhanced stereochemical symbols. In some cases, stereoisomer resolution is performed as a final step in the synthesis, thereby providing a single stereoisomer of the formula (I) compound. Alternatively, in some other cases, resolution is performed on an intermediate or starting material, wherein each constituent stereoisomer of the intermediate or starting material can be separately synthesized in subsequent steps to provide the corresponding formula (I) compound as a single stereoisomer. Resolution methods and the association between resolution intermediates and formula (I) compounds are disclosed in examples herein and in Table P1. Those skilled in the art will understand that, under any method of stereoisomer resolution, stereoisomers having (R)- and (S)- configurations at the resolved stereoisomer centers are provided. See Table C3, where the compounds in Table C1 are provided in non-stereoisomer form when their stereoisomers contain the stereochemical symbols or1 and / or2, followed by the corresponding stereoisomers having (R)- and (S)- configurations.

[0567] Table C3

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576] Exemplary compounds having formula (I) also include those shown below: Table C1 of U.S. Provisional Application Serial No. 63 / 407,006, filed September 15, 2022; Table C1 of U.S. Provisional Application Serial No. 63 / 407,012, filed September 15, 2022; Table C1 of U.S. Provisional Application Serial No. 63 / 436,009, filed December 29, 2022; Table C1 of U.S. Provisional Application Serial No. 63 / 497,054, filed April 19, 2023; and Table C1 of U.S. Provisional Application Serial No. 63 / 501,077, filed May 9, 2023; or pharmaceutically acceptable salts thereof, wherein each Table C1 is incorporated herein by reference in its entirety.

[0577] In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5) or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof reduce cell viability in cell lines expressing BCL6 protein, wherein EC 50 Less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compound reduces cell viability in cell lines expressing BCL6 protein, wherein EC 50 Less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compound can be in EC50 of about 0.1 nM to about 100 nM, about 0.1 nM to about 50 nM, about 1 nM to about 50 nM, about 1 nM to about 20 nM, or about 0.1 nM to about 1 nM. 50 It reduces cell viability in cell lines expressing BCL6 protein.

[0578] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5) or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof induces the degradation of BCL6 protein in cell lines expressing BCL6 protein, wherein DC 50Less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof induces the degradation of BCL6 protein in cell lines expressing BCL6 protein, wherein DC 50 Less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compound can induce the degradation of BCL6 protein in cell lines expressing BCL6 protein, where DC... 50 The range is approximately 0.1 nM to approximately 100 nM, approximately 0.1 nM to approximately 50 nM, approximately 1 nM to approximately 50 nM, approximately 1 nM to approximately 20 nM, or approximately 0.1 nM to approximately 1 nM.

[0579] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof induces the degradation of BCL6 protein in cell lines expressing BCL6 protein, wherein Y min Less than 70% (e.g., less than 50%, less than 30%, less than 20%, or less than 10%). In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof induces the degradation of BCL6 protein in cell lines expressing BCL6 protein, wherein Y min Less than 50% (e.g., less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%). In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof induces the degradation of BCL6 protein in cell lines expressing BCL6 protein, wherein Y minLess than 30% (e.g., less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%). For example, the compound can induce the degradation of BCL6 protein in cell lines expressing BCL6 protein, where Y min It ranges from about 1% to about 70% (e.g., about 5% to about 50% or about 10% to about 30%).

[0580] This article also provides the BCL6 protein, which is non-covalently bound to a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof.

[0581] This article also provides a ternary complex comprising BCL6 protein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))), or a pharmaceutically acceptable salt thereof, and CRBN protein or a portion thereof.

[0582] Chemical definition

[0583] The term "halogenated" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0584] The term "oxo" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, the oxo group attaches to a carbon atom to form a carbonyl group.

[0585] The term "alkyl" refers to a saturated acyclic hydrocarbon group, which may be straight-chain or branched and contains the indicated number of carbon atoms. For example, C 1-10 This indicates that the group may have 1 to 10 carbon atoms (inclusive). The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. As used in this context, the term "saturated" means that only a single bond exists between the constituent carbon atom and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0586] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by an independently selected halogen (e.g., -CF3, -CHF2, or -CH2F).

[0587] The term "alkoxy" refers to -O-alkyl (e.g., -OCH3).

[0588] The term "alkylene" refers to a divalent alkyl group (e.g., -CH2-). Similarly, terms such as "cycloalkylene" and "heterocyclic alkylene" refer to divalent cycloalkyl and heterocyclic groups, respectively. For the avoidance of doubt, in "cycloalkylene" and "heterocyclic alkylene," the two groups can be located on the same carbon atom of the ring (e.g., geminal diradical, such as...). ) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., adjacent ring carbon and / or nitrogen atoms)) (e.g., ).

[0589] The term "alkenyl" refers to a straight-chain or branched acyclic hydrocarbon chain that can have one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2-6 This indicates that the group may have 2 to 6 carbon atoms (including the terminal value). The alkenyl group may be unsubstituted or substituted with one or more substituents.

[0590] The term "alkynyl" refers to a straight-chain or branched acyclic hydrocarbon chain that can have one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2-6 This indicates that the group may have 2 to 6 carbon atoms (including the terminal value). The alkynyl group may be unsubstituted or substituted with one or more substituents.

[0591] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group consisting of 6 to 20 carbon atoms, wherein at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring can be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, etc.

[0592] As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons, or 3 to 10 ring carbons, or 3 to 6 ring carbons, wherein the cycloalkyl group may optionally be substituted. As used in this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms. Examples of saturated cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyl groups may have any degree of unsaturation, provided that one or more double bonds are present in the cycloalkyl group, the rings in the ring system are not aromatic, and the partially unsaturated cycloalkyl group is not completely saturated overall. Examples of partially unsaturated cycloalkyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. A cycloalkyl group may include multiple fused rings and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl groups include: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, etc. Cycloalkyl groups also include spirocyclic (e.g., spirobicyclic, where the two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl groups include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, etc.

[0593] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 15 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of: N, O, and S (including oxidized forms, e.g.: And at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). In some embodiments, the heteroaryl group contains 1 to 4 (e.g., 1, 2, or 3) cyclic heteroatoms, each independently selected from the group consisting of: N, O, and S (including oxidized forms, e.g.: The heteroaryl group can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thiophene, pyridinyl, furanyl, oxazolyl, oxadiazolyl, pyrroleyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl, benzothiophene, benzooxadiazolyl, benzofuranyl, benzoimidazolyl, benzotriazolyl, cenylyl, indazole, indolyl, isoquinolinyl, isothiazolyl, naphridinyl, purine, thiophenepyridinyl, pyrido[2,3-d]pyrimidinyl, and pyrrolo[2,3-b]pyridine. The heteroaryl group is selected from thienyl, pyridinyl, quinolinyl, thienzo[2,3-c]pyridinyl, 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]m-dioxacyclopentenyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxothiocyclohexadienyl, isoindololinyl, etc. In some embodiments, the heteroaryl group is selected from thienyl, pyridinyl, furanyl, pyrazolyl, imidazolyl, isoindololinyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, heteroaryl groups also include aryl lactams, aryl cyclic ureas, or their alkylene analogues, wherein each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (i.e., all three valences are occupied by non-hydrogen substituents), such as pyridones (e.g., ), pyrimidinone (e.g., ), pyridazinone (e.g., ), pyrazinone (e.g., ) and imidazolids (e.g., One or more of the following, wherein each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (i.e., the oxo group (i.e., "=O") in this article is a component of the heteroaryl ring).

[0594] The term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system having 3-15 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-15 membered tricyclic systems) and having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic or polycyclic), wherein the heteroatoms are selected from O, N, and S (including oxidized forms, e.g.: (For example, carbon atoms and 1-3, 1-6, or 1-9 N, O, S, or P heteroatoms (if monocyclic, bicyclic, or tricyclic)), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. As used in this context, the term "saturated" means that only single bonds exist between the constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclic groups include piperazine, pyrrolyl, dioxane, morpholinyl, tetrahydrofuranyl, etc. Partially unsaturated heterocyclic groups may have any degree of unsaturation, provided that one or more double bonds are present in the heterocyclic group, the rings in the ring system are not aromatic, and the partially unsaturated heterocyclic group is not completely saturated overall. Examples of partially unsaturated heterocyclic groups include, but are not limited to, tetrahydropyridinyl, dihydropyrazine, dihydropyridinyl, dihydropyrrolyl, dihydrofuranyl, and dihydrophenylthio.

[0595] Heterocyclic groups can include multiple fused rings and bridged rings. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopentadien[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, 3-Azabicyclo[3.2.1]octyl, 2-oxabicyclo[1.1.0]butyl, 2-oxabicyclo[2.1.0]pentyl, 2-oxabicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 7-oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1]heptyl, 7-oxabicyclo[4.2.0]octyl, 2-oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl, etc. Heterocyclic groups also include spirocyclic groups (e.g., spirobicyclo, where the two rings are connected by only one atom). Non-limiting examples of spirocyclic heterocyclic groups include 2-azaspiro[2.2]pentyl, 4-azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, 1,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl, 2,5-diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, 2-oxaspiro[3.5]decyl, and others. Spiro[2.2]pentyl, 4-oxaspiro[2.5]octyl, 1-oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6-oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, 1-oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl, etc.

[0596] As used herein, a nitrogen-containing heterocyclic group refers to a heterocyclic group having 1-2 cyclic nitrogen atoms and 0-2 additional cyclic heteroatoms selected from the following group: O and S (including oxidized forms, such as: Nitrogen-containing heterocyclic groups can be monocyclic, bicyclic, or polycyclic, as defined elsewhere in this document. Examples of monocyclic nitrogen-containing heterocyclic groups include aziridine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc. Examples of bicyclic nitrogen-containing heterocyclic groups include 7-azaspiro[3.5]nonyl, 1,7-diazaspiro[4.5]decyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonyl, 2,6-diazaspiro[3.3]heptyl, etc.

[0597] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation attributable to the ring itself; for example, one or more double or triple bonds between the ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc.

[0598] For the avoidance of ambiguity, and unless otherwise stated, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclic, heterocyclic alkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) containing a sufficient number of ring atoms to form bicyclic or higher-order ring systems (e.g., tricyclic, polycyclic systems), it should be understood that such rings and cyclic groups include those having fused rings, including those where the fusion point is located at (i) adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a zero-atom bridge (e.g., ...). (ii) Monocyclic atoms (spiro-fused ring systems) (e.g., (iii) A continuous array of ring atoms (a bridged ring system with all bridge lengths > 0) (e.g., Those on ).

[0599] Furthermore, the atoms constituting the compounds of the embodiments of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms with the same number of atoms but different mass numbers. By way of example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0600] Furthermore, the compounds disclosed herein, either generally or specifically, are intended to include all tautomer forms. Therefore, by way of example, compounds containing the following moiety are included: Including tautomer forms containing the following parts: Similarly, the pyridyl or pyrimidinyl moiety described as optionally substituted with a hydroxyl group includes pyridinone or pyrimidinone tautomer forms.

[0601] The compounds described herein cover a wide range of stereochemical forms. These compounds also encompass diastereomers and optical isomers, such as mixtures of enantiomers including racemic mixtures, as well as single enantiomers and diastereomers, which are the result of structural asymmetry in certain compounds. Unless otherwise stated, when a disclosed compound is named or represented by an unspecified stereochemical structure and has one or more chiral centers, it should be understood to represent all possible stereoisomers of that compound.

[0602] Treatment

[0603] Indications

[0604] This article provides methods for inducing the degradation of the BCL6 protein. For example, this article provides compounds that can induce the degradation of the BCL6 protein, and these compounds can be used to treat or prevent cancer. Exemplary compounds that bind to BCL6 are described in, 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; McCoulll, William et al., ACS Chemical Biology, ACS 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 (Cancer Letters) (2022), doi:10.1016 / j.canlet.2021.12.035; Huckvale, R. et al., Journal of Medicinal Chemistry (2022), doi:10.1021 / acs.jmedchem.1c02175; Davis, O.et al., Journal of Medicinal Chemistry (2022), doi:10.1021 / acs.jmedchem.1c02174; International Publication Nos. WO 2008 / 066887; WO 2010 / 008436; WO 2014 / 204859; WO 2018 / 215798; WO 2018 / 215801; WO2018 / 219281; WO 2019 / 119138; WO 2019 / 119144; WO 2019 / 119145; WO 2019 / 153080; WO 2019 / 197842; WO 2020 / 104820; WO 2021 / 074620; WO 2021 / 077010, and WO 2022 / 221673. .

[0605] The degradation efficacy of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or their pharmaceutically acceptable salts, as provided herein, can be obtained via DC. 50 The value is determined. As used in this article, DC 50 This refers to the concentration of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) that results in a 50% reduction in the concentration of a protein (e.g., BCL6 protein) in the cell compared to the following concentrations: the cell is exposed to a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2)))) The concentration of the protein before exposure to compounds of formula (I), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)), or before exposure to compounds of formula (I), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)). The concentration of the protein in cells not exposed to compounds of formula (I) (e.g., formula (I-1), (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)). Lower DC 50 Compounds with values ​​(as determined under substantially similar conditions) and those with higher DC values 50Compared to compounds with similar values, DC is a more effective degradation inducer. In some embodiments, DC... 50 The value can be determined in vitro or in vivo (e.g., using HiBiT assay) (e.g., in tumor cells (e.g., cell lines such as A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2); see also those disclosed below: e.g. Cardenas, Mariano G. et al. Clinical Cancer Research 23.4(2017):885-893, and International Publication No. WO 2021 / 080950, WO In WO 2021 / 077010 and WO 2022 / 221673, these tumor cells express the BCL6 protein. In some embodiments, cell lines that are BCL6-independent and / or do not significantly express BCL6 (e.g., Toledo, H929, MM.1S, or OPM2) may be used as controls.

[0606] The degradation efficacy of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or their pharmaceutically acceptable salts, as provided herein, can be determined by EC. 50 The value is determined. As used in this article, EC 50This refers to the concentration of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) that results in a 50% reduction in the concentration of a protein (e.g., BCL6 protein) in the cell relative to the trough concentration of that protein when the cell is exposed to a concentration having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1)), or formula (Ib) (e.g., formula (Ia-1)), or formula (Ib-2)))) of a protein having formula (I-1), or formula (Ia) (e.g., formula (Ia-1)), or formula (Ib-2)) of a protein having formula (I-1 ... The concentration of the protein before exposure to compounds of formula (I), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)), or the concentration of the protein in cells not exposed to compounds of formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)). Having a lower EC 50 Compounds with values ​​(as determined under substantially similar conditions) and those with higher EC values 50 Compared to compounds with similar values, EC is a more effective degradation inducer. In some embodiments, EC 50 The value can be determined in vitro or in vivo (e.g., using HiBiT detection) (e.g., in tumor cells (e.g., cell lines such as A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2); see also those disclosed below: e.g. Cardenas, Mariano G. et al. Clinical Cancer Research 23.4 (2017): 885-893, and International Publication No. WO In WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673, these tumor cells express the BCL6 protein. In some embodiments, cell lines that are BCL6-independent and / or do not significantly express BCL6 (e.g., Toledo, H929, MM.1S, or OPM2) may be used as controls.

[0607] The degradation efficacy of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or their pharmaceutically acceptable salts, as provided herein, can be determined by Y. min The value is determined. As used in this article, Y min This refers to the ratio, expressed as a percentage, of the trough concentration of a protein (e.g., BCL6 protein) in a cell to the concentration of that protein before the cell was exposed to a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)), or to the concentration of that protein in a cell that was not exposed to a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)). max It is 1-Y min Y min Measurements can be made using HiBiT assays (as described in Example B1). It has a lower Y... min Compounds with values ​​(as determined under substantially similar conditions) and those with higher Y values min Compared to compounds with similar values, Y is a more effective degradation inducer. In some embodiments, Y minThe value can be determined in vitro or in vivo (e.g., using HiBiT assay) (e.g., in tumor cells (e.g., cell lines such as A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL, or WSU-DLCL2); see also those disclosed below: e.g. Cardenas, Mariano G. et al. Clinical Cancer Research 23.4(2017):885-893, and International Publication No. WO 2021 / 080950, WO In WO 2021 / 077010 and WO 2022 / 221673, these tumor cells express the BCL6 protein. In some embodiments, cell lines that are BCL6-independent and / or do not significantly express BCL6 (e.g., Toledo, H929, MM.1S, or OPM2) may be used as controls.

[0608] In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or pharmaceutically acceptable salts thereof exhibit less than 70% (e.g., less than 50% or less than 30%) of Y in a HiBiT-based degradation assay (e.g., an assay as described in Example B1). min In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof exhibit less than 50% (e.g., less than 30%) of Y in HiBiT-based degradation assays. minIn some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof exhibit less than 30% Y in HiBiT-based degradation assays. min .

[0609] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof exhibits less than 70% (e.g., less than 50% or less than 30%) of Y in the assay described in Example B1. min In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof exhibits less than 50% (e.g., less than 30%) of Y in the assay described in Example B1. min In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof exhibit less than 30% Y in the assay described in Example B1. min .

[0610] In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof exhibit about 0% to about 70% (e.g., about 0% to about 50%, about 30% to about 50%, or about 0% to about 30%) of Y in a HiBiT-based degradation assay (e.g., an assay as described in Example B1). minIn some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof exhibit about 0% to about 50% (e.g., about 30% to about 50% or about 0% to about 30%) of Y in a HiBiT-based degradation assay. min In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof exhibit about 0% to about 30% γ in HiBiT-based degradation assays. min .

[0611] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) 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. min In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof exhibits about 0% to about 50% (e.g., about 30% to about 50% or about 0% to about 30%) of Y in the assay described in Example B1. min In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof exhibit about 0% to about 30% Y in the assay described in Example B1. min .

[0612] It should be understood that the effects of protein degradation typically increase over time, despite the presence of degradation (e.g., the percentage of degradation compared to control, or parameter Y). min DC 50 , and / or D max The degradation rate (indicated by the protein resynthesis rate) is affected. In the art, degradation is typically examined after a specified time period (e.g., 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, 5 days, 10 days, or longer). For example, degradation can be expressed as the percentage of degradation after 24 hours.

[0613] Exemplary assays for verifying the degradation-inducing mechanisms of compounds such as those presented herein are known in the art and are described, for example, in Wu et al., Nature Structural & Molecular Biology, 27.7(2020):605-614.

[0614] Degradation assays can be used to quantify the targeted and off-target degradation induction of compounds, such as those provided herein. Exemplary assays include quantitative Western blotting, other immunoassays (e.g., MesoScale Discovery (MSD) immunoassays), homogeneous time-resolved fluorescence (HTRF), and HiBiT. In some embodiments, cells may be contacted and incubated with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof, and then lysates may be prepared for gel electrophoresis (e.g., SDS-PAGE), followed by Western blotting and quantification compared to a control (e.g., a DMSO-treated control). As another example, cell lines can be engineered to express HiBiT-tagged BCL6 protein, and the observed fluorescence levels upon addition of complementary LgBiT peptides can be compared between cells treated with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof, and a control (e.g., a DMSO-treated control). See, for example, Example B1. In some embodiments, the off-target degradation induction of protein eukaryotic peptide chain releasing factor GTP-binding subunits ERF3A (GSPT1), Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and / or casein kinase I isoform α (CK1α) can be evaluated. See also, for example, International Publication Nos. WO2018 / 215798; WO 2018 / 215801; WO 2020 / 104820; McCoulll, 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.

[0615] The binding affinity of compounds of formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or their pharmaceutically acceptable salts to BCL6 can be obtained by, for example, binding IC6. 50 or K i Value (e.g., using competitive determination) or by K D The value is determined (e.g., using biophysical assays). A lower binding IC50 value indicates a lower binding affinity. 50 Compounds with values ​​(as determined under substantially similar conditions) and those having higher binding IC 50 Compared to compounds with lower binding K, it is a more effective binder. i Compounds with a value (as determined under substantially similar conditions) and a higher binding K value i Compared to compounds with lower K values, these are more effective binders. Similarly, compounds with lower K values ​​are more effective binders. D Compounds with values ​​(as determined under substantially similar conditions) and those with higher K values D Compared to compounds with similar values, they are more effective binders. For example, K D The values ​​can be determined by surface plasmon resonance (SPR) or biofilm interference techniques; see, for example, Guo, Weikai et al., Journal of Medicinal Chemistry 63.2(2020):676-695; Lloyd, Matthew G. et al., Journal of Medicinal Chemistry 64.23(2021):17079-17097, and international publications WO2019 / 153080; WO 2019 / 119144; and WO 2019 / 119145.

[0616] The ability of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or their pharmaceutically acceptable salts to inhibit BCL6 can be described using IC 50 The value is determined. It has a lower IC. 50 Compounds with values ​​(as determined under substantially similar conditions) and those with higher IC50 values ​​are compared to those with higher IC50 values. 50 Compared to compounds with similar values, these are more effective inhibitors. For example, IC50... 50The value can be calculated using FRET (e.g., homogeneous time-resolved fluorescence (HTRF)) assays, in which a labeled (e.g., His-labeled) BCL6 protein and a labeled (e.g., fluorophore-labeled (e.g., Alexa-Fluor633)) co-repressor peptide (e.g., BCOR) are incubated in the presence of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) and the FRET ratio (relative to a suitable control) can then be measured using an appropriate FRET pair (e.g., an antibody that recognizes the labeled BCL6 protein (e.g., an anti-His-terbium cavitation compound)). See, for example, international publication numbers WO 2018 / 108704; WO 2018 / 215798; WO 2019 / 197842; WO 2020 / 104820; WO 2021 / 074620. As another example, IC... 50 The value can be calculated using an enzyme-linked immunosorbent assay (ELISA) using a labeled (e.g., biotinylated) co-repressor peptide (e.g., BCOR) immobilized on a substrate and a labeled (e.g., FLAG-labeled) BCL6 (e.g., its domain, such as the BTB domain), wherein a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) can be used to prevent the interaction between the co-repressor peptide and BCL6, and the interaction between the co-repressor peptide and BCL6 can be measured using an antibody against the 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 value can be calculated using fluorescence polarization assays with fluorescently labeled co-repressive peptides (e.g., SMRT), where compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) can be used to prevent the interaction between the co-repressive peptide and BCL6. See, for example, International Publication No. WO 2019 / 119144. As another example, cellular IC50...50 Values ​​can be calculated using a BRET (bioluminescent resonance energy transfer) assay, in which a vector encoding BCL6 and a co-repressor peptide (e.g., SMRT) (which is complementary to NanoLuc or HaloTag) is inserted into cells. Cells can be treated with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof to determine the effect of the compound in inhibiting the BCL6-co-repressor interaction. See, for example, International Publications WO 2018 / 215798 and WO 2019 / 197842. In another example, the IC50 value for inhibiting BCL6 repressor function is... 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 can be incubated with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof to determine the effect of the compound on BCL6 repressor function. See, for example, International Publications WO 2019 / 119144; WO 2019 / 119145; WO 2019 / 153080.

[0617] Another exemplary approach to assessing the effects of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or their pharmaceutically acceptable salts is to measure the induction (e.g., fold induction) of genes typically repressed by BCL6 (e.g., p53, ATR, CXCR3, CD69, and CDKN1A) using methods such as RT-PCR. See, for example, Guo, Weikai et al., Journal of Medicinal Chemistry 63.2(2020):676-695.

[0618] Exemplary potency assays for determining the effects of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) on cell proliferation and / or viability include measuring the effect of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) on cell proliferation and / or viability. Cell proliferation assays can be performed in various forms, 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, cell lines that are BCL6-independent and / or do not significantly express BCL6 (e.g., Toledo, H929, MM.1S, or OPM2) can be used as controls. As an exemplary example, a 3D cell proliferation assay may include growing cells in a 3D culture medium, contacting the cells with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, using appropriate reagents (e.g., 3D) Cell proliferation is measured, and then the signal from an experiment using a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is compared with the signal from a control experiment (e.g., lack of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof). As another exemplary example, a 2D cell proliferation assay may include seeding cells onto a growth surface, optionally allowing the cells to grow for a period of time, contacting the cells with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, using appropriate reagents (e.g., Cell proliferation is measured, and then the signal from an experiment using a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is compared with the signal from a control experiment (e.g., lack of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof). Other cell viability assays include the MTT assay, which is a colorimetric determination based on the reduction of the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to insoluble purple formazan, and other similar assays based on related tetrazolium salts, ATPlite assays, and other methods known in the art. See, for example, Example B2. See also, for example, Guo, Weikai et al., Journal of Medicinal Chemistry 63.2(2020):676-695; McCoulll, William et al., ACS Chemical Biology 13.11(2018):3131-3141; Lloyd, Matthew G. et al., Journal of Medicinal Chemistry 64.23(2021):17079-17097; Bellenie, Benjamin R. et al., Journal of Medicinal Chemistry 63.8(2020):4047-4068; and international publication numbers WO 2018 / 215798; WO 2018 / 215801; WO 2018 / 219281; WO 2019 / 119145; WO 2019 / 153080; and WO 2020 / 104820.

[0619] Cell viability assays can be used to measure the effect of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) on cell death, or their pharmaceutically acceptable salts. For example, this can be used to measure the effect of compounds expressing the BCL6 protein (e.g., A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas) on cell death. 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL or WSU-DLCL2 cells) are incubated with various concentrations of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or their pharmaceutically acceptable salts, and then exposed to a detection reagent (e.g., using a celliter). A cell viability assay kit is used to determine cell viability. In some embodiments, the effect on cell viability can be compared with cell lines that are independent of BCL6 and / or do not significantly express BCL6 (which may be used as controls, such as Toledo, H929, MM.1S, or OPM2).

[0620] Cell viability assays can be used to measure the effect of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof on cell death in combination with additional therapeutic agents. For example, cells expressing the BCL6 protein (e.g., A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas) can be used. 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI1, RL, SU-DHL-4, SU-DHL-5, SU-DHL-6, SU-DHL-8, SU-DHL-10, VAL or WSU-DLCL2 cells) in a 7x7 dose matrix at various concentrations with formula (I) (e.g., formula (I-1), formula (Ia)). Compounds of formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)), or pharmaceutically acceptable salts thereof, and other therapeutic agents (e.g., any of the other therapeutic agents described herein) (e.g., half-log dilution from 316 nM to 1 nM) are incubated (e.g., for 72 or 120 hours) and then exposed to a detection reagent (e.g., using a CELLTITER- Cell viability assay kits are used to determine cell viability. Combination activity can be assessed using a Bliss-independent model, where negative values ​​indicate antagonistic effects, positive values ​​indicate synergistic effects, and zero values ​​indicate additive effects. Bliss scores from the dose matrix can be added to derive a “Bliss sum” value, reflecting the total synergistic activity of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or their pharmaceutically acceptable salts, along with additional therapeutic agents, in each cell line. In some embodiments, cell lines that are BCL6-independent and / or do not significantly express BCL6 (e.g., Toledo, H929, MM.1S, or OPM2) can be used as controls.

[0621] As another example, the potency and / or efficacy of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or their pharmaceutically acceptable salts can be evaluated in animal models, such as cell line-derived (CDX) xenograft models (e.g., using established cancer cell lines such as DB, DoHH2, OCI-Ly1, OCI-Ly7, RL, Pfeiffer, SU-DHL-5, SU- DHL-6, WSU-DLCL2, REH, BALL-1, RS4;11, SEMK2, KOPN8, NALM-6, KASUMI-2, RCH-ACV, SUP-B15, BV-173, TOM-1, NALM-20, NALM-21, MUTZ-5, or MHH-CALL-4 (e.g., OCI-Ly1, OCI-Ly7, SU-DHL-5, SU-DHL-6, WSU-DLCL2, DB, RL, Pfeiffer, or DoHH2), genetically engineered mouse models (GEMM), or patient-derived xenograft (PDX) models. For example, PDX models can be developed in immunodeficient mice (e.g., athymic nude mice, outcrossed homozygous mice (e.g., Cr1:NU(NCr)-Foxn1)). nu ) or FoxChase SCID(CB17 / Icr-Prkdc scid The procedure was performed in mice (IcrIcoCrl). Mice could be female, 6-12 weeks old at the time of tumor implantation, and had free access to food and water. Approximately 70 mg of tumor was subcutaneously implanted into the right flank of each mouse. After implantation, the tumor was measured weekly, and once the tumor volume reached 150-300 mm², it was monitored. 3 Mice can be randomly assigned to treatment and control groups. In some embodiments, one or more experimental groups may be added to evaluate pharmacokinetics and / or pharmacodynamics. Mice can be treated with compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or pharmaceutically acceptable salts thereof (e.g., administered via IP or PO) and optionally additional therapies or therapeutic agents (e.g., any other therapies or therapeutic agents described herein). Throughout the study, the health status, weight, and tumor volume of the mice can be recorded weekly. Mice can be treated on day 28 or when the tumor reaches 1 cm. 3Animals were sacrificed at the appropriate time, and tumors could be assessed (e.g., by tumor weight, tumor volume). At the end of each study, the optimal response for each treatment group could be calculated. The optimal response was defined as the Δvolume over t ≥ 10 days. tThe minimum value. The best response can be compared between the control and treatment groups to determine if the treatment group is better than the control group. In some embodiments, tumor samples can also be collected at the end of each study, and relevant proteins (e.g., BCL6) can be measured to determine if the treatment has better protein regulatory properties compared to the control. In some embodiments, tumor samples and / or blood samples can also be collected at the end of each study, and altered gene expression activities (e.g., altered ARID3A, ARID3B, ATR, B2M, BANK1, BATF, BCL11A, BCL2, BCL2A1, BLIMP1, BML1, CASP8, CCND1, CCND2, CCR6, CCR7, CD38, CD44, CD69, CDKN1A, CDKN1B, CFLAR / FLIP, CHEK1, CXCR4, CXCR5, DR5, EBI2, ETV6, FCMR, FGD4, ID2, IFITM1, IF) can be analyzed. Expression levels of ITM2, IFNAR2, IFNGR1, IL10, IL10RB, IL7R, CXCL10, IRF1, IRF4, IRF7, IRF9, JAK3, JARID2, JUN, KLF2, LITAF, MCL1, MIP-1a, MYC, MYD88, NFKBIE, NOTCH2, PDL1, PIM1, PPP3R1, PRDM1, PTEN, S1PR1, SHP1, STAT1, STAT3, STAT5A, TLR1, TLR4, TLR7, TLR9, TNF-R2, TOX, TP53, ZEB2, and / or ZNF608. For pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples from mice can be obtained at the same or different time points as in efficacy studies. For example, for pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples from mice can be obtained on days 1, 3, and / or 5 (where samples are collected at 6, 12, and / or 24 hours after administration), relevant proteins in the tumor samples can be measured, 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 MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion), DLBCL, FL, MCL, Burkitt lymphoma, or peripheral T-cell lymphoma (PTCL) (e.g., PTCL with T-follicle helper phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or nonspecific PTCL (PTCL-NOS)).See, for example, Guo, Weikai et al., Journal of Medicinal Chemistry 63.2(2020):676-695.

[0622] In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof exhibit activity in models of autoimmune diseases. Exemplary assays can be found, for example, in International Publications WO 2020 / 014599 and WO 2021 / 074620.

[0623] In some embodiments, the ability of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or pharmaceutically acceptable salts thereof to regulate (e.g., reduce) IgG antibody production and / or regulate (e.g., reduce) germinal center formation in animals (e.g., mice) stimulated with T cell-dependent antigens (e.g., keyhole hemocyanin (KLH)) can be evaluated. For example, KLH can be administered to mice (e.g., C57BL / 6 mice), followed by administration of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 14 days). After sacrifice, KLH-specific IgG in mouse serum samples can be analyzed, for example, by ELISA. Similarly, immunohistochemical staining can be used to detect germinal centers using, for example, peanut agglutinin (PNA). See, for example, Example 1 of WO 2020 / 014599.

[0624] In some embodiments, the ability of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or pharmaceutically acceptable salts thereof to regulate (e.g., reduce) the number of germinal center B cells in animals (e.g., mice) immunized with an antigen can be evaluated. For example, animals (e.g., mice) can be immunized with a complete Freund's adjuvant (CFA), and after a period of time (e.g., 8 days), the animals can be sacrificed and the spleen harvested. The spleen can be processed into a suspension and cultured in the presence of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. The cells can then be analyzed, for example, to determine the number of germinal center B cells (e.g., by flow cytometry, using lineage markers GL7 and CD95). See, for example, WO 2021 / 074620.

[0625] In some embodiments, the ability of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof to improve one or more symptoms, biomarkers, or other signs of autoimmune diseases in animal models of autoimmune diseases may be evaluated.

[0626] Experimental autoimmune encephalitis (EAE) can be used as an animal model of CNS inflammatory diseases, including multiple sclerosis (MS) and neuromyelitis optica. In some cases, EAE can be induced in animals (e.g., mice), for example, via recombinant human myelin oligodendrocyte glycoprotein (MOG) or fragments thereof (e.g., MOG). 1-125Immunization with myelin basic proteins and / or proteolipoproteins. After EAE induction, animals can be treated with compounds of formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof. Animals can be assessed, for example, by the severity of EAE, B-cell exhaustion, or both. See, for example, Constantinescu, Cris S. et al., British Journal of Pharmacology 164.4 (2011):1079-1106; Monson, Nancy L. et al., PloS One 6.2 (2011):e17103.

[0627] In some embodiments, the autoimmune disease is antisynergistic syndrome. For example, a model of antisynergistic syndrome can be induced in susceptible mice (e.g., C57BL / 6, B6.G7, and / or NOD.Idd3 / 5) by immunization with histyl-tRNA synthetase (e.g., mouse histyl-tRNA synthetase or human histyl-tRNA synthetase) or fragments thereof. Treatment with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof can be initiated at the time of immunization and continued for a period of time (e.g., short-term (e.g., 10-14 days) or long-term (e.g., 8-16 weeks)), after which the mice can be sacrificed. For example, the production of histyl-tRNA synthetase-specific antibodies in mice (e.g., via immunoprecipitation, ELISA, and / or flow cytometry), tissue (e.g., lung and / or muscle) inflammation (e.g., by pathologist review), or a combination thereof, can be assessed. See, for example, 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.

[0628] In some embodiments, the autoimmune disease is arthritis (e.g., rheumatoid arthritis or inflammatory arthritis). For example, a mouse model of rheumatoid arthritis (i.e., collagen-induced arthritis (CIA)) can be induced in susceptible mice (e.g., DBA / 1 or HLA-DR) by immunization with type II collagen (CII). Treatment with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof can be initiated at the time of immunization and continued for a period of time (e.g., 6 weeks). For example, clinical scores in mice (e.g., inflammation of the arthritic limb, foot thickness, paw volume (e.g., using a foot edema meter) or combinations thereof), production of CII-specific antibodies, B-cell depletion, or combinations thereof can be assessed. See, for example, Example 2 of WO 2020 / 014599; Brand, David D. et al. Nature Protocols 2.5 (2007): 1269-1275. Other animal models of arthritis (e.g., inflammatory arthritis) are known in the art, such as K / BxN mice. In some embodiments, such mice may be treated with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, and evaluated, for example, in a manner similar to that of CII-immunized mice, or additionally titered against autoantibodies (e.g., autoantibodies against glucose-6-phosphate isomerase). See, for example, Huang, Haochu, Christophe Benoist, and Diane Mathis. Proceedings of the National Academy of Sciences 107.10 (2010):4658-4663; and Pigott, Elizabeth, and Laura Mandik-Nayak. Arthritis & Rheumatism 64.7 (2012):2169-2178.

[0629] In some embodiments, the autoimmune disease is graft-versus-host disease (e.g., chronic graft-versus-host disease). In some cases, an animal model of graft-versus-host disease may be an animal (e.g., a mouse) treated with high doses of cyclophosphamide and lethal total body irradiation (TBI) and rescued with bone marrow (optionally including allogeneic spleen cells or purified T cells). Subsequently, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof may be administered for a period of time. The animal may be evaluated by, for example, pulmonary function tests, by assessing the presence of autoantibodies by immunohistochemistry, or by examining germinal centers in spleen sections (including, for example, examining B cell depletion (e.g., germinal center B cell depletion)). See, for example, Srinivasan, Mathangi et al., Blood, The Journal of the American Society of Hematology, 119.6 (2012):1570-1580; and Paz, Katelyn et al., Blood, The Journal of the American Society of Hematology, 133.1 (2019):94-99. Also see, for example, Dubovsky, Jason A. et al., The Journal of Clinical Investigation, 124.11 (2014):4867-4876.

[0630] In some embodiments, the autoimmune disease is IgG4-related disease (IgG4-RD). In some cases, an IgG4-RD animal model can be generated by injecting mice with IgG (e.g., IgG1 and / or IgG4) derived from patients with human IgG4-RD. Such mice can be treated with compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof. Animals can be evaluated by measuring, for example, pancreatic and / or salivary tissue damage, B-cell depletion, or both. See, for example, Shiokawa, Masahiro et al., Gut [Enter] 65.8 (2016):1322-1332.

[0631] In some embodiments, the autoimmune disease is lupus (e.g., systemic lupus erythematosus). In some cases, the lupus animal model is the MRL / lpr mouse, which may exhibit high expression of Tfh-related molecules (such as ICOS, PD-1, BCL-6, and IL-21) and produce autoantibodies against nuclear components, leading to nephritis, arthritis, and skin lesions. Such mice can be treated with compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or pharmaceutically acceptable salts thereof. Animals can be assessed by, for example, measuring B cell exhaustion (e.g., germinal center B cell exhaustion), identifying the presence and / or severity of glomerulonephritis, autoantibody titers (e.g., anti-RNA antibody titers, antinuclear antibody titers, and / or anti-dsDNA antibody titers), IL-21 expression, and / or the amount of activated CD4+ T cells. See, for example, Ahuja, Anupama et al., The Journal of Immunology 179.5(2007):3351-3361; 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. Other lupus animal models are known in the art, such as NZB / W mice, which can be treated with compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, and evaluated in a manner similar to that of 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.

[0632] 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, mouse, or rabbit model) can be generated by immunizing animals with an acetylcholine receptor (from the electric organ of a Torpedo species such as Torpedo californica, or an Electrophorus species such as Electrophorus electricus), or a recombinant acetylcholine receptor protein or a fragment thereof. Treatment with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof can be initiated, for example, about 4 weeks after immunization, but sometimes earlier or later. Rodents can be assessed based on clinical scores (e.g., grasping and / or lifting heavy objects while observing tremors, kyphosis, muscle strength, and signs of fatigue), body weight, complex muscle action potentials (e.g., using electromyography), anti-acetylcholine receptor antibodies, B cell exhaustion, or a combination thereof. See, for example, 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.

[0633] In some embodiments, the autoimmune disease is multiple sclerosis (MS). In some embodiments, MS is clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), or secondary progressive MS (SPMS). In some embodiments, the animal model of MS may be based on effusive encephalopathy (EAE), such as relapsing-remitting EAE in SJL / J mice (e.g., via protein lipoprotein (PLP)). 139-151 (Immunization), chronic EAE in C57BL / 6J mice (e.g., via MOG) 35-55 Immunization) or EAEs in transgenic mice (e.g., via expression of MOG) 35-55T cell clones with specifically responding Vα and Vβ chains, or B cell heavy chain knock-in mice. In some embodiments, animal (e.g., mouse) models are generated via infection with a microRNA virus (e.g., Theiler mouse encephalitis virus). In some embodiments, animal (e.g., mouse) models are generated by feeding C57BL / 6 mice with cuprizone (e.g., 0.2% for 6 weeks). In some embodiments, animal (e.g., mouse) models (e.g., in SJL / J mice) are generated via lysophosphatidylcholine injection. Treatment with compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof in animals can, for example, allow analysis of myelin-specific T cell levels, B cell depletion, reduction of inflammatory lesions, axonal degeneration, protection or reversal of dicyclohexanone oxaloyl dihydrazone or lysophosphatidylcholine-induced demyelination, or combinations thereof. See, for example, Procaccini, Claudio et al., European Journal of Pharmacology 759(2015):182-191.

[0634] In some embodiments, the autoimmune disease is neuromyelitis optica (NMO). In some cases, NMO animal models involve the administration of an antibody (referred to as AQP4-IgG or NMO-IgG) targeting astrocyte aquaporin 4 (AQP4) to various CNS tissues, such as the brain. In some embodiments, the antibody is administered to animals suffering from EAE. AQP4-IgG may be recombinant or derived from human NMO patients. After treatment with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, the slowing or reversal of astrocyte demyelination, the number of macrophages, the number of activated microglia, the number of activated neutrophils, B cell depletion, or combinations thereof, in euthanized animals can be analyzed, for example. See, for example, Bennett, Jeffrey L. et al., Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 66.5 (2009):617-629; 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.

[0635] In some embodiments, the autoimmune disease is pemphigus (e.g., pemphigus vulgaris). In some cases, an animal model of pemphigus (e.g., a mouse) can be generated by adoptively transferring peripheral lymphocytes from a Dsg3 knockout animal to an immunodeficient recipient mouse expressing desmosome mucin 3 to establish an artificial immune state in the recipient animal. In some cases, an animal model of pemphigus (e.g., a mouse) with a background of MHC class II gene deficiency can be generated using animals expressing the pemphigus-associated HLA-DRB1*0402 allele, which produce anti-human DSG3 antibodies after immunization with recombinant human DSG3. After treating these models with compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, the anti-desmoomin B cell clones, B cell depletion, or both of the animal's B cell repertoire can be analyzed, for example. See, for example, Kasperkiewicz, Michael et al., Nature Reviews Disease Primers 3.1 (2017):1-18.

[0636] In some embodiments, the autoimmune disease is Sjögren's syndrome. In some cases, the animal model of Sjögren's syndrome is the NOD mouse, which is sometimes further genetically manipulated or hybridized (e.g., NOD.B10.H2). bOr C57BL / 6.NOTDc3.NODc1t) to reproduce the symptoms of the syndrome. Such mice can be treated with compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof. For example, the salivary and lacrimal gland secretion flow rate, salivary protein content, autoantibodies against exocrine gland proteins (e.g., anti-Sjögren's syndrome A (SSA) antibodies, anti-Sjögren's syndrome B (SSB) antibodies, and / or anti-muscarinic acetylcholine 3 receptor (M3R) antibodies), B cell depletion, or combinations thereof, can be evaluated in animals. 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. Other animal models of Sjögren's syndrome are known in the art and include, for example, NFS / sld mice, IQI / Jic mice, Aly / aly mice, and mice immunized with M3R peptides, in some cases of which the same parameters can be evaluated as in 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.

[0637] Pharmacokinetic parameters of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or their pharmaceutically acceptable salts can be evaluated in animal models (e.g., male CD-1 mice). Pharmacokinetic (PK) studies can be conducted in animal models (e.g., male CD-1 mice) via two exemplary delivery routes: intravenous (IV) injection and oral (PO), such as oral tube feeding. Animals in the IV group (e.g., n=3) have free access to food and water; animals in the PO group have free access to food or are fasted for 6–8 hours prior to administration. Compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof can be formulated into solutions or suspensions for use in the IV route and for use in the PO route. On the day of the experiment, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof may be administered via intravenous injection (e.g., 1 mg / kg) via IV route or oral tube feeding (e.g., 3 to 90 mg / kg, or 3 to 10 mg / kg, such as 10 mg / kg) via PO route. In some cases, animals may be pre-administered orally with a cytochrome P450 inhibitor (e.g., 16 hours prior to administration of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof. Blood samples may be collected by continuous blood collection (e.g., at eight time points from 0.83 to 24 hours after administration). At each time point, blood (e.g., about 30 μL to about 125 μL, or about 75 μL to about 125 μL) may be collected (e.g., via the saphenous vein) into a tube containing an anticoagulant (e.g., K2EDTA). Blood samples can be placed on wet ice and centrifuged (e.g., 2000x g, 4–10 minutes) to obtain plasma samples.Plasma samples can be diluted (e.g., with an equal volume of pH 3.0 phosphate buffer or an equal volume of pH 5.0 sodium citrate) and submitted to LC-MS / MS for sample analysis. Pharmacokinetic parameters (including clearance (CL) and volume of distribution (V)) can be analyzed. d ), highest plasma concentration (C max ), time to maximum plasma concentration (t) max )), half-life (t) 1 / 2 The area under the curve (AUC) and oral bioavailability (%F) can be calculated using a non-compartmental model.

[0638] In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is at least 4%. In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is at least 10%. In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is at least 20%. In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is at least 30%. In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is at least 40%. In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is at least 60%. In some embodiments, the percentage of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is at least 80%.In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is about 4% to about 90% (e.g., about 4% to about 80%, about 4% to about 60%, about 4% to about 40%, about 4% to about 20%, about 4% to about 10%, about 20% to about 40%, about 40% to about 60%, about 60% to about 80%, or about 70% to about 90%). In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is from about 4% to about 20%. In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is from about 20% to about 40%. In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is about 40% to about 60%. In some embodiments, the %F of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is about 50% to about 80%.

[0639] In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof are not substrates of human cytochrome P450 enzymes. In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof are not substrates of human cytochrome P450 enzymes, wherein ≥25% clearance is attributed to the enzyme. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) 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 having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is not an inhibitor and / or inducer of one or more human cytochrome P450 enzymes, wherein for one or more human cytochrome P450 enzymes, IC 50 and / or EC 50 The concentrations were significantly higher than the estimated free fraction concentrations of compounds of formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) at clinically relevant doses, or of their pharmaceutically acceptable salts.

[0640] Exemplary human cytochrome P450 enzymes include those from the CYP1, CYP2, and CYP3 families. For example, any one 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 is responsible for the elimination of greater than or equal to 25% of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. Cytochrome P450 inhibitory and / or inducing activities can be determined using any appropriate assay, such as those described in the guidance document “In VitroDrug Interaction Studies—Cytochrome P450 Enzyme-and Transporter-Mediated Drug Interactions” provided by the U.S. Food and Drug Administration in January 2020. For example, cytochrome P450 inhibition can be assessed in a reversible and time-dependent manner in in vitro studies. In in vitro inhibition studies, the ratio of the intrinsic clearance value of the probe substrate for the enzyme pathway in the absence and presence of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof can be calculated; for reversible inhibition, this ratio is called R1, where R1 = 1 + (Ia-1) / (Ib-2) / (Ib ...1) / (Ib-1) / (Ib-1) / (Ib-1) / (Ib-1) / (Ib-1) / (Ib-1) / (Ib-1) / max,u / K i,u And I max,u It is the maximum unbound plasma concentration of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, and K i,u This is the in vivo determined unbound inhibition constant. Specifically, for CYP3A, R can be calculated. 1,gut , where R 1,gut=1+(I gut +K i,u And among them I gut The intestinal lumen concentration of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, calculated in dose / 250 mL. The time-dependent inhibition rate R² can be calculated similarly, where R² = (k obs +k deg ) / k deg And kobs (through k) obs =(k inact *50*I max,u ) / (K I,u +50*I max,u The calculation represents the observed (apparent first-order) inactivation rate of affected cytochrome P450, k. deg K is the apparent first-order degradation rate constant of the affected cytochrome P450. I,u The unbound concentration of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof that causes half-maximal inactivation, and k inact This is the maximum inactivation rate constant. If R1 ≥ 1.02, R2 ≥ 1.25, and / or R... 1,gutIf the value is ≥11, then a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof may be an inhibitor of cytochrome P450, and the potential for drug-drug interaction (DDI) may be further explored using mechanical models and / or clinical DDI studies with sensitivity index substrates. For example, cytochrome P450 induction can be assessed via a fold change method, wherein the fold change in cytochrome P450 enzyme mRNA levels is calibrated by using a cutoff value determined from known positive and negative controls when incubated with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. For example, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is interpreted as an inducer if: (1) it increases the mRNA expression of cytochrome P450 enzymes in a concentration-dependent manner; and (2) at the expected hepatic drug concentration, the fold change in cytochrome P450 mRNA expression relative to the mediator control is ≥2-fold. As another example, cytochrome P450 induction can be assessed by a correlation method, where the correlation method is used to assess relative induction scores (RIS) or I based on a set of known inducers of the same cytochrome P450. max,u / EC 50The calibration curve predicts the magnitude of the clinical induction effect (e.g., the AUC ratio of the index substrate in the presence and absence of an inducer) of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. If the predicted magnitude is greater than a predefined cutoff value (e.g., AUC ratio ≤ 0.8), then a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is considered to have in vivo induction potential.

[0641] In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof are not hERG inhibitors. In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof inhibit the IC50 of hERG. 50 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). For example, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or their pharmaceutically acceptable salts inhibiting the IC50 of hERG. 50Greater than 500 nM (e.g., 1 μM, 3 μM, 5 μM, 10 μM, 20 μM, or 30 μM). In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof inhibits the IC50 of hERG. 50 Greater than 1 μM (e.g., greater than 3 μM, 5 μM, 10 μM, 20 μM, or 30 μM). In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof inhibits the IC50 of hERG. 50 Greater than 10 μM (e.g., greater than 20 μM or 30 μM). In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or their pharmaceutically acceptable salts inhibit the IC50 of hERG. 50 Greater than 30 μM.

[0642] In some cases, heterobifunctional degraders can induce the degradation of off-target proteins. Common off-target proteins that can be degraded by heterobifunctional degraders utilizing CRBN include GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α. This degradation is generally thought to be due to the E3 binding moiety of the heterobifunctional degrader promoting the formation of a ternary complex between the off-target protein and CRBN. GSPT1 is a translation termination factor, and CK1α is a kinase involved in many key cellular processes, including cell cycle progression and chromosome segregation; these are normally essential genes, so undesirable degradation of one or both can lead to nonspecific cytotoxicity. IKZF proteins are zinc finger transcription factors involved in cell fate during hematopoiesis, and degradation of these proteins is associated with hematologic toxicity. See, for example, Moreau, Kevin et al., British Journal of Pharmacology 177.8(2020):1709-1718.

[0643] In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof can exhibit effective and selective induction of BCL6 protein degradation. In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may selectively target the degradation of the BCL6 protein, rather than a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP (cathelicidin antimicrobial peptide), CCNA2 (cyclin-A2), FSP1 (ferroptosis inhibitor 1, also known as AIFM2), JCHAIN ​​(immunoglobulin J chain), NLRP7 (NACHT, LRR, protein 7 containing the PYD domain), PTTG1 (isolation enzyme inhibitor) and / or TPX2 (target protein of Xklp2)). CAMP is an antimicrobial protein, a component of the innate immune system, and binds to bacterial lipopolysaccharide. CCNA2 controls the G1 / S and G2 / M transition phases of the cell cycle. FSP1 is a redox enzyme that inhibits ferroptosis. JCHAIN ​​links two monomeric units of IgM or IgA; the J-chain-linked dimer is the nucleation unit of the IgM pentamer, while the J-chain-linked dimer of IgA induces dimers or larger polymers. NLRP7 inhibits CASP1 / cysteine-1-dependent IL1B secretion. PTTG1 is key to chromosome stability and negatively regulates TP53. TPX2 is essential for the normal assembly of the mitotic spindle.

[0644] As used herein, in protein degradation assays, when referring to a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, “selectively” or “selectively” means that in a protein degradation assay, the specified protein performs at least 5-fold better (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) compared to a comparison protein in the assay.

[0645] In some embodiments, the compounds provided herein may exhibit potency (e.g., nanomolar potency) against the BCL6 protein, while exhibiting 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, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or pharmaceutically acceptable salts thereof may exhibit potent degradation of the BCL6 protein and, in the degradation (e.g., as by Y... min DC 50 , and / or D max The value is measured to indicate the least potency among the second proteins (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2). In some embodiments, the potency is determined relative to the degradation induction (e.g., as by Y) of the second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2). min DC 50 , and / or D maxCompounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit greater induction of BCL6 protein degradation. In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold BCL6 protein degradation induction relative to the degradation induction of the second protein. In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof can exhibit BCL6 protein degradation induction up to 1000-fold relative to the degradation induction of the second protein. In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or pharmaceutically acceptable salts thereof may exhibit degradation-inducing effects relative to a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as by Y min DC 50 , and / or D maxThe BCL6 protein degradation was induced by approximately 2 to 10 times the measured value. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof may exhibit a BCL6 protein degradation induction of approximately 10 to 100 times relative to the degradation induction of the second protein. In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit BCL6 protein degradation induction of about 100-fold to about 1000-fold relative to the degradation induction of the second protein. In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit BCL6 protein degradation induction of about 1000-fold to about 10000-fold relative to the degradation induction of the second protein. In some embodiments, the second protein is selected from the group consisting of: GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and TPX2. In some embodiments, the second protein is selected from the group consisting of: GSPT1, IKZF1, IKZF2, IKZF3, and CK1α. In some embodiments, the second protein is selected from the group consisting of: C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and TPX2. In some embodiments, the second protein is C6orf132. In some embodiments, the second protein is CAMP. In some embodiments, the second protein is CCNA2. In some embodiments, the second protein is FSP1. In some embodiments, the second protein is JCHAIN. In some embodiments, the second protein is NLRP7. In some embodiments, the second protein is PTTG1. In some embodiments, the second protein is TPX2.

[0646] In some embodiments, the compounds provided herein may exhibit potency against the BCL6 protein, having similar activity to that against a second protein (i.e., the activity against the BCL6 protein is less than twice that against the second protein, and the activity against the second protein is no more than twice that against the BCL6 protein). In some embodiments, relative to degradation induction (e.g., by means of Y) against a second protein (e.g., GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2), min DC 50 , and / or D maxCompounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or pharmaceutically acceptable salts thereof may exhibit similar induction of BCL6 protein degradation (i.e., the induction of BCL6 protein degradation is less than 2-fold compared to the induction of the second protein degradation, and the activity of the second protein is no more than 2-fold compared to the activity of the BCL6 protein). In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit less than 2-fold BCL6 protein degradation induction relative to the degradation induction of the second protein. In some embodiments, the second protein is selected from the group consisting of: GSPT1, IKZF1, IKZF2, IKZF3, CK1α, C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and TPX2. In some embodiments, the second protein is selected from the group consisting of: GSPT1, IKZF1, IKZF2, IKZF3, and CK1α. In some embodiments, the second protein is selected from the group consisting of: C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and TPX2. In some embodiments, the second protein is C6orf132. In some embodiments, the second protein is CAMP. In some embodiments, the second protein is CCNA2. In some embodiments, the second protein is FSP1. In some embodiments, the second protein is JCHAIN. In some embodiments, the second protein is NLRP7. In some embodiments, the second protein is PTTG1. In some embodiments, the second protein is TPX2.

[0647] In some embodiments, the compounds provided herein may exhibit potency against the BCL6 protein while exhibiting minimal activity against a second protein (e.g., a reduction in protein abundance of <20%, as measured by proteomics assays, such as those described herein). In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit potent degradation of BCL6 protein and minimal potency (e.g., abundance measured by proteomics assays, such as by abundance measurements in proteomics assays, such as C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG, and / or TPX2) in degradation (e.g., as measured by abundance measurements in proteomics assays, such as those described herein). In some embodiments, compounds having formula (I) (e.g., abundance measurements in proteomics assays (e.g., as described herein), or pharmaceutically acceptable salts of formula (I-1), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or (Ib-1) (e.g., formula (Ib-1) or (Ib-2)) may exhibit greater induction of BCL6 protein degradation compared to degradation induction of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2). In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold BCL6 protein degradation induction relative to a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in a proteomics assay (e.g., as described herein).In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit up to 1000-fold BCL6 protein degradation induction relative to the degradation of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in proteomics assays (e.g., proteomics assays as described herein)). In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit approximately 2 to approximately 10-fold BCL6 protein degradation induction relative to the degradation induction of a second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in proteomics assays (e.g., proteomics assays as described herein)). In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit BCL6 protein degradation induction of about 10-fold to about 100-fold relative to the degradation induction of the second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in proteomics assays (e.g., proteomics assays as described herein)).In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit BCL6 protein degradation induction of about 100-fold to about 1000-fold relative to the degradation induction of the second protein (e.g., C6orf132, CAMP, CCNA2, FSP1, JCHAIN, NLRP7, PTTG1, and / or TPX2) (e.g., as measured by abundance in proteomics assays (e.g., proteomics assays 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.

[0648] In some embodiments, the compounds provided herein may exhibit potency against the BCL6 protein while exhibiting minimal activity against any other detectable protein (e.g., a reduction in protein abundance of <20%, as measured by proteomics assays, such as those described herein). In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or pharmaceutically acceptable salts thereof may exhibit potent degradation of the BCL6 protein and minimal potency against any other detectable protein (e.g., as measured by abundance in proteomics assays, such as those described herein). In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit greater induction of BCL6 protein degradation (e.g., as measured by abundance in proteomics assays (e.g., proteomics assays as described herein)) compared to degradation induction of any other detectable protein. In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold degradation induction of BCL6 protein relative to any other detectable protein (e.g., as measured by abundance in a proteomics assay (e.g., a proteomics assay as described herein)). In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit up to 1000-fold BCL6 protein degradation induction relative to any other detectable protein (e.g., as measured by abundance in proteomics assays (e.g., proteomics assays as described herein)).In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit BCL6 protein degradation induction of about 2 to about 10 times relative to any other detectable protein (e.g., as measured by abundance in proteomics assays (e.g., proteomics assays as described herein)). In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit BCL6 protein degradation induction of about 10-fold to about 100-fold relative to any other detectable protein (e.g., as measured by abundance in proteomics assays (e.g., proteomics assays as described herein)).

[0649] In some embodiments, compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof may exhibit potent degradation of the BCL6 protein and minimal potency in the degradation of one or more other proteins, as measured by abundance in proteomics assays. The following are exemplary proteomics experiments. OCI-Ly1 (DSMZ: ACC 722) cells were incubated for six hours with 100 nM of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof, or dimethyl sulfoxide (DMSO). The cells were then washed twice with phosphate-buffered saline and collected. Cells were lysed to extract total protein, and the protein was processed according to EASYPEP. TM Total protein for mass spectrometry analysis was prepared using the MS Sample Preparation Kit (Fisher Scientific). In short, the protein was reduced with dithiothreitol, alkylated with iodoacetamide, and digested with trypsin and LysC enzyme. The resulting peptides were then processed using TMTPRO according to the manufacturer's protocol. TMLabeled peptides were prepared using 18plex reagent (Feisil Scientific). The labeled peptides from each sample were mixed in equal volumes and the peptide mixture was separated by basic reversed-phase chromatography. A total of 85 fractions were combined into 18 pooled fractions. The pooled fractions were dried with Centrivap and resuspended in 5% acetonitrile and 0.1% formic acid for mass spectrometry analysis. A Vanquish Neo chromatography system (Feisil Scientific) and an Orbitrap FUSION were used. TM LUMOS TM The mass spectrometer (Feisher Technologies) quantifies peptide abundance using tandem mass spectrometry. In short, two micrograms of total peptides are loaded into a two-centimeter C8 capture column, followed by loading into a 50-centimeter C18 column. Data-dependent acquisition is performed to obtain peptide sequence and abundance information. Peptide and protein abundance are measured using PROTEOME DISCOVERER. TM Software and the Homo sapiens proteome database (TaxID 9606) were used to identify the results, and the results were filtered to FDR < 0.01. Significance thresholds were set at p < 0.001 and fold change in abundance < 50%.

[0650] This article provides a method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has not received treatment for cancer. In some embodiments, the subject has received one or more prior lines of cancer therapy.

[0651] This article also provides a method of treating cancer in a subject in need, the method comprising administering, as a monotherapy, a therapeutically effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)))) or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the subject has not received treatment for cancer. In some embodiments, the subject has received one or more prior lines of cancer therapy.

[0652] This article also provides a method of treating cancer in a subject in need, the method comprising administering a therapeutically effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy to the subject. In some embodiments, the subject has not received treatment for cancer. In some embodiments, the subject has received one or more prior lines of cancer therapy.

[0653] This document provides the use of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of cancer (e.g., any of the cancers provided herein).

[0654] This document provides the use of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines for the treatment of cancer (e.g., any of the cancers provided herein).

[0655] This document provides for the use of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of cancer (e.g., any of the cancers provided herein).

[0656] This document provides compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament. This document also provides compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament for treating cancer (e.g., any of the cancers provided herein).

[0657] This document provides compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of cancer (e.g., any of the cancers provided herein).

[0658] As used herein, cancer treatment may include treatment of primary tumors (i.e., non-metastatic cancer) (e.g., as a first, second, third, or subsequent line of therapy, including but not limited to relapsed / refractory environments), treatment of metastatic (or secondary) tumors, neoadjuvant therapy (e.g., before treatment with another therapy or treatment agent (e.g., surgery, radiation, chemotherapy, or a line of therapy), adjuvant therapy (e.g., after treatment with another therapy or treatment agent (e.g., surgery, radiation, chemotherapy, or a line of therapy)), or maintenance therapy (e.g., after a response to another therapy or treatment agent (e.g., surgery, radiation, chemotherapy, or a line of therapy)).

[0659] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat a primary tumor. In some embodiments, the subject has not received treatment for cancer. In some embodiments, the subject has received one or more lines of cancer therapy. In some embodiments, the patient has received chemotherapy, cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy) or both. In some embodiments, the patient has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R 2 R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapies, or two or more thereof. In some embodiments, the patient has received a regimen containing rituximab. In some embodiments, the patient has received a regimen containing oxtuzumab. In some embodiments, the patient has received a regimen containing motuzumab. In some embodiments, the patient has received a regimen containing icoretuzumab. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat patients who have received one or more lines of systemic cancer therapy. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat patients who have received two or more lines of systemic cancer therapy.

[0660] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat metastatic tumors. In some embodiments, the subject has not received treatment for metastatic tumors. In some embodiments, the subject has received one or more lines of secondary tumor therapy. In some embodiments, the patient has received chemotherapy, cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy) or both. In some embodiments, the patient has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R 2 R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapies, or two or more thereof. In some embodiments, the patient has received a regimen containing rituximab. In some embodiments, the patient has received a regimen containing oxtuzumab. In some embodiments, the patient has received a regimen containing motuzumab. In some embodiments, the patient has received a regimen containing icoretuzumab. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat patients who have received one or more lines of systemic cancer therapy. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat patients who have received two or more lines of systemic cancer therapy.

[0661] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used as a neoadjuvant therapy. In some embodiments, the neoadjuvant therapy precedes surgery (e.g., surgical resection, such as partial or complete, total, or all surgical resection). In some embodiments, the neoadjuvant therapy precedes radiotherapy. In some embodiments, the neoadjuvant therapy precedes chemotherapy.

[0662] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is an adjunctive therapy. In some embodiments, the patient has received chemotherapy, cell-based therapies (e.g., adoptive cell therapies (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapies) or both. In some embodiments, the patient has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R 2R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapies, or two or more thereof. In some embodiments, the patient has received a regimen containing rituximab. In some embodiments, the patient has received a regimen containing oxtuzumab. In some embodiments, the patient has received a regimen containing motuzumab. In some embodiments, the patient has received a regimen containing icoretuzumab. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat patients who have received one or more lines of systemic cancer therapy. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formulas (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat patients who have received two or more lines of systemic cancer therapy. In some embodiments, adjuvant therapy follows surgery (e.g., surgical resection, such as partial or complete, total, or all surgical resection). In some embodiments, adjuvant therapy follows radiation therapy. In some embodiments, adjuvant therapy follows chemotherapy.

[0663] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is a maintenance therapy. In some embodiments, the patient has received chemotherapy, cell-based therapies (e.g., adoptive cell therapies (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapies), stem cell transplantation, or combinations thereof. In some embodiments, the patient has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R 2R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapies, or two or more thereof. In some embodiments, the patient has received a regimen containing rituximab. In some embodiments, the patient has received a regimen containing oxtuzumab. In some embodiments, the patient has received a regimen containing motuzumab. In some embodiments, the patient has received a regimen containing icoretuzumab. In some embodiments, the patient has received stem cell transplantation. In some embodiments, the patient has received cell-based therapies (e.g., CAR-T therapy). In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat patients who have received one or more lines of systemic cancer therapy. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat patients who have received two or more lines of systemic cancer therapy.

[0664] As used herein, when referring to a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, "monotherapy" means that a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is the only therapeutic agent or the only therapy (e.g., an anticancer agent or anticancer therapy) administered to the subject during a treatment cycle (e.g., no additional targeted therapy, anticancer agent, chemotherapeutic agent, or checkpoint inhibitor is administered to the subject during a treatment cycle). Those skilled in the art will understand that monotherapy does not preclude the co-administration of medications used to treat side effects or general symptoms related to cancer or treatment, such as pain, rash, edema, photosensitivity, itching, skin discoloration, brittle hair, hair loss, brittle nails, nail cracking, nail discoloration, keratin swelling, fatigue, weight loss, malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms, including nausea, diarrhea, and loss of appetite.

[0665] As used herein, “subject has previously received one or more therapeutic agents or therapies for cancer” means that during a previous treatment cycle, the subject had previously received one or more therapeutic agents or therapies for cancer (e.g., anticancer agents or anticancer therapies) other than a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))). In some embodiments, lack of response, insufficient response, or interrupted response may be determined by the subject's physician.

[0666] As used in this article, "the subject has not received any treatment for cancer" means that the subject has not previously received one or more treatments or therapies for cancer.

[0667] For any of the solid tumors described herein, the solid tumor can be a primary tumor or a metastatic (or secondary) tumor. As used herein, a "primary" tumor is a tumor located at the site where the tumor begins to grow (i.e., the place of origin of the tumor). 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, a metastatic or secondary tumor is the same type of cancer as the primary tumor. In some embodiments, a metastatic or secondary tumor is genetically different from the primary tumor.

[0668] In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal carcinoma of the breast), cancer of the central or peripheral nervous system (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligodendroastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple neuroendocrine type I and II tumors, parathyroid cancer, pituitary tumor, thyroid cancer (e.g., papillary thyroid carcinoma)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, biliary tract cancer (e.g., bile duct cancer), colorectal cancer (e.g., colon cancer)). Cancers include: adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, liver cancer (e.g., hepatocellular carcinoma, intrahepatic biliary tract cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell carcinoma), small bowel cancer, or stomach cancer (e.g., gastric adenocarcinoma, gastric signet ring cell carcinoma)), genitourinary cancers (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., clear cell renal carcinoma, papillary renal carcinoma, chromophobe renal carcinoma), prostate cancer (e.g., prostate adenocarcinoma), testicular cancer (e.g., testicular germ cell tumor), or ureteral cancer), gynecological cancers (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer). The following cancers are considered cancers: ovarian cancer (e.g., serous ovarian cystadenocarcinoma, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, endometrioid uterine carcinoma, serous uterine carcinoma, papillary serous uterine carcinoma, endometrial carcinoma of the uterine body), or vulvar cancer), head and neck cancer (e.g., ear cancer (e.g., middle ear cancer), squamous cell carcinoma of the head and neck), nasal cavity cancer, oral cavity cancer, pharyngeal cancer (e.g., hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), hematologic malignancies (e.g., leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) (e.g., Philadelphia chromosome-positive ALL, Philadelphia chromosome-negative ALL), acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia (APL)), chronic myeloid leukemia (CML)), lymphatic cancer, etc.). Tumors (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)), non-Hodgkin lymphomas (e.g., Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), diffuse histiocytic lymphoma (DHL), follicular lymphoma (FL), intravascular large B-cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL) (e.g., PTCL with T-follicular helper phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or nonspecific PTCL (PTCL-NOS)), small lymphocytic lymphoma (SLL))), or myeloma (e.g.,Multiple myeloma, Leo-Flaumeni tumors, mesenteric cancers (e.g., omental cancer, peritoneal cancer), pleural cancers, respiratory tract cancers (e.g., laryngeal cancer, lung cancer (e.g., squamous cell carcinoma, adenocarcinoma, mesothelioma, non-small cell lung cancer (NSCLC)), tracheal cancer), sarcomas (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcomas (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancers (e.g., melanoma), thymic carcinomas (e.g., thymoma), or combinations thereof.

[0669] In some embodiments, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal carcinoma of the breast), cancer of the central or peripheral nervous system (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligodendroastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), thyroid cancer (e.g., papillary thyroid carcinoma)), eye cancer (e.g., uveal carcinoma (e.g., uveal melanoma)), gastrointestinal cancer (e.g., biliary tract cancer (e.g., bile duct cancer), colorectal cancer (e.g., colonic adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), liver cancer (e.g., hepatocellular carcinoma), pancreas Cancers including: pancreatic adenocarcinoma (e.g., gastric adenocarcinoma, gastric signet ring cell carcinoma); urogenital cancers including: bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., clear cell renal carcinoma, papillary renal carcinoma, chromophobe renal carcinoma); prostate cancer (e.g., prostate adenocarcinoma), or testicular cancer (e.g., testicular germ cell tumor); gynecological cancers including: cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma, mucinous carcinoma); ovarian cancer (e.g., serous ovarian carcinoma, ovarian serous cystadenocarcinoma); uterine cancer (e.g., uterine carcinosarcoma, uterine endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine body endometrial carcinoma); and head and neck cancers including: head and neck squamous cell carcinoma. Hematologic malignancies (e.g., leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) (e.g., B-cell lineage ALL (B-ALL), Philadelphia chromosome-positive ALL (e.g., Philadelphia chromosome-positive B-ALL), Philadelphia chromosome-negative ALL (e.g., Philadelphia chromosome-negative B-ALL)), acute myeloid leukemia (AML), chronic myeloid leukemia (CML)) or lymphomas (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)), non-Hodgkin lymphomas (e.g., Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), diffuse histiocytic lymphoma (DHS))) DHL), follicular lymphoma (FL), intravascular large B-cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL) (e.g., PTCL with T-follicular helper phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or nonspecific PTCL (PTCL-NOS)), small lymphocytic lymphoma (SLL)), respiratory tract cancers (e.g., lung cancer (e.g., squamous cell carcinoma of the lung, adenocarcinoma of the lung, mesothelioma, non-small cell lung cancer (NSCLC)), sarcomas (e.g., leiomyosarcoma, myxofibrosarcoma), skin cancers (e.g., melanoma), thymic carcinoma (e.g., thymoma), or combinations thereof.

[0670] In some embodiments, the cancer is a hematologic malignancy (e.g., lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), diffuse histiocytic lymphoma (DHL), intravascular large B-cell lymphoma (IVLBCL), peripheral T-cell lymphoma (PTCL) (e.g., PTCL with T-follicular helper phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or nonspecific PTCL (PTCL-NOS))). Small lymphocytic lymphoma (SLL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL)) or leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) (e.g., B-cell lineage ALL (B-ALL), Philadelphia chromosome-positive ALL (e.g., Philadelphia chromosome-positive B-ALL), Philadelphia chromosome-negative ALL (e.g., Philadelphia chromosome-negative B-ALL)), chronic myeloid leukemia (CML)), breast cancer, gastrointestinal cancer, brain cancer (e.g., glioblastoma) or lung cancer (e.g., NSCLC). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), nodular lymphocytic 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 lymphoblastic leukemia (ALL), or chronic myeloid leukemia (CML). In some embodiments, the cancer is a hematologic malignancy, specifically DLBCL, FL, MCL, BL, PTCL, or ALL (e.g., B-ALL). In some embodiments, the cancer is FL or DLBCL. In some embodiments, the cancer is DLBCL, FL, MCL, or ALL (e.g., B-ALL).See, 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 [Clinical Cancer Research] 23.4 (2017):885-893; Walker, Sarah R. et al., Oncogene [Oncogene] 34.9 (2015):1073-1082; International Publication Nos. WO 2021 / 080950, WO2021 / 077010, and WO 2022 / 221673.

[0671] In some embodiments, the cancer is a non-Hodgkin lymphoma (e.g., Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), diffuse histiocytic lymphoma (DHL), follicular lymphoma (FL), intravascular large B-cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL) (e.g., PTCL with a T-follicular helper phenotype (PTPCL-TFH)), or small lymphocytic lymphoma (SLL)). In some embodiments, the non-Hodgkin lymphoma is a B-cell non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is CD20 positive. In some embodiments, the non-Hodgkin lymphoma is a CD20-positive B-cell non-Hodgkin lymphoma. In some embodiments, the patient has not previously received treatment for non-Hodgkin lymphoma. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously received monotherapy with rituximab or octotuzumab or in combination with other therapies or treatment agents. In some embodiments, the patient has previously received rituximab monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously received oxtuzumab monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously used R-CHOP ( (rituximab), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) or G-CHOP ( (Obinutuzumab), cyclophosphamide, daunorubicin, vincristine, and prednisone). In some cases, the patient has previously been treated with etoposide and R-CHOP (called R-EPOCH). In some cases, the patient has previously been treated with R-CHOP in combination with lenalidomide, venetoclax, ibrutinib, acalabrutinib, obinutuzumab, polotuzumab, pembrolizumab, durvalumab, or mosunetuzumab. In some embodiments, the patient has previously been treated with cyclophosphamide, vincristine, and prednisone (CVP) (with or without rituximab or obinutuzumab). In some embodiments, the patient has received one or more lines of systemic therapy. In some embodiments, the patient has received two or more lines of systemic therapy. In some embodiments, the patient has previously been treated with cell-based 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-armed cell therapy). In some embodiments, the non-Hodgkin lymphoma is non-progressive (including stable disease) non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is relapsed or refractory non-Hodgkin 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 oxutuzumab-containing regimen. In some such embodiments, treatment efficacy can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, the cancer is non-Hodgkin's lymphoma, and a compound of formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered as a monotherapy.

[0672] In some embodiments, the cancer is DLBCL. In some embodiments, DLBCL is characterized by BCL2 translocation, BCL6 translocation, CD79B mutation (e.g., H225Y, A205D, Y196del, Y196F, Y196D, Y207X, Y196N, A205fs, Y196S, Y196H, A205fs, T206fs, H194_E197delinsQ, E197G, K219T, E192fs, or Y196C), EZH2 mutation (e.g., Y646F, Y646N, A682G, or A692V mutation), MYC translocation, MYD88 mutation (e.g., L265P mutation), NOTCH1 mutation (e.g., Q2394X, Q2501X, Q2459X, Y2...). 490X, G2427fs, Q2444X, P2514fs, or P2517S), NOTCH2 mutations (e.g., Q2285K, S2136fs, Q2361X, P2288fs, L2415fs, G2410fs, Q2409X, S2388X, I2304fs, Q2364X, Q2360fs), S2395X, E2261fs, M2267fs, Q2285fs, R2400X, P2303fs, Q2285fs, A2273fs, K2133fs, Q2389X, E2399X, E2290X, Q2325X, Y2340X, Y2392X, or E2411fs), TP53 mutations (e.g.,R181C, E336A, R248W, P98fs, P152L, R280I, S149fs, P151H, G245D, Y236D, S127F, A 161T, D148fs, M246I, Y126C, H179R, A159P, C238G, L93fs, Y220C, R283fs, G244D, G2 45S, E171X, R209X, T155_R156dup, E271K, R306X, G105D, L93fs, G262V, W53X, G244 V, H214Y, R282W, R337C, Q331fs, R273G, R273C, C176Y, S215R, R213Q, I195T, G245R, I232T, R175H, Y126D, R273H, R196X, Y205C, C141Y, C229X, Y126N, P278S, P151S, Y2 36H, R282G, Y103X, V216M, G244S, G266E, V173A, V173fs, I254S, T125M, R342X, P152 fs, Y205D, V274L, L257P, C135Y, C176R, Y234N, R248Q, G244R, Y234H, R248G, M237I, R213X, E258D, V173M, L252_I254del, L252I, Y234C, or C176F), 17p deletion, 18q addition, or combinations thereof. In some embodiments, DLBCL has BCL6 rearrangement, 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, a DLBCL is a DLBCL of germinal center B cell (GCB) origin. In some embodiments, a DLBCL is a BN2 type DLBCL (e.g., with BCL6 rearrangement and / or NOTCH2 mutation). In some embodiments, a DLBCL is an EZB type DLBCL (e.g., with EZH2 mutation and / or BCL2 translocation). In some embodiments, a DLBCL is a C1 genetic cluster DLBCL (e.g., with BCL6 rearrangement and / or NOTCH2 mutation). See, for example,Schmitz, Roland, et al., New England Journal of Medicine 378.15(2018):1396-1407; Chapuy, Bjoern, et al., Nature Medicine 24.5(2018):679-690. Learn more about these classifications.

[0673] In some embodiments, the cancer is FL. In some embodiments, the FL has a BCL2 translocation (e.g., t(14;18) translocation). In some embodiments, the FL has an EZH2 mutation (e.g., Y646F, Y646N, A682G, or A692V mutation). See, for example, Kridel, Robert, Laurie H. Sehn, and Randy D. Gascoyne. The Journal of Clinical Investigation 122.10 (2012):3424-3431. In some embodiments, the cancer is FL, and a compound of formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof is administered as a monotherapy.

[0674] In some embodiments, the cancer is B-ALL. In some embodiments, B-ALL has MLL rearrangements (e.g., MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion), is pre-B cell receptor positive (Pre-BCR+), has a Philadelphia chromosome, is Philadelphia chromosome-like, depends on Ras signaling, has BCL2 amplification, has JAK2 mutations (with or without high cytokine receptor-like factor 2 (CRLF2) expression), or a combination thereof. See, for example, Knight, Thomas, and Julie Anne Elizabeth Irving. Frontiers in Oncology 4 (2014):160; Geng, Huimin et al. Cancer Cell 27.3 (2015):409-425; Jain, Nitin et al. Blood 129.5 (2017):572-581; and Hurtz, Christian et al. Genes & Development 33.17-18 (2019):1265-1279. In some embodiments, the cancer is B-ALL, and a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat a patient with B-ALL. In some embodiments, B-ALL is relapsed or refractory B-ALL after two or more lines of systemic therapy.

[0675] In some embodiments, the patient has previously been treated with another anticancer agent, chemotherapy agent, surgery, radiation, multikinase inhibitor, or a combination thereof.

[0676] In some embodiments, the cancer is DLBCL. In some embodiments, the patient has not previously received treatment for DLBCL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously received monotherapy with rituximab or oxetuzumab or in combination with other therapies or treatments. In some embodiments, the patient has previously received monotherapy with rituximab or in combination with other therapies or treatments. In some embodiments, the patient has previously received monotherapy with oxetuzumab or in combination with other therapies or treatments. In some embodiments, the patient has previously received lenalidomide in combination with rituximab or oxetuzumab. In some embodiments, the patient has previously been treated with cyclophosphamide, vincristine, and prednisone (CVP) (optionally in combination with rituximab or oxetuzumab). In some embodiments, the patient has previously received R-CHOP ( (rituximab), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) or G-CHOP ( (Octuzumab), cyclophosphamide, daunorubicin, vincristine, and prednisone). In some cases, the patient has previously been treated with etoposide and R-CHOP (called R-EPOCH). In some cases, the patient has previously been treated with R-CHOP in combination with lenalidomide, venetoclax, ibrutinib, acalabrutinib, oxuzumab, polotuzumab, pembrolizumab, duvalumab, or motuzumab. In some embodiments, the patient has previously been treated with a rituximab-containing regimen. In some embodiments, the patient has previously been treated with an oxuzumab-containing regimen. In some embodiments, the patient has previously been treated with a motuzumab-containing regimen. In some embodiments, the patient has previously been treated with an icoretuzumab-containing regimen. In some embodiments, the patient has previously received one or more lines of systemic therapy. In some embodiments, the patient has received two or more lines of systemic therapy. In some embodiments, the patient has previously been treated with cell-based 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-armed cell therapy). In some embodiments, DLBCL is non-progressive (including stable disease) DLBCL. In some embodiments, DLBCL is relapsed or refractory DLBCL. In some embodiments, the patient is a patient who has relapsed or is refractory to a rituximab-containing regimen. In some embodiments, the patient is a patient who has relapsed or is refractory to an oxutuzumab-containing regimen. In some such embodiments, treatment efficacy can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, the cancer is DLBCL, and a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat a patient with DLBCL. In some embodiments, the DLBCL is relapsed or refractory DLBCL after two or more lines of systemic therapy.

[0677] In some embodiments, the cancer is FL. In some embodiments, the patient has not previously received treatment for FL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously received rituximab or oxotuzumab as monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously received rituximab as monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously received oxotuzumab as monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously received rituximab or oxotuzumab as monotherapy. In some embodiments, the patient has previously received bendamustine in combination with rituximab or oxotuzumab. In some embodiments, the patient has previously received lenalidomide in combination with rituximab or oxotuzumab (the combination with rituximab is sometimes referred to as "R"). 2Treatment. In some embodiments, the patient has previously been treated with cyclophosphamide, vincristine, and prednisone (CVP) (optionally in combination with rituximab or oxotuzumab). In some embodiments, the patient has previously been treated with R-CHOP or G-CHOP. In some embodiments, the patient has received one or more lines of systemic therapy. In some embodiments, the patient has received two or more lines of systemic therapy. In some embodiments, the patient has previously received cell-based therapies (e.g., adoptive cell therapy, e.g., CAR). Treatment may include T-therapy, cytokine-induced killer (CIK) cells, natural killer (e.g., CAR-modified NK cells), or antibody-armed cell therapy. In some embodiments, non-Hodgkin lymphoma is non-progressive (including stable disease) FL. In some embodiments, FL is relapsed or refractory FL. In some embodiments, the 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 oxutuzumab-containing regimen. In some such embodiments, treatment efficacy may be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments... In the example, the cancer is FL, and a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat a patient with FL. In some embodiments, FL is relapsed or refractory FL after two or more lines of systemic therapy.

[0678] In some embodiments, the cancer is BL. In some embodiments, the patient has not previously received treatment for BL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously received rituximab or oxetuzumab as monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously received rituximab as monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously received oxetuzumab as monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously received rituximab or oxetuzumab as monotherapy. In some embodiments, the patient has previously received bendamustine in combination with rituximab or oxetuzumab. In some embodiments, the patient has previously received R-CHOP or G-CHOP. In some embodiments, the patient has previously received rituximab, cyclophosphamide, vincristine, doxorubicin, and methotrexate (R-CODOX-M). In some embodiments, the patient has previously received rituximab, ifosfamide, etoposide, and cytarabine (R-IVAC). In some embodiments, the patient has previously been treated with rituximab in combination with dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH-R). In some embodiments, the patient has received one or more lines of systemic therapy. In some embodiments, the patient has received two or more lines of systemic therapy. In some embodiments, the patient has previously been treated with cell-based 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-armed cell therapy). In some embodiments, the BL is non-progressive (including stable disease) BL. 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 or is refractory to an oxutuzumab-containing regimen. In some such embodiments, treatment efficacy can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, the cancer is BL, and a compound having a formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered as a monotherapy.In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat patients with BL. In some embodiments, BL is relapsed or refractory BL after two or more lines of systemic therapy.

[0679] In some embodiments, the cancer is PTCL (e.g., PTCL with a T-follicular helper phenotype (PTPCL-TFH), angioimmunoblastic T-cell lymphoma (AITL), or nonspecific PTCL (PTCL-NOS)). In some embodiments, the patient has not previously received treatment for PTCL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously received rituximab or oxetuzumab as monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously received rituximab as monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously received oxetuzumab as monotherapy or in combination with other therapies or treatments. In some embodiments, the patient has previously received rituximab or oxetuzumab as monotherapy. In some embodiments, the patient has previously received bendamustine in combination with rituximab or oxetuzumab. In some embodiments, the patient has previously received lenalidomide in combination with rituximab or oxetuzumab (the combination with rituximab is sometimes referred to as "R"). 2Treatment. In some embodiments, the patient has previously been treated with cyclophosphamide, vincristine, and prednisone (CVP) (optionally in combination with rituximab or oxotuzumab (R-CVP or G-CVP, respectively)). In some embodiments, the patient has previously been treated with R-CHOP or G-CHOP. In some embodiments, the patient has received one or more lines of systemic therapy. In some embodiments, the patient has received two or more lines of systemic therapy. In some embodiments, the patient has previously received cell-based therapies (e.g., adoptive cell therapy (e.g., CAR)). Treatment may include T-therapy, cytokine-induced killer (CIK) cells, natural killer (e.g., CAR-modified NK cells), or antibody-armed cell therapy. In some embodiments, PTCL is non-progressive (including stable disease) PTCL. In some embodiments, PTCL is relapsed or refractory PTCL. In some embodiments, the patient is a patient who has relapsed or is refractory to a rituximab-containing regimen. In some embodiments, the patient is a patient who has relapsed or is refractory to an oxutuzumab-containing regimen. In some such embodiments, treatment efficacy may be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, The cancer is PTCL, and a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat a patient with PTCL. In some embodiments, PTCL is relapsed or refractory PTCL after two or more lines of systemic therapy.

[0680] In some embodiments, the cancer is B-ALL. In some embodiments, B-ALL is Philadelphia chromosome-positive B-ALL. In some embodiments, B-ALL is Philadelphia chromosome-negative B-ALL. In some embodiments, the patient has previously received chemotherapy. In some embodiments, the patient has previously been treated with at least one cycle of induction, consolidation, intensification, and optionally maintenance. In some cases, induction therapy may include anthracyclines, vincristine, corticosteroids, and cyclophosphamide. In some embodiments, the anthracycline is doxorubicin. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the combination of doxorubicin, vincristine, dexamethasone, and cyclophosphamide is called CVAD. In some embodiments, induction therapy may further include a tyrosine kinase inhibitor (e.g., a BCR-ABL inhibitor for patients with this fusion). In some embodiments, induction therapy may further include asparaginase (e.g., for pediatric patients). In some cases, 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 cases, intensification therapy may include anthracyclines, vincristine, corticosteroids, and cyclophosphamide. In some embodiments, intensification therapy may further include a tyrosine kinase inhibitor (e.g., a BCR-ABL inhibitor for patients with this fusion). In some embodiments, intensification therapy may further include asparaginase (e.g., for pediatric patients). Typically, pediatric and adolescent regimens include higher cumulative doses of asparaginase and vincristine compared to adult regimens, but may have lower cumulative doses of anthracyclines and cyclophosphamide. In any of these cycle phases, anti-CD20 immunotherapy (e.g., rituximab) may be added for patients whose cells express the CD20 protein. See, for example, Muffly, Lori, and Emily Curran. Hematology 2014, the American Society of Hematology Education Program Book 2019.1(2019):17-23. In some embodiments, the patient has received one or more lines of systemic therapy. In some embodiments, the patient has received two or more lines of systemic therapy. In some embodiments, B-ALL is relapsed or refractory B-ALL.In some such embodiments, treatment efficacy can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof. In some embodiments, the cancer is B-ALL, and a compound of formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered as a monotherapy. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used to treat patients with B-ALL. In some embodiments, B-ALL is relapsed or refractory B-ALL after two or more lines of systemic therapy.

[0681] This article also provides a method for treating subjects with cancer, wherein the method includes:

[0682] The subject is given a therapeutically effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof as a monotherapy or in combination with a first anticancer agent, the subject having been given one or more doses of the first anticancer agent for a period of time.

[0683] This article also provides a method for treating subjects with cancer, wherein the method includes:

[0684] (a) administering one or more doses of a first anticancer agent to the subject for a period of time; and

[0685] (b) Following (a), a therapeutically effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject as a monotherapy or in combination with the first anticancer agent.

[0686] This article also provides a method for treating subjects with cancer, wherein the method includes:

[0687] (a) administering one or more doses of a first anticancer agent to the subject for a period of time; and

[0688] (b) Following (a), a therapeutically effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject as a monotherapy or in combination with a second anticancer agent.

[0689] In some embodiments of any of the methods for treating cancer provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject once daily (qd). In some embodiments of any of the methods for treating cancer provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject twice daily (bid). In some embodiments of any of the methods for treating cancer provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject tid (three times daily). In some embodiments of any of the methods for treating cancer provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject qid (four times daily). In some embodiments of any of the methods for treating cancer provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject at qod (every other day). In some embodiments of any of the methods for treating cancer provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject at q.week (once a week).In some embodiments of any of the methods for treating cancer provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject biw (twice a week). In some embodiments of any of the methods for treating cancer provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject tiw (three times a week).

[0690] BCL6 activity is also associated with autoimmunity. See, for example, Li, Qing et al., European Journal of Immunology 50.4(2020):525-536; Pearce, Andrew C. et al., Journal of Biological Chemistry 297.2(2021); Venkatadri, Rajkumar et al., European Journal of Immunology 52.5(2022):825-834; Patel, Preeyam S. et al., Science Advances 8.25(2022):eabo1782; Ding, Shu, Yu Rao, and Qianjin Lu. Cellular & Molecular Immunology 19.7(2022):863-865. Therefore, this article also provides a method for treating an autoimmune disease in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof.

[0691] This document provides the use of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of autoimmune diseases (e.g., any of the autoimmune diseases provided herein).

[0692] This document provides the use of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines for the treatment of autoimmune diseases (e.g., any of the autoimmune diseases provided herein).

[0693] This document provides for the use of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of autoimmune diseases (e.g., any of the autoimmune diseases provided herein).

[0694] This document provides compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament for treating autoimmune diseases (e.g., any of the autoimmune diseases provided herein).

[0695] This document provides compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of autoimmune diseases (e.g., any of the autoimmune diseases provided herein).

[0696] In some embodiments, autoimmune diseases include acquired hemophilia, Addison's disease, ankylosing spondylitis, antineutrophil cytoplasmic antibody-associated vasculitis (ANCA vasculitis), antisynthetic enzyme syndrome, atherosclerosis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune sclerosing cholangitis, autoimmune thyroiditis, autoimmune uveitis, Crohn's disease, dermatomyositis, diffuse scleroderma, Goodpassuu syndrome, graft-versus-host disease (GVHD) (e.g., chronic graft-versus-host disease (cGVHD)), Graves' disease, Guillain-Barré syndrome, and bridge disease. This includes thyroiditis, Hughes syndrome, IgG4-related disease, immune thrombocytopenic purpura (ITP), inflammatory bowel disease, localized scleroderma, multiple sclerosis, myasthenia gravis (MG), neuromyelitis optica spectrum disorders (NMOSD) (e.g., neuromyelitis optica (NMO)), bullous pemphigoid, pemphigus, pernicious anemia, polymyositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, seronegative spondyloarthritis, Sjögren's syndrome, systemic lupus erythematosus, thrombocytopenic purpura, type 1 diabetes mellitus, ulcerative colitis, vitiligo, or combinations thereof. In some embodiments, the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or combinations thereof. In some embodiments, the autoimmune disease is ANCA vasculitis, GVHD (e.g., cGVHD), myasthenia gravis, NMO, or combinations thereof. In some embodiments, the autoimmune disease is ANCA vasculitis, antisynthetic enzyme syndrome, arthritis (e.g., rheumatoid arthritis or inflammatory arthritis), GVHD (e.g., cGVHD), IgG4-RD, lupus (e.g., systemic lupus erythematosus), ITP, MG (e.g., muscle-specific tyrosine kinase (MuSK) positive MG), MS, NMOSD (e.g., NMO), pemphigus (e.g., pemphigus vulgaris), Sjögren's syndrome, or a combination thereof. In some embodiments, the autoimmune disease is ANCA vasculitis, antisynthetic enzyme 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 disease is arthritis (e.g., rheumatoid arthritis or inflammatory arthritis), GVHD (e.g., cGVHD), IgG4-RD, lupus (e.g., systemic lupus erythematosus), MG (e.g., muscle-specific tyrosine kinase (MuSK) positive MG), MS, NMOSD (e.g., NMO), pemphigus (e.g., pemphigus vulgaris), Sjögren's syndrome, or a combination thereof.See, for example, Pearce, Andrew C. et al., Journal of Biological Chemistry 297.2 (2021); Ding, Shu, Yu Rao, and Qianjin Lu, Cellular & Molecular Immunology (2022):1-3; Lee, Dennis SW, Olga L. Rojas, and Jennifer L. Gommerman, Nature Reviews Drug Discovery 20.3 (2021):179-199; and international publications WO2020 / 014599 and WO 2021 / 074620.

[0697] In some embodiments of any of the methods for treating autoimmune diseases provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject once daily (qd). In some embodiments of any of the methods for treating autoimmune diseases provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject twice daily (bid). In some embodiments of any of the methods for treating autoimmune diseases provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject tid (three times daily). In some embodiments of any of the methods for treating autoimmune diseases provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject qid (four times daily). In some embodiments of any of the methods for treating autoimmune diseases provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject at qod (every other day).In some embodiments of any of the methods for treating autoimmune diseases provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject at q.week (once a week). In some embodiments of any of the methods for treating autoimmune diseases provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject at biw (twice a week). In some embodiments of any of the methods for treating autoimmune diseases provided herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered to the subject tiw (three times a week).

[0698] This article also provides a method for treating a subject with lymphoproliferative disorders, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof.

[0699] This document provides the use of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of lymphoproliferative disorders (e.g., any of the lymphoproliferative disorders provided herein).

[0700] This document provides the use of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines for the treatment of lymphoproliferative disorders (e.g., any of the lymphoproliferative disorders provided herein).

[0701] This document provides for the use of compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of lymphoproliferative disorders (e.g., any of the lymphoproliferative disorders provided herein).

[0702] This document provides compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament for treating lymphoproliferative disorders (e.g., any of the lymphoproliferative disorders provided herein).

[0703] This document provides compounds having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of lymphoproliferative disorders (e.g., any of the lymphoproliferative disorders provided herein).

[0704] In some embodiments, lymphoproliferative disorder is EBV-associated lymphoproliferative disorder.

[0705] A method for modulating (e.g., reducing) the activity of BCL6 protein in cells is also provided, the method comprising contacting the cells with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is performed in vitro. In some embodiments, the contact is performed in vivo. In some embodiments, the contact is performed in vivo, wherein the method comprises administering to a subject an effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. 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 as described herein. As used herein, the term “contact” means bringing together indicated portions of an in vitro or in vivo system. For example, “contacting” a cell with a compound provided herein includes applying the compound provided herein to the cell in vitro or in vivo, including, for example, introducing the compound provided herein into a sample containing cells (e.g., cells grown in culture or derived from a patient), organoids, or organisms (e.g., animals (e.g., tumor-carrying animals) or humans).

[0706] A method for regulating (e.g., reducing) the level of BCL6 protein in cells is also provided, the method comprising contacting the cells with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. In some embodiments, compared to cells not exposed to a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, 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%). In some embodiments, the exposure is performed in vitro. In some embodiments, the exposure is performed in vivo. In some embodiments, the contact is performed in vivo, wherein the method comprises administering to a subject having cells containing the BCL6 protein an effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer as described herein.

[0707] A method for inducing BCL6 protein ubiquitination in cells is also provided, the method comprising contacting the cells with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is performed in vitro. In some embodiments, the contact is performed in vivo. In some embodiments, the contact is performed in vivo, wherein the method comprises administering to a subject having cells containing BCL6 protein an effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein.

[0708] A method is also provided for forming a ternary complex in cells comprising BCL6 protein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))), or a pharmaceutically acceptable salt thereof, and CRBN protein or a fragment thereof, the method comprising contacting the cells with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))), or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is performed in vitro. In some embodiments, the contact is performed in vivo. In some embodiments, the contact is performed in vivo, wherein the method comprises administering to a subject having cells containing the BCL6 protein an effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are cancer cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are mammalian cancer cells. In some embodiments, the cancer cells are any cancer as described herein.

[0709] This article also provides a method for inducing the degradation of BCL6 protein in mammalian cells, the method comprising contacting the mammalian cells with an effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof.

[0710] This article also provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0711] This document further provides a method for increasing cell death in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. This document also provides a method for increasing tumor cell death in a subject. This method comprises administering to a subject an amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, as defined herein.

[0712] When used as a medicine, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof can be administered in the form of a pharmaceutical composition as described herein.

[0713] combination

[0714] In any of the indications described herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof may be used as a monotherapy. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof may be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need may be administered one or more doses of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) 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 having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof to reduce tumor size (e.g., tumor burden) before at least partial resection of the tumor.

[0715] In some embodiments, a subject in need may be administered one or more doses of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof for a period of time, and receive one or more rounds of radiotherapy. In some embodiments, treatment with one or more doses of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, prior to one or more rounds of radiotherapy, reduces tumor size (e.g., tumor burden).

[0716] In some embodiments of any of the methods described herein, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of at least one other therapeutic agent (e.g., a chemotherapeutic agent).

[0717] Other non-limiting examples of therapeutic agents include: RAS pathway-targeting therapies (e.g., Ras / RAF / MEK / PI3K pathway inhibitors (e.g., Ras inhibitors, KRas-targeting therapies, SOS1 inhibitors, SOS1 / Ras protein-protein interaction inhibitors, SHP2 inhibitors, PI3K-AKT-mTOR pathway inhibitors)), kinase-targeting therapies (e.g., MEK inhibitors, ERK inhibitors, Raf inhibitors (e.g., BRaf inhibitors), PI3K inhibitors, AKT inhibitors, BTK inhibitors, mTOR inhibitors, CDK4 / 5 inhibitors, CDK4 / 6. Inhibitors, MET inhibitors, JAK inhibitors (e.g., JAK2 inhibitors), FAK inhibitors, ErbB family inhibitors (e.g., EGFR inhibitors, Her2 inhibitors, Src inhibitors), menin inhibitors, mTORC1 inhibitors, YAP inhibitors, proteasome inhibitors, farnesyltransferase inhibitors, HSP90 inhibitors, PTEN inhibitors, polycomb inhibitory complex 2 (PRC2) inhibitors (e.g., EZH1 / 2 or EZH2 inhibitors), signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., BCL-2 inhibitors, BCL-X inhibitors). LInhibitors), XPO1 inhibitors, steroids, chemotherapy drugs, angiogenesis-targeted therapies, immune-targeting agents (including immunomodulatory imide drugs (sometimes called "IMiD" or "CELMoD")), immunotherapies (e.g., anti-PD1, anti-PD-L1, anti-CD19, anti-CD20, anti-CD22, anti-CD3, anti-CD30, anti-CD79B, or anti-CD47 therapies), including antibodies (e.g., single-target antibodies targeting one or more of PD1, PD-L1, CD19, CD20, CD22, CD3, CD30, CD79B, or CD47, and single-target antibodies targeting PD1, PD-L1, CD19, CD20, CD22, CD3, C Bispecific antibodies (including bispecific T-cell connectives (BiTEs)) of one or more of D30, CD79B, or CD47, and antibody-drug conjugates (ADCs) that bind to one or more of PD1, PD-L1, CD19, CD20, CD22, CD3, CD30, CD79B, or CD47 antibodies, or their antigen-binding fragments, PD-1 inhibitors, or PD-L1 inhibitors, cell-based therapeutics (e.g., adoptive cell therapy (e.g., CAR-T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy), and radiotherapy.

[0718] As used herein, a biosimilar antibody is an antibody or antigen-binding fragment having the same primary amino acid sequence as a reference antibody, and optionally having detectable differences (e.g., different glycoforms) in post-translational modifications (e.g., glycosylation and / or phosphorylation) compared to the reference antibody.

[0719] In some embodiments, additional therapeutic agents are PI3K inhibitors, Abl inhibitors (e.g., BCR-Abl inhibitors), BTK inhibitors, JAK inhibitors (e.g., JAK2 inhibitors), BRaf inhibitors, MEK inhibitors, menin inhibitors, BCL-2 inhibitors, and BCL-X inhibitors. L Inhibitors, MCL-1 inhibitors, XPO1 inhibitors, inhibitors of polycomb inhibitory complex 2 (e.g., EZH1 / 2 or EZH2 inhibitors), immunomodulatory imide drugs, steroids, anti-CD19 therapy, anti-CD20 therapy, anti-CD3 therapy, chemotherapy, or combinations thereof.

[0720] Unbound by any particular theory, it is believed that targeting BCL6 can lead to the induction of genes typically repressed by BCL6, such as BCL2. In some embodiments, additional therapeutic agents are BCL-2 inhibitors (e.g., venetoclax, navitoclax, lisaftoclax, obatoclax, pelcitoclax, AZD-0466, BGB-11417, UBX-1325, UBX-1967, ZN-d5, oblimersen (e.g., oblimersen sodium), or beclanorsen).

[0721] In some embodiments, the PI3K inhibitor is alpelisib (BYL719), amdizalisib, apitolisib (GDC-0980), bimiralisib, buparlisib (BKM120), or copanlisib (ALIQOPA). TMBAY80-6946 (e.g., copanolis dihydrochloride or copanolis dihydrochloride hydrate), dactolisib (NVP-BEZ235, BEZ-235), dezapelisib, dordaviprone, duvelisib (e.g., duvelisib hydrate), eganelisib, fimepinostat, gedatolisib (PF-05212384, PKI-587), idelalisib, inavolisib, lenalisib iolisib (e.g., lenilisib phosphate), linperlisib, omipalisib (GSK2126458, GSK458), parsaclisib, pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), paxalisib, rigosertib, risovalisib, seletalisib, serabelisib (TAK-117, MLN1117, INK) 1117), Sonolisib (PX-866), Taselisib (GDC-0032, RG7604), Umbralisib (e.g., Umbralisib tosylate), Voxtalisib (XL756, SAR245409), Wortmannin, Zandelisib, AMG 511, AMG319, ASN003, AZD8835, BGT-226 (NVP-BGT226), CH5132799, CUDC-907, GDC-0077, GDC-0084 (RG7666), GS-9820, GSK1059615, GSK2636771, KIN-193 (AZD-6428), LY2023414, LY294002, PF-04691502, PI-103, PKI-402, PQR309, SAR260301, SF1126, SHC-014748-M, TQ-B-3525, VS-5584 (SB2343), WX-037, XL-765, ZSTK474 or combinations thereof.In some embodiments, the PI3K inhibitor is apelis, dapelis, atorolis, bismilis, bupalis, copanlis (e.g., copanlis dihydrochloride or copanlis dihydrochloride hydrate), dapelis, dezalis, dodaviridone, duvelis (e.g., duvelis hydrate), egalis, femenoxetine, gidalis, alarilis, inalis, lenilis (e.g., lenilis phosphate), limprilis, passalis, rasalis, celelis, celelis, sonolis, tenalisib, erbilis (e.g., erbilis tosylate), zandelis, PF-04691502, SHC-014748-M, TQ-B-3525, or a combination thereof.

[0722] In some embodiments, the Abl inhibitor (e.g., a BCR-Abl inhibitor) is aciminib (e.g., aciminib hydrochloride), bafetinib, bosutinib (e.g., bosutinib monohydrate), danusertib, dasatinib (e.g., dasatinib monohydrate), flumatinib (e.g., flumatinib mesylate), or imatinib (e.g., imatinib mesylate). Nilotinib (e.g., nilotinib chloride monohydrate), olverembatinib (e.g., olverembatinib mesylate), ponatinib (e.g., ponatinib hydrochloride), raditinib (e.g., raditinib dihydrochloride), ruserontinib, vandetanib, AN-019, AT-9283, IkT-148009, NPB-001-056, or combinations thereof.

[0723] In some embodiments, the cancer is B-ALL, and the additional therapy or treatment is an Abl inhibitor. In some embodiments, the cancer is Philadelphia chromosome-positive B-ALL, and the additional therapy or treatment is an Abl inhibitor. In some embodiments, the cancer is Philadelphia chromosome-like B-ALL, and the additional therapy or treatment is an Abl inhibitor. In some embodiments, the Abl inhibitor is selected from the group consisting of imatinib, dasatinib, ponatinib, or combinations thereof.

[0724] In some embodiments, BTK inhibitors are abivertinib, acalabrutinib, atuzabrutinib, branebrutinib, dasatinib (e.g., dasatinib monohydrate), edralbrutinib (SHR-1459), elsubrutinib, evobrutinib, fenebrutinib, ibrutinib, luxeptinib, nemtabrutinib, olafertinib, and nemtabrutinib. Orelabrutinib, pirtobrutinib, remibrutinib, rilzabrutinib, spebrutinib, sunvozertinib, tirabrutinib (e.g., tirabrutinib hydrochloride), tolebrutinib, vecabrutinib, zanubrutinib, AC-0058 (AC-0058TA), BMS-986142, CT-1530, DTRMWXHS-12, LY-3337641 (HM-71224), M-7583, TAS-5315, or combinations thereof. In some embodiments, the BTK inhibitor is abitinib, acalabrutinib, atubutinib, brumbutinib, dasatinib (e.g., dasatinib monohydrate), edrabrutinib, esoubrutinib, evobrutinib, fenibrutinib, ibrutinib, nemtatinib, orelabrutinib, pitobrutinib, rebrutinib, rizarutinib, suvortinib, telarabrutinib (e.g., telarabrutinib hydrochloride), tolebrutinib, zanubrutinib, AC-0058, BMS-986142, DTRMWXHS-12, LY-3337641, TAS-5315, or a combination thereof.

[0725] In some embodiments, the cancer is B-ALL, and the additional therapy or treatment is a BTK inhibitor. In some embodiments, the cancer is pre-BCR+B-ALL, and the additional therapy or treatment is a BTK inhibitor. In some embodiments, the cancer is Ras signaling-dependent B-ALL, and the additional therapy or treatment is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or acalabrutinib.

[0726] In some embodiments, JAK inhibitors are abrocitinib, baricitinib, brepocitinib, decernotinib, delgocitinib, deuruxolitinib, esuebubrutinib, fedratinib (e.g., fedratinib dihydrochloride monohydrate), filgotinib (e.g., filgotinib maleate), gandotinib, gusacitinib, ilginatinib, itacitinib, ivarmacitinib, izencitinib, jaktinib, momelotinib, nezulcitinib, and pacitinib. Peficitinib (e.g., pafertinib citrate), peficitinib (e.g., pefertinib hydrobromide), povorcitinib (INCB-54707), ropsacitinib, ruxolitinib (e.g., ruxolitinib phosphate), socitinib, and tasocitinib (e.g., tofacitinib citrate) are all terminating ... ), tinengotinib, upadacitinib (e.g., upadacitinib hydrate), zasocitinib, AGA-201, ATI-1777, ATI-501, ESK-001, GLPG-3667, INCB-52793, LNK-01001, LNK-01003, R-348, TD-8236, TLL-018, TQ-05105, VTX-958, or combinations thereof.In some embodiments, the JAK inhibitor is abuxitinib, baricitinib, bupoxitinib, decetinib, digotinib, decitrulinib, fentatinib (e.g., fentatinib dihydrochloride monohydrate), fenatotinib (e.g., fenatotinib maleate), gandrolinib, gusartinib, igagtinib, itatinib, amaxitinib, gensetertinib, jaktinib, molotinib, nezuzitinib, pappatinib (e.g., pappatinib citrate), perfitinib (e.g., perfitinib hydrobromide), povaxitinib (INCB-5). 4707), roxatinib, ruxotetinib (e.g., ruxotetinib phosphate), soxitinib, tofacitinib (e.g., tofacitinib citrate), tenengagotinib, utpatinib (e.g., utpatinib hydrate), zanoxutinib, 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 combinations thereof.

[0727] In some embodiments, the cancer is B-ALL, and the additional therapy or treatment is a JAK inhibitor. In some embodiments, the cancer is JAK2 (e.g., JAK2...). R683G or JAK2 I682F The cancer is a mutant B-ALL, and the additional therapy or treatment is a JAK inhibitor. In some embodiments, the cancer is a JAK2 (e.g., JAK2) cancer with high CRLF2 expression. R683G or JAK2 I682F Mutant B-ALL, and the alternative therapies or treatments are JAK inhibitors and BCL-2 inhibitors (e.g., venetoclax).

[0728] In some embodiments, BRaf inhibitors are avutometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), and encorafenib (e.g., BRAFTOVI). TM LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, PLX-4720 or combinations thereof.

[0729] In some embodiments, MEK inhibitors are evometinib (RO5126766) and binimetinib (…). MEK162), cobimetinib (e.g., cobimetinib fumarate), ), mirdametinib (PD0325901), pimasertib (MSC1936369B), refametinib, selumetinib (e.g., selumetinib sulfate, AZD6244), trametinib (e.g., trametinib dimethyl sulfoxide, GSK-1120212), zapnometinib, CI1040 (PD184352), CS3006, FCN-159, GSK-1120212, NFX-179, PD98059, SHR7390, TAK-733, WX-554, or combinations thereof. In some embodiments, the MEK inhibitor is endometinib, bimetinib, cobimetinib (e.g., cobimetinib fumarate), midametinib, pimasitinib, refatinib, selmetinib (e.g., selmetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide, GSK-1120212), zapnometinib, FCN-159, NFX-179, TAK-733, or a combination thereof.

[0730] In some embodiments, the menin inhibitor is revumenib (e.g., revumenib fumarate), ziftomenib, BMF-219, DS-1594, JNJ-6617, or a combination thereof.

[0731] In some embodiments, the cancer is B-ALL, and the additional therapy or treatment is a menin inhibitor. In some embodiments, the cancer is B-ALL with MLL rearrangements (e.g., MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion), and the additional therapy or treatment is a menin inhibitor.

[0732] In some embodiments, the BCL-2 inhibitor is lisatorax, navitorax, obatax, venetox, olmexone (e.g., olmexone sodium), belanoxen, AZD-0466, BGB-11417, UBX-1325, UBX-1967, ZN-d5, or a combination thereof.

[0733] In some embodiments, the cancer is B-ALL, and the additional therapy or treatment is a BCL-2 inhibitor. In some embodiments, the cancer is B-ALL with MLL rearrangements (e.g., MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion), and the additional therapy or treatment is a BCL-2 inhibitor. In some embodiments, the cancer is B-ALL with BCL2 amplification, and the additional therapy or treatment is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is venetoc.

[0734] In some embodiments, the cancer is DLBCL, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is venetoc.

[0735] In some embodiments, the cancer is FL, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is venetoc.

[0736] In some embodiments, the cancer is MCL, and the additional therapy or treatment agent is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is venetoclax.

[0737] In some embodiments, BCL-X L The inhibitors are lisatox, navittox, obatax, pecitox, mirzotamab clezutoclax, ABBV-155, APG-1252-12A, AZD-0466, DT-2216, PA-15227, UBX-1325, UBX-1967, XZ-739, 753-B, or combinations thereof. In some embodiments, BCL-X... L The inhibitors are lisatox, navittox, obatax, or combinations thereof.

[0738] In some embodiments, the MCL-1 inhibitor is omacetaxine (e.g., omacetaxine mepesuccinate).

[0739] In some embodiments, the XPO1 inhibitor is eltanexor, felezonexor, selinexor, verdinexor, BIIB-100, JS-110, or a combination thereof. In some embodiments, the XPO1 inhibitor is selinexor.

[0740] In some embodiments, the PRC2 inhibitor is lirametostat, tazemetostat (e.g., tazemetostat hydrobromide), tulmimetostat (CPI-0209), valemetostat (e.g., valemetostat tosylate), EBI-2511, HH-2853, HM-97662, PF-6821497, SHR-2554, XNW-5004, or a combination thereof. In some embodiments, the PRC2 inhibitor is an EZH1 / 2 inhibitor, an EZH2 inhibitor, or a combination thereof. Non-limiting examples of EZH2 and / or EZH1 / 2 inhibitors are described in international publications WO2011 / 140325, WO 2012 / 005805, WO 2012 / 050532, WO 2012 / 118812, WO 2012 / 142513, WO2012 / 142504, WO 2013 / 049770, WO 2013 / 039988, WO 2013 / 067300, WO 2015 / 141616, WO2017 / 084494, WO 2018 / 210296, WO 2018 / 210302, WO 2019 / 091450, WO 2019 / 204490, WO2019 / 226491, WO 2020 / 063863, WO 2020 / 171606, WO 2020 / 228591, WO 2021 / 016414, WO2021 / 063332, WO 2021 / 063340, WO 2021 / 180235, and WO 2022 / 035303.

[0741] In some embodiments, the cancer is DLBCL, and the additional therapy or treatment is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is B-ALL (e.g., Philadelphia chromosome-positive B-ALL, Philadelphia chromosome-negative B-ALL, or B-ALL with MLL rearrangements (e.g., MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion)), and the additional therapy or treatment is a PRC2 inhibitor. In some embodiments, the cancer is FL, and the additional therapy or treatment is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor). In some embodiments, the cancer is MCL, and the additional therapy or treatment is a PRC2 inhibitor (e.g., an EZH1 / 2 or EZH2 inhibitor).

[0742] The following shows an exemplary wild-type human EZH2 sequence. This is one of several isomers of EZH2, and it can be understood that the residue numbering can be changed according to a reference isomer.

[0743] SEQ ID NO:1(UniParc ID UPI000006D77C):

[0744] MGQTGKKSEKGPVCWRKRVKSEYMRLRQLKRFRRADEVKSMFSSNRQKILERTEILNQEWKQRRIQPVHILTSVSSLRGTRECSVTSDLDFPTQVIPLKTLNAVASVPIMYSWSPLQQNFMVEDETVLHNIPYMGDEVLDQDGTFIEELIKNYDGKVHGDRECGFINDEIFVELVNALGQYNDDDDD DDGDDPEEREEKQKDLEDHRDDKESRPPRKFPSDKIFEAISSMFPDKGTAEELKEKYKELTEQQLPGALPPECTPNIDGPNAKSVQREQSLHSFHTLFCRRCFKYDCFLHRKCNYSFHATPNTYKRKNTETALDNKPCGPQCYQHLEGAKEFAAALTAERIKTPPKRPGGRRRGRLPNNSSRPSTPTI NVLESKDTSDREAGTETGGENNDKEEEEKKDETSSSSEANSRCQTPIKMKPNIEPPENVEWSGAEASMFRVLIGTYYDNFCAIARLIGTKTCRQVYEFRVKESSIIAPAPAEDVDTPPRKKKRKHRLWAAHCRKIQLKKDGSSNHVYNYQPCDHPRQPCDSSCPCVIAQNFCEKFCQCSSECQNRFP GCRCKAQCNTKQCPCYLAVRECDPDLCLTCGAADHWDSKNVSCKNCSIQRGSKKHLLLAPSDVAGWGIFIKDPVQKNEFISEYCGEIISQDEADRRGKVYDKYMCSFLFNLNNDFVVDATRKGNKIRFANHSVNPNCYAKVMMVNGDHRIGIFAKRAIQTGEELFFDYRYSQADALKYVGIEREMEIP

[0745] In some embodiments, the steroid is dexamethasone, prednisone, or a combination thereof.

[0746] In some embodiments, the immunomodulatory imide is avadolamide, lenalidomide, eberlidomide, pomalidomide, thalidomide, CC-99282, or a combination thereof.

[0747] In some embodiments, additional therapies or treatments include lenalidomide and rituximab or oxotuzumab.

[0748] In some embodiments, anti-CD19 therapy is blinatumomab (e.g., (Britumomab) or its biosimilars), coltuximabravtansine, inebilizumab (e.g., inbuximab-cdon or its biosimilars), loncastuximab tesirine (e.g., loncastuximab-lpyl or its biosimilars), obexelimab, tafasitamab (e.g., tafasitamab-cxix or its biosimilars), dDT-2219, their biosimilars, or combinations thereof. In some embodiments, anti-CD19 therapy is a bispecific antibody or its antigen-binding fragment (e.g., (Britumomab) or its biosimilar). In some embodiments, anti-CD19 therapy is an anti-CD19 and anti-CD3 bispecific antibody or its antigen-binding fragment (e.g., (Britumomab) or its biosimilar). In some embodiments, the anti-CD19 therapy is an antibody-drug conjugate (e.g., Rastar-cotuximab, Tarantuximab (e.g., Tarantuximab-lpyl or its biosimilar)).

[0749] In some embodiments, anti-CD20 therapy is divozilimab, epcoritamab (e.g., epcoritamab-bysp or its biosimilar), glofitamab (e.g., ... (Grofitumab) or its biosimilar), ibritumomabtiuxetan (e.g.) (e.g., mosunetuzumab-axgb or its biosimilar), mosunetuzumab (e.g., mosunetuzumab-axgb or its biosimilar), obinutuzumab (e.g., (ocrelizumab) or its biosimilar), ocrelizumab (e.g.) (Orelizumab) or its biosimilar), odronextamab, ofatumumab (e.g.) (ofofatumumab) or its biosimilar), paramotumab, rituximab (e.g.) (rituximab) or its biosimilars (e.g., rituximab-abbs, rituximab-arrx, rituximab-pvvr, ...) (rituximab), (rituximab), (rituximab), (Rituximab), REDITUX TM (Rituximab), Retuxira (rituximab), BI-695500, GB-241, Mabion-CD20, RTXM-83, SAIT-101) ublituximab (e.g., ublituximab-xiiy or its biosimilar), veltuzumab, zuberitamab, MIL-62, SCT-400, TQB-2303, their biosimilars, or combinations thereof. In some embodiments, anti-CD20 therapy is a bispecific antibody or its antigen-binding fragment (e.g., icoretuzumab (e.g., icoretuzumab-bysp or its biosimilar), grofituzumab (e.g., (Grofitumab) or its biosimilar), motuzumab (e.g., motuzumab-axgb or its biosimilar), peramutumab, onatuzumab, their biosimilars, or combinations thereof. In some embodiments, anti-CD20 therapy is an anti-CD20 and anti-CD3 bispecific antibody or its antigen-binding fragment (e.g., icoretuzumab (e.g., icoretuzumab-bysp or its biosimilar), grofitumab (e.g., ... (Grofitumab) or its biosimilar), motuzumab (e.g., motuzumab-axgb or its biosimilar), peramutumab, onintuzumab, their biosimilars, or combinations thereof. In some embodiments, anti-CD20 therapy is an antibody-drug conjugate (e.g., tetan-etrumumab (e.g., ...). (Tetan-Eritumobab or its biosimilar)).

[0750] In some embodiments, the additional therapy or therapeutic agent is rituximab. In some such embodiments, rituximab is used as maintenance therapy in combination with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. In some such embodiments, the cancer is FL.

[0751] In some embodiments, an additional therapy or therapeutic agent is oxutuzumab. In some such embodiments, oxutuzumab is used as a maintenance therapy in combination with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof. In some such embodiments, the cancer is FL.

[0752] In some embodiments, the cancer is DLBCL, and the additional therapy or treatment agent is an anti-CD20 therapy. In some embodiments, the anti-CD20 therapy is rituximab, oxotuzumab, or a combination thereof.

[0753] In some embodiments, the cancer is FL, and the additional therapy or treatment agent is an anti-CD20 therapy. In some embodiments, the anti-CD20 therapy is rituximab, oxotuzumab, or a combination thereof.

[0754] In some embodiments, antiCD22 therapy is an antibody-drug conjugate (e.g., osintuzumab).

[0755] In some embodiments, the cancer is B-ALL, and the additional therapy or treatment is an anti-CD22 therapy. In some embodiments, the anti-CD22 therapy is an anti-CD22 antibody-drug conjugate (e.g., oxintuzumab or a biosimilar thereof).

[0756] In some embodiments, the anti-CD3 therapy is buritumab (e.g., (Britumomab) or its biosimilar), catumaxomab, elranatamab, icostatumab (e.g., icostatumab-bysp or its biosimilar), ertumaxomab, grofitumab (e.g., (Grofitumab) or its biosimilars), rivocelumab, motuzumab (e.g., motuzumab-axgb or its biosimilars), onatuzumab, otelixizumab, peramutuzumab, talquetamab, tarlatamab, tebentafusp (e.g., tebentafusp-tebn or its biosimilars), teclistamab (e.g., teclistamab-cqyv or its biosimilars), teplizumab (e.g., teplizumab-mzwv or its biosimilars), visilizumab, their biosimilars, or combinations thereof. In some embodiments, anti-CD3 therapy is a bispecific antibody or its antigen-binding fragment (e.g., bumetumab (e.g., ... (Britumomab) or its biosimilar), caputomasumab, enatumab, icoretumab (e.g., icoretumab-bysp or its biosimilar), ertumasumab, grofitumab (e.g., (Grofitumab) or its biosimilar), rivosaltimumab, motuzumab (e.g., motuzumab-axgb or its biosimilar), peramutumab, onitumab, taquitumab, talatumab, terbungutavsp (e.g., terbungutavsp-tebn or its biosimilar), territorumab (e.g., territorumab-cqyv or its biosimilar), biosimilars thereof, or combinations thereof). In some embodiments, anti-CD3 therapy is an anti-CD3 and anti-CD19 bispecific antibody or its antigen-binding fragment (e.g., (Britumomab) or its biosimilar). In some embodiments, the anti-CD3 therapy is an anti-CD20 and anti-CD3 bispecific antibody or its antigen-binding fragment (e.g., icoretuzumab (e.g., icoretuzumab-bysp or its biosimilar), grofituzumab (e.g., (Grofitumab) or its biosimilar), motuzumab (e.g., motuzumab-axgb or its biosimilar), peramutumab, onitumab, its biosimilar or combinations thereof).

[0757] In some embodiments, the anti-CD30 therapy is brentuximab, brentuximab vedotin, iratumumab, AFM-13, a biosimilar thereof, or a combination thereof. In some embodiments, the anti-CD30 therapy is a bispecific antibody or its antigen-binding fragment (e.g., AFM-13). In some embodiments, the anti-CD30 therapy is an antibody-drug conjugate (e.g., brentuximab vedotin or a biosimilar thereof).

[0758] In some embodiments, the anti-CD79B therapy is polotuzumab (e.g., vitin-polotuzumab (e.g., vitin-polotuzumab-piiq or a biosimilar thereof)), MGD-010, RG-7986, their biosimilars, or combinations thereof. In some embodiments, the anti-CD79B therapy is polotuzumab (e.g., vitin-polotuzumab (e.g., vitin-polotuzumab-piiq or a biosimilar thereof)), MGD-010, their biosimilars, or combinations thereof. In some embodiments, the anti-CD79B therapy is a bispecific antibody or its antigen-binding fragment (e.g., MGD-010). In some embodiments, the anti-CD79B therapy is an antibody-drug conjugate (e.g., vitin-polotuzumab (e.g., vitin-polotuzumab-piiq or a biosimilar thereof)).

[0759] In some embodiments, anti-PD1 therapy includes balstilimab, budigalimab, cadonilimab, camrelizumab, cemiplimab (e.g., cimiprimab-rwlc or its biosimilar), cetrelimab, dostarlimab (e.g., dostarlimab-gxly or its biosimilar), ezabenlimab, geptanolimab, ivonescimab, and nivolumab (e.g., (nivorumab or its biosimilar), nofazinlimab, pembrolizumab (e.g.) (pembrolizumab) or its biosimilars), penpulimab, pidilizumab, pimivalimab, prolgolimab, puctenlimab, retifanlimab (e.g., retifanlimab-dlwr or its biosimilars), rilvegostomig, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab (e.g., (sintilimab or its biosimilars), spartalizumab, tebotelimab, tislelizumab, toripalimab, volrustomig, vudalimab, zimberelimab, QL-1604, HX-009, INCB-086550, RG-6139, BAT-1306, SG-001, AZD7709, their biosimilars, or combinations thereof. In some embodiments, anti-PD1 therapy is a bispecific antibody or its antigen-binding fragment (e.g., canducilimab, ewocidumab, regorafenib, tebotelimab, volrustomig, vudalimab, zimberelimab, QL-1604, HX-009, INCB-086550, RG-6139, their biosimilars, or combinations thereof). In some embodiments, the anti-PD1 therapy is an anti-PD1 and anti-CD47 bispecific antibody or an antigen-binding fragment thereof (e.g., HX-009 or a biosimilar thereof).

[0760] In some embodiments, anti-PD-L1 therapy is adebrelimab, atezolizumab (e.g., (atelizumab) or its biosimilar), avelumab (e.g., (Averumab or its biosimilar), bintrafuspalfa, cosibelimab, dabustumab, duvalumab (e.g.) (dulvarubicin) or its biosimilars), envafolimab (e.g.) (Envorimab or its biosimilar), erfonrilimab, pacmilimab, socazolimab, sugemalimab (e.g., (sugemalimab) or its biosimilars), A-167, APL-502, AUPM-170, BNT-311, SHR-1701, their biosimilars, or combinations thereof. In some embodiments, the anti-PD-L1 therapy is a bispecific antibody or its antigen-binding fragment (e.g., elemalimab, BNT-311, their biosimilars, or combinations thereof).

[0761] In some embodiments, the PD-L1 inhibitor is INCB-086550.

[0762] In some embodiments, the anti-CD47 therapy is lemzoparlimab, letaplimab, magrolimab, 6MW-3211, AO-176, CPO-107, HX-009, TTI-621, TTI-622, their biosimilars, or combinations thereof. In some embodiments, the anti-CD47 therapy is lemzoparlimab, magrolimab, HX-009, TTI-621, TTI-622, their biosimilars, or combinations thereof. In some embodiments, the anti-CD47 therapy is a bispecific antibody or its antigen-binding fragment (e.g., HX-009). In some embodiments, the anti-CD47 therapy is an anti-CD47 and anti-PD1 bispecific antibody or its antigen-binding fragment (e.g., HX-009 or its biosimilar).

[0763] In some embodiments, the cell-based therapy is adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIK), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy. In some embodiments, the cell-based therapy is CAR T therapy. In some embodiments, the cell-based therapy is axicabtagene ciloleucel (e.g., (Akirencin or its biosimilar), brexucabtagene autoleucel (e.g.) (Brekiolencel) or its biosimilar), inaticabtagene autoleucel, lisocabtagene maraleucel (e.g.) (relmacabtagene autoleucel or its biosimilar), rapcabtagene autoleucel, relmacabtagene autoleucel (e.g.) (Resalicylate) or its biosimilars), tisagenlecleucel (e.g.) (Seriflumin) or its biosimilars), varnimcabtagene autoleucel (e.g., IMN-003A or its biosimilars), zamtocabtagene autoleucel, BZ-019, CD19CAR CTL, CTL-119, TAK-007, XLCART-001, their biosimilars or combinations thereof.

[0764] In some embodiments, the additional therapy or treatment is chemotherapy. In some embodiments, chemotherapy is CVAD, hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), CHOP, R-CHOP, G-CHOP, EPOCH, R-EPOCH, Pola-R-CHP (vitin-pollotuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone), R-CODOX-M, R-IVAC, DA-EPOCH-R, CVP, R-CVP, G-CVP, CVD (cyclophosphamide, vincristine, dacarbazine, including mini-CVD), bendamustine with rituximab or oxutuzumab, methotrexate-cytarabine, vincristine (with or without a steroid (e.g., dexamethasone)), nelarabine, demethylating agents (e.g., azacitidine and / or decitabine), CALGB8811, or pediatric-inspired multidrug chemotherapy (e.g., GRAALL-2003, COG). AALL-0434, CCG-1961, CALGB10403, or DFCI scheme).

[0765] In some embodiments, the cancer is B-ALL, and the additional treatment or therapeutic agent is chemotherapy (e.g., CVAD). In some embodiments, the cancer is B-ALL with MLL rearrangements (e.g., MLL-Af4 fusion, MLL-Af6 fusion, MLL-Af9 fusion, MLL-ENL fusion, or MLL-PTD fusion), and the additional treatment or therapeutic agent is chemotherapy (e.g., CVAD). In some embodiments, the cancer is Philadelphia chromosome-positive B-ALL, and the additional treatment or therapeutic agent is chemotherapy (e.g., CVAD). In some embodiments, the cancer is Philadelphia chromosome-like B-ALL, and the additional treatment or therapeutic agent is chemotherapy (e.g., CVAD). In some embodiments, the cancer is pre-BCR+ B-ALL, and the additional treatment or therapeutic agent is chemotherapy (e.g., CVAD). In some embodiments, the cancer is Ras signaling-dependent B-ALL, and the additional treatment or therapeutic agent is chemotherapy (e.g., CVAD).

[0766] In some embodiments, the cancer is FL, and the additional therapy or therapeutic agent is R-CHOP. In some such embodiments, R-CHOP is used as a treatment for the primary tumor in combination with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))). In some such embodiments, R-CHOP is used as a maintenance therapy in combination with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))).

[0767] In some embodiments, the cancer is DLBCL, and the additional therapy or therapeutic agent is R-CHOP. In some such embodiments, R-CHOP is used as a treatment for the primary tumor in combination with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))). In some such embodiments, R-CHOP is used as a maintenance therapy in combination with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))).

[0768] In some embodiments, the cancer is DLBCL, and the additional therapy or therapeutic agent is R-EPOCH. In some such embodiments, R-EPOCH is used as a treatment for the primary tumor in combination with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))). In some such embodiments, R-EPOCH is used as a maintenance therapy in combination with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))).

[0769] In some embodiments, the cancer is DLBCL, and the additional therapy or treatment agent is R-CHP. In some such embodiments, Pola-R-CHP is used as a treatment for the primary tumor in combination with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))). In some such embodiments, Pola-R-CHP is used as a maintenance therapy in combination with a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))).

[0770] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is used in combination with one or more steps of induction, consolidation, enhancement, or maintenance in a chemotherapy regimen.

[0771] This article also provides a method for treating cancer, the method comprising administering to a subject in need (a) a compound having formula (I-1) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, for simultaneous, alone, or sequential treatment of cancer, wherein the amount of the compound having formula (I-1) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, together with the additional therapeutic agent, is effective in treating cancer. In some embodiments, the method includes administering (c) at least one pharmaceutically acceptable carrier.

[0772] In some such embodiments, the additional therapeutic agent is an inhibitor of PRC2 (e.g., an EZH1 / 2 inhibitor or an EZH2 inhibitor (e.g., any one of the EZH1 / 2 inhibitors or EZH2 inhibitors described herein)), and the cancer is a cancer with an EZH2 alteration. In one aspect of this embodiment, the EZH2 alteration is a mutation relative to SEQ ID NO. 1 located at residues 27, 34, 59, 141, 162, 172, 197, 238, 239, 246, 395, 401, 452, 510, 516, 556, 583, 618, 644, 646, 682, 690, 692, 716, 732, 744, 745, or a combination thereof. In another aspect of this embodiment, the EZH2 alteration is a translocation. In another aspect of this embodiment, the EZH2 mutations are R27*, R34*, E59*, Q141*, E162*, V172Cfs*11, E197Rfs*12, E238*, E239*, E246*, G395Efs*29, E401Kfs*22, E401*, Y452*, K510Yfs*3, X516_splice, S556*, R583*, X618_splice, S644*, Y646F, Y646N, Y646S, R690G, R690H, A692V, F716Lfs*24, X732_splice, I744Mfs*25, E745Afs*24, EZH2-AUTS2, EZH2-TMEM176B, GALNT11-EZH2, or combinations thereof. In another aspect of this embodiment, the EZH2 mutation is located at residue 646, residue 682, or residue 692 relative to SEQ ID NO:1. In another aspect of this embodiment, the EZH2 mutation is Y646F, Y646N, A682G, or A692V relative to SEQ ID NO:1. In another aspect of this embodiment, the cancer is lymphoma (e.g., FL or DLBCL), and the EZH2 mutation is Y646F, Y646N, A682G, or A692V relative to SEQ ID NO:1.

[0773] These additional therapeutic agents may be administered, as part of the same or separate dosage forms, via the same or different routes of administration, and / or at the same or different schedules of administration in accordance with standard pharmaceutical practices known to those skilled in the art. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent are administered simultaneously as separate doses. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)) or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent are administered in combination at therapeutically effective amounts (e.g., as daily or intermittent doses), as separate doses, simultaneously, alone, or sequentially in any order. In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent are administered simultaneously as a combined dose. When administered simultaneously, the two agents may be administered as a single dosage form (e.g., a fixed dosage form) or as separate doses (e.g., a non-fixed dosage form).

[0774] As used herein, the term "treat / treatment" refers to a therapeutic or alleviating measure. Beneficial or desired clinical outcomes include, but are not limited to, complete or partial relief of symptoms associated with the disease or disorder or condition, reduction of disease severity, stabilization (i.e., non-exacerbation) of the disease state, delay or alleviation of disease progression, improvement or reduction of the disease state (e.g., one or more symptoms of the disease), and alleviation (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean extended survival compared to expected survival without treatment.

[0775] As used herein, the terms “subject,” “individual,” or “patient” are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of a disease, disorder, or condition for which treatment and / or prevention are sought.

[0776] In some embodiments, the subjects are pediatric subjects.

[0777] As used herein, the term “pediatric subject” refers to a subject who is under 21 years of age at the time of diagnosis or treatment. The term “pediatric” can be further subdivided into different subgroups, including: newborns (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 years to 21 years (until, but not including, their 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th edition, Philadelphia: WBSaunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st edition, New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd edition, Baltimore: Williams & Wilkins Publishing, 1994. In some embodiments, pediatric subjects are defined as those from birth to the first 28 days of life, from 29 days to less than two years of age, from two years to less than 12 years of age, or from 12 years to 21 years of age (up to but not including the twenty-second birthday). In some embodiments, pediatric subjects are those aged from birth to the first 28 days of life, from 29 days to less than 1 year, from one month to less than four months, from three months to less than seven months, from six months to less than 1 year, from 1 year to less than 2 years, from 2 years to less than 3 years, from 2 years to less than 7 years, from 3 years to less than 5 years, from 5 years to less than 10 years, from 6 years to less than 13 years, from 10 years to less than 15 years, or from 15 years to less than 22 years.

[0778] As used herein, the term “prevention” means delaying the onset, recurrence, or spread (in whole or in part) of a disease or condition or its symptoms as described herein.

[0779] The term "regulatory agency" refers to a national agency responsible for approving and administering medicines for medical purposes. For example, a non-restrictive example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0780] The phrase “therapeuticly effective amount” means, when administered to a subject in need, an amount sufficient to (i) treat a disease, disorder, or condition, (ii) alleviate, improve, or eliminate one or more symptoms of a particular disease, disorder, or condition, or (iii) delay the onset of one or more symptoms of a particular disease, disorder, or condition described herein. The amount of a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2)) or a pharmaceutically acceptable salt thereof (which would correspond to such an amount) will vary depending on factors such as the specific compound, the disease or condition and its severity, and the identity (e.g., weight) of the subject requiring treatment, but may still be routinely determined by those skilled in the art.

[0781] Pharmaceutical composition and administration

[0782] Overview

[0783] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents (as described herein).

[0784] In some embodiments, the compound may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (such as d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (such as Tween, poloxamer, or other similar polymer delivery matrices), serum proteins (such as human serum albumin), buffering substances (such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glycerol ester mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts)), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrins), or other dissolved derivatives, may also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions containing 0.005% to 100% of the compounds described herein, with the balance made up by non-toxic excipients, can be prepared. The intended compositions may contain 0.001% to 100%, 0.1% to 95% in one example, 75% to 85% in another example, and 20% to 80% in yet another example of the compounds provided herein. Practical methods for preparing such dosage forms are known or will be obvious to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd edition (Pharmaceutical Press, London, UK, 2012).

[0785] Application route and composition components

[0786] In some embodiments, a compound having formula (I) (e.g., formula (I-1), formula (Ia) (e.g., formula (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), or (Ia-6)), or formula (Ib) (e.g., formula (Ib-1) or (Ib-2))) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may be administered to a subject in need via any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, skin, intracervical, intrasinusial, tracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intracystic, intracerebral, intracisary, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepithelial, intraepithelial, intraesophageal, intragastric, intragingival, intraileum, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinusial, spinal, intrasynovial, intratestinal, intrasheath, intracanthal, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, inhalation, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal administration. In some embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0787] In some embodiments, compounds having formula (I) as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, may be administered orally to subjects in need. Without being bound by any particular theory, it is believed that patients may prefer oral administration (e.g., compared to IV administration) due to convenience, perceived efficacy, and / or past experience.

[0788] The composition can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectable liquid solutions or suspensions; they can also be prepared in solid forms suitable for preparing solutions or suspensions when liquids are added prior to injection; and the formulation can also be emulsified. The preparation of such formulations will be known to those skilled in the art according to this disclosure.

[0789] Suitable drug forms for injectable applications include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the provisional preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must have a degree of flowability sufficient for easy injection. It should also be stable under manufacturing and storage conditions and must be preserved against microbial contamination such as bacteria and fungi.

[0790] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Suitable flowability can be maintained, for example, by using coatings (e.g., lecithin), by maintaining the desired particle size in the case of dispersions, and by using surfactants. Prevention of microbial action can be achieved using various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In most cases, isotonic agents, such as sugars or sodium chloride, are preferred. Extended absorption of injectable compositions can be achieved by using delayed-absorption agents such as aluminum monostearate and gelatin in the composition.

[0791] Sterile injectable solutions are prepared by combining the active compound in the required amount with various other components listed above (as needed) in a suitable solvent, followed by filtration sterilization. Typically, dispersions are prepared by incorporating various sterilized active ingredients into a sterile medium containing an alkaline dispersion medium and desired other components from those listed above. For sterile powders used to prepare sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying techniques, which produce powders of the active ingredient accompanied by any additional desired components from its previously sterile filtered solution.

[0792] Intratumoral injection is discussed, for example, by Lammers et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems”, Neoplasia. [Tumor Formation] 2006, 10, 788-795.

[0793] Pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include, bu...

Claims

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

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

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

4. A compound as described in any one of claims 1 to 3, wherein each R 4 It's H.

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

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

7. The compound of claims 1-6, wherein A 2 is -C(O)NH2, -C(O)NHMe or -C(O)NMe2; or A 2 It is -C(O)NHMe.

8. The compound of claim 1 or 2, wherein R 3 Yes-A 1 -C(R 4 R 4 )-A 2 ; A 1 is O; each R 4 is H; and A 2 is -C(O)NH2 or -C(O)NR 3A R f , where R 3A is optionally replaced by 1-6 R c Substituted C 1-3 alkyl.

9. The compound of claim 8, wherein A 2 It is -C(O)NH2, -C(O)NHMe or -C(O)NMe2.

10. The compound of claim 1, wherein R 3 yes 11. The compound of any one of claims 1 to 10, wherein X a Yes N; X c is N; and X b Yes CR x1 (e.g., CH); or X a is CH; X c is N; and X b Yes CR x1 (e.g., CH).

12. A compound as described in any one of claims 1 to 11, wherein R 6 It is -Cl or -F.

13. A compound as described in any one of claims 1 to 12, wherein each R 2 It's H.

14. A compound as described in any one of claims 1 to 13, wherein m3 is 0; or m3 is 1; and X 3 It is C 1-3 Alkylene (e.g., methylene, ethylene, or isopropylene).

15. The compound of any one of claims 1 to 14, wherein R 1 It's H.

16. A compound as described in any one of claims 1 to 13, wherein m3 is 1; X 3 is methylene, ethylene or isopropylene; and R 1 It's H.

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

18. The compound of claim 17, wherein m3 is 1; X 3 is methylene, ethylene or isopropylene; and R 1 It's H.

19. The compound of claim 17 or 18, wherein X a It is N.

20. The compound of any one of claims 1 to 19, wherein ring C is Ring C is Ring C is 21. The compound of any one of claims 1 to 20, wherein c1 is 0; or c1 is 1; and R Y is halogenated (eg, -F).

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

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

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

25. A compound as described in any one of claims 1 to 19, wherein the The portion is selected from the group consisting of:

26. A compound as described in any one of claims 1-19 or 25, wherein the The portion is selected from the group consisting of: Should The portion is selected from the group consisting of:

27. A compound as described in any one of claims 1-26, wherein L is -(L A ) n1 -, where L A and n1 are defined according to (AA).

28. A compound as described in any one of claims 1 to 27, wherein n1 is an integer from 1 to 5; or n1 is an integer from 2 to 5 (eg, 2 or 3).

29. The compound of any one of claims 1-28, wherein L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -L A1 -L A1 -L A4 - bb ;as well as -L A4 -L A3 -L A4 - bb , where bb represents the point of attachment to ring C.

30. The compound of claim 29, wherein each L A4 Independently C 3-10 cycloalkylene or 4-12 membered heterocyclylene, each of which is optionally substituted by 1-6 R a replace; or Each L A4 are independently optionally substituted by 1-6 R a a substituted 4-12 membered heterocyclylene; or Each L A4 are independently optionally substituted by 1-3 R a a substituted 4-10 membered heterocyclylene; or Each L A4 are independently optionally substituted by 1-3 R a A substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group.

31. The compound of claim 29 or 30, wherein one L A4 is optionally replaced by 1-3 R a substituted monocyclic 4-6 membered monocyclic nitrogen-containing heterocyclylene; and another L A4 is optionally replaced by 1-3 R a Substituted bicyclic 6-12 membered nitrogen-containing heterocyclylene.

32. The compound of claim 31, wherein another L A4 is optionally replaced by 1-3 R a A substituted spirobicyclic 6-10 membered nitrogen-containing heterocyclylene group; or Another L A4 is optionally replaced by 1-3 R a Substituted bridged bicyclic 6-10 membered nitrogen-containing heterocyclylene.

33. A compound as described in any one of claims 29-32, wherein L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH, and C optionally substituted with 1-3 F 1-3 Alkyl; or L A4 Every R that exists on a Independently selected from the group consisting of: F, methyl, CF3, CHF2 and CH2F.

34. A compound as described in any one of claims 29-33, wherein each L A4 Contains 1-2 ring nitrogen atoms and no additional ring heteroatoms.

35. A compound as described in any one of claims 29-34, wherein L is -L A4 -L A1 -L A4 - bb , where bb represents the point of attachment to ring C.

36. The compound of claim 35, wherein L A1 is -CH2-; or L A1 is -C(Me)2-; or L A1 It is -CHMe-.

37. A compound as described in any one of claims 29-34, wherein L is -L A4 -L A3 -L A4 - bb , where bb represents the point of attachment to ring C.

38. The compound of claim 37, wherein L A3 is -O-, -NH- or -N(C 1-3 alkyl)-.

39. A compound as described in any one of claims 29-34, wherein L is -L A4 -L A1 -L A1 -L A4 - bb , where bb represents the point of attachment to ring C.

40. The compound of claim 39, wherein each L A1 It is CH2.

41. A compound as described in any one of claims 1-28, wherein L is -L A4 -L A1 -(L A3 ) 1-2-bb , where bb represents the point of attachment to ring C.

42. The compound of claim 41, wherein L is -L A4 -L A1 -L A3 - bb , where bb represents the point of attachment to ring C.

43. The compound of claim 41 or 42, wherein L A1 It is -CH2-.

44. The compound of claim 41 or 42, wherein L A3 is NH or N(C 1-3 alkyl) (e.g., NH).

45. A compound as described in any one of claims 41-44, wherein L is -L A4 -CH2-NH- bb , where bb represents the point of attachment to ring C.

46. ​​A compound as described in any one of claims 41-45, wherein L A4 is optionally replaced by 1-3 R a a substituted 4-10 membered heterocyclylene; or L A4 is optionally replaced by 1-3 R a A substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group.

47. A compound as described in any one of claims 1-28, wherein L is -L A4 -L A3 - bb , where bb represents the point of attachment to ring C.

48. The compound of claim 47, wherein L A3 It is -NH- or -O-.

49. The compound of claim 47 or 48, wherein L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-8 (eg, 4-6) membered nitrogen-containing heterocyclylene group; or L A4 is optionally replaced by 1-3 R a Substituted spirobicyclic 6-12 (eg, 8-12) membered nitrogen-containing heterocyclylene.

50. The compound of any one of claims 1-28, wherein L is selected from the group consisting of a moiety depicted in Table L or Table L1a, wherein bb represents the point of attachment to ring C.

51. The compound of claim 1, wherein: Should The parts are: in: R 6 is -F or -Cl; X a is N or CH; L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -L A1 -L A1 -L A4 - bb ;as well as -L A4 -L A3 -L A4 - bb , where bb represents the point of attachment to ring C, where: Each L A4 are independently optionally substituted by 1-3 R a A substituted monocyclic 4-6 membered nitrogen-containing heterocyclic group; and The portion is selected from the group consisting of: Should The parts are: in: R 6 is -F or -Cl; X a is N or CH; L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -L A1 -L A1 -L A4 - bb ;as well as -L A4 -L A3 -L A4 - bb , where bb represents the point of attachment to ring C, where: One L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and Another L A4 is optionally replaced by 1-3 R a Substituted bicyclic 6-12 membered nitrogen-containing heterocyclylene; and Should The portion is selected from the group consisting of: Should The parts are: in: R 6 is -F or -Cl; X a is N or CH; L is selected from the group consisting of: a portion depicted in Table L, Table L1a or Table L3a; and Should The portion is selected from the group consisting of:

52. The compound of claim 51, wherein m3 is 1; X 3 is methylene, ethylene or isopropylene; and R 1 It's H.

53. The compound of claim 51 or 52, wherein X a It is N.

54. The compound of claim 51 or 52, wherein the The portion is selected from the group consisting of:

55. The compound of claim 1, wherein the compound is a compound having formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L is selected from the group consisting of: -L A4 -L A1 -L A4 - bb ; -L A4 -L A4 - bb ; -L A4 -L A1 -L A1 -L A4 - bb ;as well as -L A4 -L A3 -L A4 - bb ; where bb represents the point of attachment to ring C; and L A1 is CH2, CHMe, or CMe2; and Each L A4 are independently optionally substituted by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH and C optionally substituted by 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-1): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe or CMe2; and Each L A4 are independently optionally substituted by 1-3 R a A substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group, wherein: Each L A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms, and L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH and C optionally substituted by 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-2): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe or CMe2; Z 1 and Z 2 Independently selected from the group consisting of: CH, CR a4 , and N; Z 3 and Z 4 Independently selected from the group consisting of: CH, CR a5 and N, The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When N is 3 Is CH or CR a5 ; m4 and m5 are independently selected from the group consisting of: 0, 1, and 2; and Each R a4 and R a5 Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH and C optionally substituted by 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-3): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe or Cme2; and One L A4 is optionally replaced by 1-3 R a a substituted monocyclic 4-6 membered nitrogen-containing heterocyclylene group; and Another L A4 is optionally replaced by 1-3 R a A substituted bicyclic 6-12 membered nitrogen-containing heterocyclylene group, wherein: Each L A4 contains 1-2 ring nitrogen atoms and no additional ring heteroatoms, and L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH and C optionally substituted by 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ia-4): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L A1 is CH2, CHMe or CMe2; Z 1 and Z 2 Independently selected from the group consisting of: CH, CR a4 and N; Z 3 and Z 4 Independently selected from the group consisting of: CH, CR a5 and N, The condition is Z 1 and Z 2 At least one of them is N; Z 3 and Z 4 At least one of them is N; and when Z 2 When N is 3 Is CH or CR a5 ; m4 and m6 are independently 0 or 1; m5 is 0, 1, or 2; and Each R a4 , R a5 , and R a6 Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH and C optionally substituted by 1-3 F 1-3 Alkyl; or The compound is a compound having formula (Ib): or a pharmaceutically acceptable salt thereof, wherein: X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 Alkylene, and R 1 It is H; Ring C is selected from the group consisting of: Where: c1 is 0 or 1, R Y is selected from halo (e.g., -F) and C optionally substituted with 1-3 F 1-3 The group consisting of alkyl groups, and R aN It is C 1-3 alkyl; L is -L A4 -L A3 - bb or -L A4 -L A1 -L A3 - bb , where bb represents the point of attachment to ring C; and L A4 is optionally replaced by 1-3 R a A substituted 4-12 membered nitrogen-containing heterocyclylene group, wherein: L A4 Every R that exists on a Independently selected from the group consisting of: -F, CN, C 1-3 alkoxy, OH and C optionally substituted by 1-3 F 1-3 alkyl.

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

57. A pharmaceutical composition comprising a compound according to any one of claims 1 to 56 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

58. 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 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 57.

59. The method of claim 58, wherein the cancer is a hematological cancer, breast cancer, gastrointestinal cancer, brain cancer, lung cancer, or a combination thereof.

60. The method of claim 59, wherein the hematological cancer is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), diffuse histiocytic lymphoma (DHL), intravascular large B-cell lymphoma (IVLBCL), small lymphocytic lymphoma (SLL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or chronic myeloid leukemia (CML); or wherein the hematological cancer is selected from the group consisting of DLBCL, FL, MCL, BL, PTCL, and ALL (e.g., B-ALL); or The hematological cancer is FL or DLBCL; or The blood cancer is DLBCL; or The hematological cancer is FL; or the haematological cancer is BL; or The blood cancer is PTCL; or The hematological cancer is ALL (eg, B-ALL).

61. The method of any one of claims 58-60, wherein the therapeutically effective amount of the compound of any one of claims 1-56 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 57 is administered to the subject as a monotherapy.

62. The method of any one of claims 58-60, comprising administering to the subject an additional therapy or therapeutic agent.

63. The method of claim 62, wherein the additional therapy or therapeutic agent is a PI3K inhibitor, an Abl inhibitor (e.g., a BCR-Abl inhibitor), a BTK inhibitor, a JAK inhibitor, a BRaf inhibitor, a MEK inhibitor, a BCL-2 inhibitor, a BCL-X inhibitor, a L inhibitors, XPO1 inhibitors, inhibitors of polycomb repressive complex 2 (PRC2), immunomodulatory imide drugs, anti-CD19 therapy, anti-CD20 therapy, anti-CD3 therapy, chemotherapy, or a combination thereof.

64. A method for treating an autoimmune disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57.

65. A method for treating a lymphoproliferative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-56 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57.

66. A compound having formula (SII): or a salt thereof, wherein: L g It is halogenated; X a is N or CH; R 6 is -F or -Cl; m3 is 1, X 3 It is C 1-3 an alkylene group, and R 1 It's H.

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

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