Tetrahydroisoquinoline isobifunctional BCL-XL degradation agent

Abstract

The present disclosure provides Formula (I) (e.g. (I-A) (e.g. (I-A-1), (I-A-2) or (I-A-3)), (I-B) (e.g. (I-B-1), (I-B-2) or (I-B-3)), (I-C), (I-D), (I-E) (e.g. (I-E-1), (I-Ea-2) or (I-E-3)), (I-Eb) (e.g. (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (I-F) (e.g. (I-F-1), (I-F-2) or (I-F-3)), (I-G), (I-Ga), (I-H) (e.g. (I- a compound or a pharmaceutically acceptable salt thereof. These compounds are useful, for example, in the treatment of cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the compounds provided herein as well as methods of using and making the compositions. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims priority to U.S. Provisional Application Serial No. 63 / 457,997, filed on April 7, 2023; U.S. Provisional Application Serial No. 63 / 454,545, filed on March 24, 2023; U.S. Provisional Application Serial No. 63 / 449,756, filed on March 3, 2023; U.S. Provisional Application Serial No. 63 / 429,862, filed on December 2, 2023; U.S. Provisional Application Serial No. 63 / 398,783, filed on August 17, 2022; and U.S. Provisional Application Serial No. 63 / 339,253, filed on May 6, 2022, each of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure provides a method for inducing BCL-X L Compounds of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof, that degrade proteins. These compounds can be used, for example, to treat cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the compounds provided herein and methods of using and making the compositions. Background Art

[0004] The BCL-2 protein family is involved in the regulation of cell apoptosis and includes pro-apoptotic proteins, pro-survival proteins, and BH3-only proteins. At high levels, the balance of binding of BH3-only proteins to pro-apoptotic and pro-survival members of the BCL-2 family can determine whether a cell will undergo apoptosis. Protein BCL-X L (encoded by the BCL2L1 gene) is a pro-survival member of the BCL-2 family. In many cancers, it may be desirable to initiate apoptosis in tumor cells by reducing the availability of pro-survival proteins (e.g., BCL-X) that can compete for BH3-only protein binding. L ) amount to achieve. Summary of the Invention

[0005] The present disclosure provides a method for inducing BCL-X L Compounds of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof, that inhibit the degradation of proteins. These compounds can be used, for example, to treat cancer in a subject (e.g., a human). The present disclosure also provides compositions containing the compounds provided herein and methods of using and making the compositions.

[0006] Provided herein are compounds of formula (I) or (II):

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] Ring A is selected from:

[0010] (a)C 3-15 Cycloalkylene or 3 to 15 membered heterocyclylene, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: R a and R b ;as well as

[0011] (b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R a and R b ;

[0012] L T1 is key or C 1-3 Alkylene, which is optionally substituted by 1 to 3 independently selected oxo and R c Substituents substituted, wherein the C 1-3 A CH2 unit of the alkylene group is optionally replaced by -O- or -N(R d )-alternative;

[0013] A* is selected from:

[0014] (a)C 3-15 cycloalkyl or 3 to 15 membered heterocyclyl, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: R a and R b ;

[0015] (b)C 6-15 aryl or 5- to 15-membered heteroaryl, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: R a and R b ;as well as

[0016] (c)H;

[0017] R 1 Selected from:

[0018] (a)C(O)OH,

[0019] (b)C(O)NR d R e ,and

[0020] (c)C(O)OC 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 R c replace;

[0021] Each R 2 、R 3 、R 4 and R 5 Independently selected from: halo, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH and NR d R e ;

[0022] m2 is 0, 1, or 2;

[0023] m3 and m4 are independently 0, 1, 2 or 3;

[0024] m5 is 0, 1, 2, 3, or 4;

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

[0026] (AA)

[0027] n1 is an integer from 3 to 15; and

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

[0029] (BB)

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

[0031] Each L A Independently selected from: L A1 and L A3 ;

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

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

[0034] Each L A4 Independently selected from:

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

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

[0038] Each R L Independently selected from: 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 to 6 R c Replace C 1-6 alkyl;

[0039] Ring C is selected from:

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

[0041] Each R Y Independently selected from: R a and R b ;

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

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

[0044] yy represents the point of attachment to L;

[0045] X is CH, C or N;

[0046] Is a single bond or a double bond;

[0047] L C Selected from: bond, -CH2-, -CHR a -、-C(R a )2-、-N(R d )- and O, provided that when X is N, then L C Not O;

[0048] Each R a Independently selected from:

[0049] (a) halo;

[0050] (b) cyano;

[0051] (c) -OH;

[0052] (d) oxo;

[0053] (e)-C 1-6 alkoxy;

[0054] (f)-C1-6 haloalkoxy;

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

[0056] (h)C(=O)C 1-6 alkyl;

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

[0058] (j) C(=O)OH;

[0059] (k)C(=O)OC 1-6 alkyl;

[0060] (l)C(=O)OC 1-6 alkyl halide;

[0061] (m)C(=O)N(R f )2;

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

[0063] (o)S(O) 0-2 (C 1-6 haloalkyl);

[0064] (p)S(O) 1-2 N(R f )2; and

[0065] (q)C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, each optionally substituted by 1 to 6 R c replace;

[0066] Each R b Independently selected from: -(L b ) b -R b1 and -R b1 ,in:

[0067] Each b is independently 1, 2 or 3;

[0068] Each -L b Independently selected from: -O-; -N(H)-; -N(C 1-3 alkyl)-;-S(O) 0-2 -; C(=O); and C 1-3 alkylene; and

[0069] Each Rb1 Independently selected from: C 3-10 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R g replace;

[0070] Each R c Independently selected from: 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;

[0071] Each R d and R e Independently selected from: 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 to 3 R h Substituted C 1-6 alkyl;

[0072] Each R f Independently selected from: H and optionally 1 to 3 R h Substituted C 1-6 alkyl;

[0073] Each R g Independently selected from: R h ; C 1-3 Alkyl; and C 1-3 haloalkyl; and

[0074] Each R h Independently selected from: halo; cyano; -OH; -C 1-6 Alkoxy; -C 1-6 Haloalkoxy; -NH2, -N(H)(C 1-3 alkyl); and -N(C 1-3 Alkyl)2.

[0075] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0076] Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0077] This article also provides a BCL-X LA protein that non-covalently binds to a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof.

[0078] Also provided herein is a ternary complex comprising BCL-X L A protein, a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, and a CRBN protein or a portion thereof.

[0079] For ease of understanding the disclosure set forth herein, many other terms are provided. Typically, the nomenclature used herein and the laboratory procedures in described organic chemistry, medicinal chemistry and pharmacology are those well known in the art and commonly used. Unless otherwise defined, all technical and scientific terms used herein typically have the same meaning as that commonly understood by those of ordinary skill in the art of the disclosure. Each of the patents, patent applications, published applications and other publications mentioned throughout the specification and the appendix are incorporated herein by reference in their entirety.

[0080] The details of one or more embodiments of the invention are set forth in the following drawings and description. Other features and advantages of the invention will be apparent from these descriptions and drawings, and from the claims. DETAILED DESCRIPTION

[0081] The present disclosure provides a method for inducing BCL-X L Compounds of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof, that inhibit the degradation of Bcl-xL proteins. These compounds can be used, for example, to treat cancer. The present disclosure also provides compositions containing the compounds provided herein and methods of using and making the compositions.

[0082] Without being bound by any particular theory, it is believed that in healthy cells, pro-apoptotic effectors such as BAX and BAK can move between the cytosol and the mitochondrial outer membrane (MOM), where voltage-dependent anion channel 2 (VDAC2) can serve as a receptor. L and MCL-1) can transport BAX back to the cytosol. BH3-only proteins (e.g., BIM) can engage the late site on pro-apoptotic effectors (e.g., BAX or BAK) and release the C-terminal transmembrane domain (α9) of the effector, enabling binding to MOM. The binding of BIM to the classic BH3 binding groove of BAX or BAK releases the N-terminus and α1 of BAX or BAK, and then the unfolding of the "latch" domain releases BIM from the BH3 binding groove. If the pro-survival BCL-2 family member then binds to BAX or BAK, apoptotic signaling is usually stopped. However, if BAX or BAK is allowed to dimerize and then oligomerize, MOM can be permeabilized, causing apoptosis.

[0083] Large amounts of pro-survival BCL-2 family members are sometimes thought to "trigger" cell death (e.g., by cytotoxic therapies, including BH3 mimetics). It is believed that oncogenic mutations and stress may cause upregulation of BH3-only proteins, thereby creating a selective pressure on cancer cells to upregulate pro-survival BCL-2 family proteins. Therefore, it is believed that the more BH3-only proteins around, the more sensitive the cell is to further manipulation of the BCL-2 family balance. See, e.g., Adams and Cory, Cell Death & Differentiation 25.1 (2018): 27-36.

[0084] Compounds that induce degradation of target proteins are sometimes referred to as heterobifunctional compounds, PROTACs or degradation agents. Such compounds typically include a portion that is bound to the target protein and a portion that is bound to an ubiquitin E3 ligase (sometimes referred to as an E3 ligase or simply referred to as E3), and these two portions are optionally separated by a joint. It is believed that in order to induce degradation, heterobifunctional compounds induce the formation of a ternary complex between the target protein, the compound, and the E3 ligase. The formation of the ternary complex is followed by ubiquitination of the target protein and degradation of the target protein by the proteasome through ubiquitination. Several E3 ligases have been used as partner E3 ligases of heterobifunctional degradation agents. In this article, cereblon (CRBN) E3 ligase (also referred to as CRBN protein in this article) is used.

[0085] Degradation of the target protein may have potential advantages over, for example, small molecule inhibition of the target protein. One potential advantage is that the duration of action of the heterobifunctional compound is generally based on the rate of resynthesis of the target protein. Another potential advantage is that many heterobifunctional compounds are believed to be released from the ubiquitinated target protein-E3 ligase complex and are available to form additional ternary complexes; this is sometimes referred to as "catalytic" conversion of the heterobifunctional compound. In some cases, degradation of the target protein may also be more advantageous than small molecule inhibition because degradation can weaken the scaffolding function of the target protein, while small molecules cannot weaken this function. It is also generally believed that a high affinity for the target protein is not always required for the formation of the ternary complex.

[0086] Heterobifunctional compounds are disclosed in, for example, International Publications WO 2017 / 184995; WO 2019 / 144117; WO 2020 / 163823; WO 2021 / 078301; WO 2021 / 146536; WO 2021 / 007307; WO 2021 / 222114; WO 2022 / 169780; WO 2023 / 044046; Chamberlai 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 Further description is provided in Medicinal Chemistry 64.15(2021):10606-10620; Yang et al., Targeted Oncology 16.1(2021):1-12; Lv et al., Nature Communications 12.1(2021):6896.

[0087] Compound Implementation

[0088] Provided herein are compounds of formula (I) or (II):

[0089]

[0090]

[0091] or a pharmaceutically acceptable salt thereof, wherein:

[0092] Ring A is selected from:

[0093] (a)C 3-15 Cycloalkylene or 3 to 15 membered heterocyclylene, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: R a and R b ;as well as

[0094] (b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R a and R b ;

[0095] L T1 is key or C 1-3 Alkylene, which is optionally substituted by 1 to 3 independently selected oxo and Rc Substituents substituted, wherein the C 1-3 A CH2 unit of the alkylene group is optionally replaced by -O- or -N(R d )-alternative;

[0096] A* is selected from:

[0097] (a)C 3-15 cycloalkyl or 3 to 15 membered heterocyclyl, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: R a and R b ;

[0098] (b)C 6-15 aryl or 5- to 15-membered heteroaryl, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: R a and R b ;as well as

[0099] (c)H;

[0100] R 1 Selected from:

[0101] (a)C(O)OH,

[0102] (b)C(O)NR d R e ,and

[0103] (c)C(O)OC 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 R c replace;

[0104] Each R 2 、R 3 、R 4 and R 5 Independently selected from: halo, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH and NR d R e ;

[0105] m2 is 0, 1, or 2;

[0106] m3 and m4 are independently 0, 1, 2 or 3;

[0107] m5 is 0, 1, 2, 3, or 4;

[0108] L is -(L A ) n1 -, where L Aand n1 is defined according to (AA) or (BB):

[0109] (AA)

[0110] n1 is an integer from 3 to 15; and

[0111] Each L A Independently selected from: L A1 , L A3 and L A4 , the condition is 1 to 3 occurrences of L A It's L A4 ;

[0112] (BB)

[0113] n1 is an integer from 0 to 20; and

[0114] Each L A Independently selected from: L A1 and L A3 ;

[0115] Each L A1 Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0116] Each L A3 Independently selected from: -N(R d )-、-N(R b )-、-O-、-S(O) 0-2 - and C(=O);

[0117] Each L A4 Independently selected from:

[0118] (a)C 3-15 Cycloalkylene or 3 to 15 membered heterocyclylene, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: R a and R b ;as well as

[0119] (b)C 6-15 arylene or 5- to 15-membered heteroarylene, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: R a and R b ;

[0120] Provided that L does not contain any NO, OO, NN, NS(O)0 or OS(O) 0-2 key;

[0121] Each R LIndependently selected from: 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 to 6 R c Replace C 1-6 alkyl;

[0122] Ring C is selected from:

[0123] c1 is 0, 1, 2, or 3;

[0124] Each R Y Independently selected from: R a and R b ;

[0125] R aN is H or optionally 1 to 3 R c Substituted C 1-6 alkyl;

[0126] Y 1 and Y 2 are independently N, CH or CR Y ;

[0127] yy represents the point of attachment to L;

[0128] X is CH, C or N;

[0129] Is a single bond or a double bond;

[0130] L C Selected from: bond, -CH2-, -CHR a -、-C(R a )2-、-N(R d )- and O, provided that when X is N, then L C Not O;

[0131] Each R a Independently selected from:

[0132] (a) halo;

[0133] (b) cyano;

[0134] (c) -OH;

[0135] (d) oxo;

[0136] (e)-C 1-6 alkoxy;

[0137] (f)-C 1-6 haloalkoxy;

[0138] (g)-NR d R e ;

[0139] (h)C(=O)C 1-6 alkyl;

[0140] (i) C(=O)C 1-6 alkyl halide;

[0141] (j) C(=O)OH;

[0142] (k)C(=O)OC 1-6 alkyl;

[0143] (l)C(=O)OC 1-6 alkyl halide;

[0144] (m)C(=O)N(R f )2;

[0145] (n)S(O) 0-2 (C 1-6 alkyl);

[0146] (o)S(O) 0-2 (C 1-6 haloalkyl);

[0147] (p)S(O) 1-2 N(R f )2; and

[0148] (q)C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, each optionally substituted by 1 to 6 R c replace;

[0149] Each R b Independently selected from: -(L b ) b -R b1 and -R b1 ,in:

[0150] Each b is independently 1, 2 or 3;

[0151] Each -L bIndependently selected from: -O-; -N(H)-; -N(C 1-3 alkyl)-;-S(O) 0-2 -; C(=O); and C 1-3 alkylene; and

[0152] Each R b1 Independently selected from: C 3-10 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6-10 Aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R g replace;

[0153] Each R c Independently selected from: 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;

[0154] Each R d and R e Independently selected from: 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 to 3 R h Substituted C 1-6 alkyl;

[0155] Each R f Independently selected from: H and optionally 1 to 3 R h Substituted C1-6 alkyl;

[0156] Each R g Independently selected from: R h ; C 1-3 Alkyl; and C 1-3 haloalkyl; and

[0157] Each R h Independently selected from: halo; cyano; -OH; -C 1-6 Alkoxy; -C 1-6 Haloalkoxy; -NH2, -N(H)(C 1-3 alkyl); and -N(C 1-3 Alkyl)2.

[0158] In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, Ring A is phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted with 1 to 3 substituents independently selected from: R a and R b .

[0161] In some embodiments, Ring A is phenylene optionally substituted with 1 to 3 substituents selected from: R a and R b In some embodiments, Ring A is optionally substituted with 1 to 3 R a Substituted phenylene.

[0162] In some embodiments, Ring A is phenylene (eg, 1,3-phenylene or 1,4-phenylene).

[0163] In some embodiments, Ring A is Where aa represents L or L T1 attachment point.

[0164] In some embodiments, Ring A is Where aa represents L or L T1 For example, ring A can be Where aa represents L or L T1 attachment point.

[0165] In some embodiments, Ring A is Where aa represents L or L T1 attachment point.

[0166] In some embodiments, Ring A is Where aa represents L or L T1 For example, ring A can be Where aa represents L or L T1 attachment point.

[0167] In some embodiments, Ring A is optionally substituted with 1 to 3 R a In some embodiments, Ring A is optionally substituted with 1 to 2 R a In some embodiments, Ring A is optionally substituted with 1 to 2 R a In some embodiments, Ring A is optionally substituted with 1 to 2 R a For example, ring A can be selected from: Where aa represents L or L T1 attachment point.

[0168] In some embodiments, Ring A is optionally substituted with 1 to 6 R a Substituted C 3-10 In some embodiments, Ring A is optionally substituted with 1 to 3 R a Substituted C 4-6 In some embodiments, Ring A is optionally substituted with 1 to 3 R a Substituted cyclohexylene. For example, Ring A may be 1,4-cyclohexylene.

[0169] In some embodiments, one R present on Ring A a is C optionally substituted with 1 to 3 F 1-3 In some embodiments, one R present on ring A a It is methyl or CF3.

[0170] In some embodiments, R 1 is C(O)OH. In some embodiments, R 1 It is C(O)OC 1-6 In some embodiments, R 1 It is C(O)NHR e .

[0171] In some embodiments, R 1 is C(O)OH; and Ring A is Where aa represents L or L T1 In some embodiments, Ring A is Where aa represents L or L T1 For example, ring A can be Where aa represents L or L T1 In some embodiments, Ring A is Where aa represents L or L T1 For example, ring A can be Where aa represents L or L T1 attachment point.

[0172] In some embodiments, R 1 is C(O)OH; and Ring A is Where aa represents L or L T1 attachment point.

[0173] In some embodiments, R 1 Is C(O)OH or C(O)OC 1-6 alkyl; and Ring A is selected from: where R a1 is C optionally substituted with 1 to 3 F 1-3 and aa represents an alkyl group with L or L T1 attachment point.

[0174] In some embodiments, L T1 It is C 1-3 Alkylene. For example, L T1 It can be -CH2-.

[0175] In some embodiments, A* is H. In some embodiments, A* is C 3-15 cycloalkyl or 3 to 15 membered heterocyclyl, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of: R a and R b In some embodiments, A* is optionally replaced by 1 to 3 R a Substituted C 3-15 For example, A* can be optionally substituted with 1 to 3 R a Substituted adamantyl.

[0176] In some embodiments, m2 is 0. In some embodiments, m3 is 0. In some embodiments, m4 is 0. In some embodiments, m5 is 0.

[0177] In some embodiments, m2 is 0; m3 is 0; m4 is 0; and m5 is 0.

[0178] In some embodiments, m2 is 0; m3 is 0; m4 is 0; and m5 is 0;

[0179] R 1Is C(O)OH or C(O)OC 1-6 Alkyl; and

[0180] Ring A is selected from: where R a1 is C optionally substituted with 1 to 3 F 1-3 and aa represents an alkyl group with L or L T1 attachment point.

[0181] In some embodiments, m2 is 0; m3 is 0; m4 is 0; and m5 is 0;

[0182] R 1 Is C(O)OH or C(O)OC 1-6 Alkyl; and

[0183] Ring A is selected from: Where aa represents L or L T1 attachment point.

[0184] In some embodiments, Ring C is In some embodiments, Ring C is (For example ). For example, ring C can be (For example ). For example, ring C can be (For example ). For example, ring C can be (For example (For example ).

[0185] In some embodiments, Ring C is Where c1 is 0 or 1; and R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 -F 1-3 In some embodiments, ring C is where R aN It is C 1-3 alkyl (eg, methyl); c1 is 0 or 1; and R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 -F 1-3 In some embodiments, Ring C is selected from:

[0186]

[0187] In some embodiments, Ring C is In some embodiments, Ring C is For example, ring C can be (For example ). For example, ring C can be (For example ).

[0188] In some embodiments, c1 is 0.

[0189] In some embodiments, c1 is 1. In some embodiments, c1 is 1; and R Y It is R a In some embodiments, R Y Yes - F, C 1-3 alkyl or C optionally substituted by 1 to 3 -F 1-3 alkyl.

[0190] In some embodiments, R aN It is C 1-3 Alkyl. For example, R aN It may be methyl.

[0191] In some embodiments, L C is a bond or -N(R d )-. In some embodiments, L C is a bond or -N(H)-. For example, L C Can be a key. For example, L C It can be -NH-.

[0192] In some embodiments, X is CH.

[0193] In some embodiments, Partly In some embodiments, Partly In some embodiments, Partly In some embodiments, Partly

[0194] In some embodiments, L is -(L A ) n1 -;L A and n1 is defined as (AA). In some embodiments, n1 is an integer from 3 to 5. In some embodiments, n1 is an integer from 5 to 9. In some embodiments, n1 is 6, 7, or 8. In some embodiments, n1 is an integer from 9 to 12.

[0195] In some embodiments, L A and n1 is defined as (AA); and 1 to 2 occurrences of L A It's L A4In some embodiments, one occurrence of L A It's L A4 In some embodiments, two occurrences of L A It's L A4 In some embodiments, each L A4 Independently selected from:

[0196] a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3

[0197] R a Replacement; and

[0198] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace.

[0199] In some embodiments, L A and n1 is defined as (AA); and 1 to 4 occurrences of L A It's L A3 In some embodiments, 1 to 3 (e.g., 1 to 2 or 2 to 3) occurrences of L A It's L A3 In some embodiments, 0 to 1 occurrences of L A3 is C(=O); each remaining occurrence of L A3 are independently selected from: -O-; -N(H)-; and -N(C 1-3 alkyl)-.

[0200] In some embodiments, L A and n1 is defined as (AA); and 2 to 7 occurrences of L A It's L A1 In some embodiments, 2 to 5 occurrences of L A It's L A1 In some embodiments, 0 to 2 (e.g., 0 to 1) occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 In some embodiments, each occurrence of L A1 In some embodiments, one occurrence of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. In some embodiments, each R L Independently selected from: -F and -C optionally substituted with 1 to 3 F1-3 Alkyl (eg, CH3 or CF3).

[0201] In some embodiments, L is -(L A ) n1 -, and L A and n1 is defined according to (AA), wherein n1 is an integer from 5 to 9; 1 to 2 occurrences of L A It's L A4 ; 2 to 7 occurrences of L A It's L A1 ; and 1 to 3 occurrences of L A It's L A3 In some embodiments, each L A4 Independently selected from: C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a and phenylene or 5 to 6 membered heteroarylene, each of which is optionally substituted by 1 to 3 R a In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. In some embodiments, 0 to 1 occurrences of L A3 is C(=O); each remaining occurrence of L A3 are independently selected from: -O-; -N(H)-; and -N(C 1-3 alkyl)-.

[0202] In some embodiments, L is selected from:

[0203] (i)-(L A3 ) 0-2 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(L A3 ) 1-2-bb ;

[0204] (ii)-(L A3 ) 0-2 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A4 - bb ;

[0205] (iii)-(L A3 )0-2 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 -L A4 - bb ;as well as

[0206] (iv)-(L A3 ) 0-1 -(L A1 ) 2-3 -L A3 -L A4 -(L A1 ) 0-5 -(L A3 ) 1-2-bb ;

[0207] Provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, each L A4 Independently selected from: C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a and phenylene or 5 to 6 membered heteroarylene, each of which is optionally substituted by 1 to 3 R a In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. In some embodiments, 0 to 1 occurrences of L A3 is C(=O); each remaining occurrence of L A3 are independently selected from: -O-; -N(H)-; and -N(C 1-3 alkyl)-.

[0208] In some embodiments, L is -(L A3 ) 0-2 -(L A1 ) 2-9 -(L A3 ) 0-1 -L A4 - bb , wherein bb represents the point of attachment to ring C. In some embodiments, L A4 Selected from: C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a and phenylene or 5 to 6 membered heteroarylene, each of which is optionally substituted by 1 to 3 Ra In some embodiments, L A4 is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered heterocyclylene (e.g., 5- to 6-membered heterocyclylene (e.g., 6-membered heterocyclylene (e.g., piperazinylene))). In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. In some embodiments, 0 to 1 occurrences of L A3 is C(=O); each remaining occurrence of L A3 are independently selected from: -O-; -N(H)-; and -N(C 1-3 alkyl)-.

[0209] In some embodiments, L is: -(L A3 ) 0-2 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(L A3 ) 1-2-bb ; Provided that L contains 1 to 7 (e.g., 2 to 7) L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(L A3 ) 2-bb ; Provided that L contains 1 to 5 (e.g., 2 to 5) L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L A4 Selected from: C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a and phenylene or 5 to 6 membered heteroarylene, each of which is optionally substituted by 1 to 3 R a In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. In some embodiments, 0 to 1 occurrences of L A3 is C(=O); each remaining occurrence of LA3 are independently selected from: -O-; -N(H)-; and -N(C 1-3 alkyl)-.

[0210] In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -C(=O)-N(R d )- bb ; Provided that L contains 1 to 5 (e.g., 2 to 5) L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L A4 Selected from: C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a and phenylene or 5 to 6 membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replace. For example, L A4 may be optionally replaced by 1 to 3 R a In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. For example, L can be selected from:

[0211] wherein bb represents the point of attachment to ring C. For example, L may be selected from: wherein bb represents the point of attachment to ring C. For example, L may be selected from:

[0212] where bb represents the point of attachment to ring C.

[0213] In some embodiments, L is a divalent group of formula (L-1):

[0214]

[0215] in:

[0216] a3 is 0 or 1;

[0217] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0218] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5 (e.g., 2 to 5);

[0219] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0220] L A4 Selected from:

[0221] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0222] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0223] bb indicates the point of attachment to ring C.

[0224] In some embodiments of (L-1), a3 is 1. In some embodiments, L A3 is -O-. In some embodiments of (L-1), a3 is 1; and L A3 In some embodiments of (L-1), a3 is 0.

[0225] In some embodiments of (L-1), a1a+a1b is 3 or 4. For example, a1a+a1b can be 3. For example, a1a+a1b can be 4.

[0226] In some embodiments of (L-1), a1a+a1b is 2 or 5. For example, a1a+a1b can be 5. For example, a1a+a1b can be 2.

[0227] In some embodiments of (L-1), a1a+a1b is 1.

[0228] In some embodiments of (L-1), each occurrence of L A1a and L A1b is -CH2-. In some embodiments of (L-1), one occurrence of L A1a Yes-CHR L -or-C(R L )2-; Each remaining L A1a is -CH2-; and each occurrence of L A1b is -CH2-. In some embodiments of (L-1), one occurrence of LA1b Yes-CHR L -or-C(R L )2-; Each remaining L A1b is -CH2-; and each occurrence of L A1a It is -CH2-.

[0229] In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 - bb ; provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -O- bb 、-(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -N(H)- bb or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -N(C 1-3 alkyl)- bb ; provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L A4 Selected from: C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a and phenylene or 5 to 6 membered heteroarylene, each of which is optionally substituted by 1 to 3 R a In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. For example, L can be where bb represents the point of attachment to ring C.

[0230] In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5-bb ; provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L A4 Selected from: (a) C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a and (b) phenylene or 5 to 6 membered heteroaryl, each of which is optionally substituted by 1 to 3 R a In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. For example, L can be where bb represents the point of attachment to ring C.

[0231] In some embodiments, L is a divalent group of formula (L-2) or (L-2a):

[0232]

[0233] in:

[0234] a3a is 0 or 1;

[0235] L A3a and L A3b Independently selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0236] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 7;

[0237] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0238] L A4 Selected from:

[0239] a)C3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0240] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0241] bb indicates the point of attachment to ring C.

[0242] In some embodiments of (L-2) or (L-2a), a3a is 1. In some embodiments, L A3a In some embodiments of (L-2) or (L-2a), a3a is 1 and L A3a Yes -O-.

[0243] In some embodiments of (L-2), L A3b Is -N(H)- or -N(C 1-3 In some embodiments of (L-2), L A3b Yes -O-.

[0244] In some embodiments of (L-2) or (L-2a), a1a+a1b is 2, 3, or 4. For example, a1a+a1b can be 3. For example, a1a+a1b can be 4. In some embodiments, a1a is 3.

[0245] In some embodiments of (L-2) or (L-2a), a1a+a1b is 5 or 6.

[0246] In some embodiments of (L-2) or (L-2a), each occurrence of L A1a and L A1b In some embodiments of (L-2) or (L-2a), one occurrence of L A1a Yes-CHR L -or-C(R L )2-; Each remaining L A1a is -CH2-; and each occurrence of L A1b In some embodiments of (L-2) or (L-2a), one occurrence of L A1b Yes-CHR L -or-C(R L )2-; Each remaining L A1b is -CH2-; and each occurrence of L A1a It is -CH2-.

[0247] In some embodiments, L is: -(L A3) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A4 - bb ;-(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 -L A4 - bb ; or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A4 -L A3 - bb , provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(4- to 10-membered (e.g., 6-membered) heterocyclylene)- bb ;-(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 -(4- to 10-membered (e.g., 6-membered) heterocyclylene)- bb ; or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 -(4 to 10 (e.g., 6) membered heterocyclylene)-L A3 - bb , provided that L contains 2 to 7 L A1 , wherein the 4 to 10 (e.g. 6) membered heterocyclylene group is optionally substituted by 1 to 3 R asubstituted; and wherein bb represents the point of attachment to ring C.

[0248] In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(Piperazinylene)- bb ;-(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(Piperidinylene)- bb ;-(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(pyrrolidinylene)- bb ;-(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -C(=O)-(piperazinylene)- bb ;-(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -C(=O)-(piperidinylene)- bb ; or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(Piperidinylene)-O- bb , provided that L contains 2 to 5 L A1 wherein the piperazinylene, piperidinylene and pyrrolidinylene are each optionally substituted by 1 to 3 R a substituted, and wherein bb represents the point of attachment to ring C. In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L)2-; and each remaining occurrence of L A1 It is -CH2-.

[0249] In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(4- to 10-membered heterocyclylene)- bb ; or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 -(4- to 10-membered heterocyclylene)- bb ; provided that L contains 2 to 7 L A1 , further, provided that the 4 to 10 membered heterocyclylene contains two ring nitrogen atoms and no additional ring heteroatoms, wherein the 4 to 10 membered heterocyclylene is optionally substituted by 1 to 3 R a and wherein bb represents the point of attachment to ring C. In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(Piperazinylene)- bb ; or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -C(=O)-(piperazinylene)- bb ; provided that L contains 2 to 5 L A1 wherein the piperazinyl group is optionally substituted by 1 to 3 R a and bb represents the point of attachment to Ring C. In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(Piperazinylene)- bb ; or -(L A3 ) 0-1 -(L A1 )0-5 -L A4 -(L A1 ) 0-5 -C(=O)-(piperazinylene)- bb ; provided that L contains 2 to 5 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 It is -CH2-.

[0250] For example, L may be selected from: where bb represents the point of attachment to ring C.

[0251] For example, L may be selected from:

[0252]

[0253] where bb represents the point of attachment to ring C.

[0254] In some embodiments, L is a divalent group of formula (L-3) or (L-4):

[0255]

[0256] in:

[0257] a3 is 0 or 1;

[0258] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0259] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5 (e.g., 2 to 5);

[0260] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0261] L A4 Selected from:

[0262] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0263] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0264] m8 is 0, 1, or 2; and

[0265] bb indicates the point of attachment to ring C.

[0266] In some embodiments of (L-3) or (L-4), m8 is 0. In some embodiments of (L-3) or (L-4), m8 is 1. In some embodiments of (L-3) or (L-4), m8 is 2.

[0267] In some embodiments of (L-3) or (L-4), a3 is 1. In some embodiments, L A3 Is O. In some embodiments of (L-3) or (L-4), a3 is 1; and L A3 Yes -O-.

[0268] In some embodiments of (L-3) or (L-4), a1a+a1b is 3 or 4. For example, a1a+a1b can be 3. For example, a1a+a1b can be 4.

[0269] In some embodiments of (L-3) or (L-4), a1a+a1b is 5.

[0270] In some embodiments of (L-3) or (L-4), a1a+a1b is 2.

[0271] In some embodiments of (L-3) or (L-4), a1a+a1b is 2 to 5.

[0272] In some embodiments of (L-3) or (L-4), each occurrence of L A1a and L A1b In some embodiments of (L-3) or (L-4), one occurrence of L A1a Yes-CHR L -or-C(R L )2-; Each remaining L A1a is -CH2-; and each occurrence of L A1b In some embodiments of (L-3) or (L-4), one occurrence of L A1b Yes-CHR L -or-C(R L )2-; Each remaining L A1b is -CH2-; and each occurrence of L A1a It is -CH2-.

[0273] In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(4- to 10-membered (e.g., 6-membered) heterocyclylene)- bb ;-(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 -(4- to 10-membered (e.g., 6-membered) heterocyclylene)- bb ; or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(4 to 10 (e.g., 6) membered heterocyclylene)-L A3 - bb ; provided that L contains 2 to 7 L A1 , further, provided that the 4 to 10 (e.g. 6) membered heterocyclylene group contains one ring nitrogen atom and no additional ring heteroatoms, wherein the 4 to 10 membered heterocyclylene group is optionally substituted by 1 to 3 R a and wherein bb represents the point of attachment to ring C. In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(Piperidinylene)- bb ;-(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -C(=O)-(piperidinylene)- bb ; or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(Piperidinylene)-O- bb ; provided that L contains 2 to 5 L A1wherein the piperidinyl group is optionally substituted by 1 to 3 R a and bb represents the point of attachment to Ring C. In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(Piperidinylene)- bb ; provided that L contains 2 to 5 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 It is -CH2-.

[0274] For example, L may be selected from: where bb represents the point of attachment to ring C.

[0275] In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A4 -L A3 - bb ; provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(4- to 10-membered (e.g., 6-membered) heterocyclylene)-O- bb , provided that L contains 2 to 7 L A1 , wherein the 4 to 10 (e.g. 6) membered heterocyclylene group is optionally substituted by 1 to 3 R a and wherein bb represents the point of attachment to ring C. In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. For example, L can be where bb represents the point of attachment to ring C.

[0276] In some embodiments, L is a divalent group of formula (L-3a) or (L-3b):

[0277]

[0278] in:

[0279] a3 is 0 or 1;

[0280] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0281] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0282] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0283] L A4 Selected from:

[0284] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0285] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0286] n2 and n3 are independently 0, 1 or 2;

[0287] m8 is 0, 1, or 2; and

[0288] bb indicates the point of attachment to ring C.

[0289] In some embodiments, L is a divalent group of formula (L-3c):

[0290]

[0291] in:

[0292] a3 is 0 or 1;

[0293] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0294] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0295] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0296] L A4a Selected from:

[0297] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0298] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0299] n2 and n3 are independently 0, 1 or 2;

[0300] m8 is 0, 1, or 2;

[0301] L A4b is optionally replaced by 1 to 3 R a substituted 7- to 10-membered bicyclic nitrogen-containing heterocyclylene; and bb represents the point of attachment to Ring C.

[0302] In some embodiments of Formula (L-3c), L A4b is optionally replaced by 1 to 3 R a Substituted 7- to 10-membered spirocyclic nitrogen-containing heterocyclic group. For example, L A4b Can be In some embodiments of Formula (L-3c), L A4a is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered heterocyclylene.

[0303] In some embodiments, L is a divalent group of formula (L-3d) or (L-4a):

[0304]

[0305] in:

[0306] a3 is 0 or 1;

[0307] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0308] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0309] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0310] L A4 Selected from:

[0311] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0312] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0313] n2 and n3 are independently 0, 1 or 2;

[0314] m8 is 0, 1, or 2; and

[0315] bb indicates the point of attachment to ring C.

[0316] In some embodiments of (L-3a), (L-3b), (L-3c), (L-3d), or (L-4a), a3 is 1. In some embodiments, L A3 is O. In some embodiments of (L-3a), a3 is 1; and L A3 Yes -O-.

[0317] In some embodiments of (L-3a), (L-3b), (L-3c), (L-3d), or (L-4a), a1a+a1b is 3 or 4. For example, a1a+a1b can be 3. For example, a1a+a1b can be 4.

[0318] In some embodiments of (L-3a), (L-3b), (L-3c), (L-3d), or (L-4a), a1a+a1b is 5.

[0319] In some embodiments of (L-3a), (L-3b), (L-3c), (L-3d), or (L-4a), a1a+a1b is 2.

[0320] In some embodiments of (L-3a), (L-3b), (L-3c), (L-3d), or (L-4a), each occurrence of L A1a and L A1b In some embodiments of (L-3a), (L-3b), (L-3c), (L-3d), or (L-4a), one occurrence of LA1a Yes-CHR L -or-C(R L )2-; Each remaining L A1a is -CH2-; and each occurrence of L A1b In some embodiments of (L-3a), (L-3b), (L-3c), (L-3d), or (L-4a), one occurrence of L A1b Yes-CHR L -or-C(R L )2-; Each remaining L A1b is -CH2-; and each occurrence of L A1a It is -CH2-.

[0321] In some embodiments of (L-3a), (L-3b), or (L-4a), m8 is 0. In some embodiments of (L-3a), (L-3b), (L-3c), or (L-4a), m8 is 1. In some embodiments of (L-3a), (L-3b), (L-3c), or (L-4a), m8 is 2.

[0322] In some embodiments of (L-3a), (L-3b), (L-3d), or (L-4a), n2 is 1; n3 is 1. In some embodiments of (L-3a), (L-3b), (L-3d), or (L-4a), n2 is 0; n3 is 1.

[0323] In some embodiments, L is: -(L A3 ) 0-1 -(L A1 ) 2-3 -L A3 -L A4 -(L A1 ) 0-5 -(L A3 ) 1-2-bb ; provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L is: -(L A3 ) 0-1 -CH2CH2-OL A4 -(L A1 ) 0-5 -(L A3 ) 1-2-bb ; wherein bb represents the point of attachment to ring C. In some embodiments, L A4 Selected from: C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R aand phenylene or 5 to 6 membered heteroarylene, each of which is optionally substituted by 1 to 3 R a In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. For example, L can be where bb represents the point of attachment to ring C.

[0324] In some embodiments, L is a divalent group of formula (L-5):

[0325]

[0326] in:

[0327] a1 is an integer from 0 to 3;

[0328] L A4 Selected from:

[0329] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a replace;

[0330] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0331] bb indicates the point of attachment to ring C.

[0332] In some embodiments of (L-5), a1 is 1.

[0333] In some embodiments of (L-5), 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 It is -CH2-.

[0334] In some embodiments, L is: -(L A1 ) 1-5 -L A3 -L A4 -(L A1 ) 0-5 -(L A3 ) 1-2-bb ; provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L is: -(L A1 ) 2-3 -OLA4 -(L A1 ) 0-5 -C(=O)N(R d )- bb ; provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C. In some embodiments, L A4 is optionally replaced by 1 to 3 R a In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. For example, L can be where bb represents the point of attachment to ring C.

[0335] In some embodiments, L is a divalent group of formula (L-5a):

[0336]

[0337] in:

[0338] a1a and a1b are independently 1, 2 or 3;

[0339] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0340] L A4 Selected from:

[0341] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0342] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0343] bb indicates the point of attachment to ring C.

[0344] In some embodiments of Formula (L-5a), a1a is 3. In some embodiments of Formula (L-5a), a1b is 1.

[0345] In some embodiments of Formula (L-5a), each occurrence of L A1a and L A1bIn some embodiments of Formula (L-5a), one occurrence of L A1a Yes-CHR L -or-C(R L )2-; Each remaining L A1a is -CH2-; and each occurrence of L A1b In some embodiments of Formula (L-5a), one occurrence of L A1b Yes-CHR L -or-C(R L )2-; Each remaining L A1b is -CH2-; and each occurrence of L A1a It is -CH2-.

[0346] In some embodiments of (L-1), (L-2), (L-2a), (L-3), (L-3a), (L-3b), (L-3d), (L-4), (L-4a), (L-5), or (L-5a), L A4 Optionally 1 to 3 R a In some embodiments, L A4 is optionally replaced by 1 to 3 R a a substituted 4- to 10-membered nitrogen-containing heterocyclylene group.

[0347] In some embodiments of (L-1), (L-2), (L-2a), (L-3), (L-3a), (L-3b), (L-3d), (L-4), (L-4a), (L-5), or (L-5a), L A4 Selected from Each of them is optionally substituted at one or more ring carbon atoms with 1 to 3 R a Substitution, where cc represents L A1b or L A1 In some embodiments, the attachment point is present in L A4 Each R on a is independently F or C optionally substituted with 1 to 3 F 1-3 alkyl.

[0348] In some embodiments of (L-1), (L-2), (L-2a), (L-3), (L-3a), (L-3b), (L-3d), (L-4), (L-4a), (L-5), or (L-5a), L A4 is optionally replaced by 1 to 3 R a Substituted C 3-10 Cycloalkylene. For example, L A4may be optionally replaced by 1 to 3 R a Substituted 1,4-cyclohexylene.

[0349] In some embodiments of (L-1), (L-2), (L-2a), (L-3), (L-3a), (L-3b), (L-3d), (L-4), (L-4a), (L-5), or (L-5a), L A4 phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a In some embodiments, L A4 is optionally replaced by 1 to 3 R a In some embodiments, L A4 is optionally replaced by 1 to 3 R a In some embodiments, L A4 is optionally replaced by 1 to 3 R a In some embodiments, L A4 is optionally replaced by 1 to 3 R a Substituted 1,3-phenylene.

[0350] In some embodiments, L is -(L A3 ) 0-1 -(L A1 ) 2-9 -(L A3 ) 0-1 -(Piperazinylene)- bb , wherein bb represents the point of attachment to ring C. In some embodiments, 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 It is -CH2-.

[0351] In some embodiments, L is a divalent group of formula (L-6):

[0352]

[0353] in:

[0354] L A3a Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0355] a3a is 0 or 1;

[0356] a1 is an integer from 2 to 11;

[0357] a3c is 0 or 1; and

[0358] bb indicates the point of attachment to ring C.

[0359] In some embodiments of (L-6), a3a is 1. In some embodiments, L A3a In some embodiments of (L-6), a3a is 1 and L A3a Yes -O-.

[0360] In some embodiments of (L-6), 0 to 1 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 It is -CH2-.

[0361] In some embodiments of (L-6), a1 is an integer from 2 to 5. In some embodiments of (L-6), a1 is an integer from 5 to 7 (e.g., 6). In some embodiments of (L-6), a1 is an integer from 7 to 9 (e.g., 8). In some embodiments of (L-6), a1 is an integer from 9 to 11.

[0362] In some embodiments, L is selected from:

[0363]

[0364] where bb represents the point of attachment to ring C.

[0365] In some embodiments, L is selected from:

[0366]

[0367] where bb represents the point of attachment to ring C.

[0368] In some embodiments, L is selected from:

[0369]

[0370] where bb represents the point of attachment to ring C.

[0371] In some embodiments, L is selected from:

[0372]

[0373] where bb represents the point of attachment to ring C.

[0374] In some embodiments, L is where bb represents the point of attachment to ring C.

[0375] In some embodiments, L is selected from:

[0376]

[0377] where bb represents the point of attachment to ring C.

[0378] In some embodiments, L is selected from:

[0379]

[0380] where bb represents the point of attachment to ring C.

[0381] In some embodiments, L is wherein bb represents the point of attachment to ring C. In some embodiments, L is where bb represents the point of attachment to ring C.

[0382] In some embodiments, L is -(L A ) n1 -;L A and n1 is defined according to (BB). In some embodiments, n1 is an integer from 3 to 5. In some embodiments, n1 is an integer from 5 to 9. In some embodiments, n1 is an integer from 9 to 15. In some embodiments, 1 to 4 occurrences of L A It's L A3 In some embodiments, 1 to 3 occurrences of L A It's L A3 In some embodiments, 2 to 3 occurrences of L A It's L A3 In some embodiments, 0 to 1 occurrences of L A3 is C(=O); each remaining occurrence of L A3 are independently selected from: -O-; -N(H)-; and -N(C 1-3 In some embodiments, 0 to 2 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 It is -CH2-.

[0383] In some embodiments, L A and n1 is defined as (BB); and n1 is an integer from 3 to 5. In some embodiments, L A and n1 is defined according to (BB); and n1 is an integer from 9 to 15.

[0384] In some embodiments, L A and n1 is defined according to (BB); and L is -(L A3 ) 0-2-(L A1 ) 1-15 -(L A3 ) 0-2-bb , wherein bb represents the point of attachment to ring C. In some embodiments, L is -(L A3 ) 0-1 -(L A1 ) 1-15 -(L A3 ) 1-2-bb , wherein bb represents the point of attachment to ring C. In some embodiments, L contains 2 or 3 L A3 In some embodiments, 0 to 1 occurrences of L A3 is C(=O); each remaining occurrence of L A3 are independently selected from: -O-; -N(H)-; and -N(C 1-3 In some embodiments, 0 to 2 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 In some embodiments, each occurrence of L A1 In some embodiments, one occurrence of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 is -CH2-. In some embodiments, each R L Independently selected from: -F and -C optionally substituted with 1 to 3 F 1-3 alkyl.

[0385] In some embodiments, L is a divalent group of formula (L-7):

[0386]

[0387] in:

[0388] L A3a Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0389] a3a is 0 or 1;

[0390] a1 is an integer from 1 to 15;

[0391] Each L A3b Independently selected from: C(=O), -O-, N(H)- and -N(C 1-3 alkyl)-;

[0392] a3b is 1 or 2; and

[0393] bb indicates the point of attachment to ring C.

[0394] In some embodiments of (L-7), -(L A3b ) a3b -yes

[0395] In some embodiments of (L-7), -(L A3b ) a3b - is -N(H)- or -N(C 1-3 alkyl)-.

[0396] In some embodiments of (L-7), 0 to 2 occurrences of L A1 Yes-CHR L -or-C(R L )2-; and each remaining occurrence of L A1 In some embodiments, each occurrence of L A1 It is -CH2-.

[0397] In some embodiments, L is (L-1); Ring A is where aa represents the point of attachment to L, and R present on ring A a is methyl or CF3; R 1 Is C(O)OH or C(O)OC 1-6 alkyl.

[0398] In some embodiments, L is (L-3); Ring A is where aa represents the point of attachment to L, and R present on ring A a is methyl or CF3; R 1 Is C(O)OH or C(O)OC 1-6 alkyl.

[0399] In some embodiments, L is (L-3a); Ring A is where aa represents the point of attachment to L, and R present on ring A a is methyl or CF3; R 1 Is C(O)OH or C(O)OC 1-6 alkyl.

[0400] In some embodiments, L is (L-3b); Ring A is where aa represents the point of attachment to L, and R present on ring A a is methyl or CF3; R 1Is C(O)OH or C(O)OC 1-6 alkyl.

[0401] In some embodiments, Ring A is where aa represents the point of attachment to L, and R present on ring A a is methyl or CF3; R 1 Is C(O)OH or C(O)OC 1-6 alkyl; and Ring C is where R aN It is C 1-3 alkyl (eg, methyl); c1 is 0 or 1; and R a2 is selected from halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl.

[0402] In some embodiments of Formula (I), L is (L-1); Ring A is aa represents the point of attachment to L, where R is present on ring A a is methyl or CF3; R 1 Is C(O)OH or C(O)OC 1-6 alkyl; and Ring C is where R aN It is C 1-3 alkyl (eg, methyl); c1 is 0 or 1; and R a2 is selected from halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl.

[0403] In some embodiments of Formula (I), L is (L-3); Ring A is aa represents the point of attachment to L, where R is present on ring A a is methyl or CF3; R 1 Is C(O)OH or C(O)OC 1-6 alkyl; and Ring C is where R aN It is C 1-3 alkyl (eg, methyl); c1 is 0 or 1; and R a2 is selected from halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl.

[0404] In some embodiments of Formula (I), L is (L-3a); Ring A is aa represents the point of attachment to L, where R is present on ring A a is methyl or CF3; R 1Is C(O)OH or C(O)OC 1-6 alkyl; and Ring C is where R aN It is C 1-3 alkyl (eg, methyl); c1 is 0 or 1; and R a2 is selected from halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl.

[0405] In some embodiments of Formula (I), L is (L-3b); Ring A is aa represents the point of attachment to L, where R is present on ring A a is methyl or CF3; R 1 Is C(O)OH or C(O)OC 1-6 alkyl; and Ring C is where R aN It is C 1-3 alkyl (eg, methyl); c1 is 0 or 1; and R a2 is selected from halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl.

[0406] In some embodiments, L is selected from the moieties described in Table (L), wherein bb represents the point of attachment to ring C:

[0407] Table (L)

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420] In some embodiments of Formula (I), L is selected from the moieties described in Table (L); and

[0421] Ring A is where aa represents the point of attachment to L, and R present on ring A a is methyl or CF3; R 1 Is C(O)OH or C(O)OC 1-6 alkyl.

[0422] In some embodiments of Formula (I), L is selected from the moieties described in Table (L);

[0423] R aN It is C 1-3 alkyl (eg, methyl); c1 is 0 or 1; and R a2 is selected from halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl.

[0424] In some embodiments of Formula (I), L is selected from the moieties described in Table (L);

[0425] Ring A is aa represents the point of attachment to L, where R is present on ring A a is methyl or CF3; R 1 Is C(O)OH or C(O)OC 1-6 Alkyl; and

[0426] Ring C is where R aN It is C 1-3 alkyl (eg, methyl); c1 is 0 or 1; and R a2 is selected from halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl.

[0427] In some embodiments, L is (L-1); and the compound of formula (I) is a compound of formula (IA):

[0428]

[0429] or a pharmaceutically acceptable salt thereof, wherein:

[0430] m6 is 0 or 1;

[0431] a3 is 0 or 1;

[0432] L A3Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0433] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5 (e.g., 2 to 5);

[0434] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0435] L A4 Selected from:

[0436] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0437] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace.

[0438] In some embodiments, L is (L-1); and the compound of formula (I) is a compound of formula (IB):

[0439]

[0440] or a pharmaceutically acceptable salt thereof, wherein:

[0441] m6 is 0 or 1;

[0442] a3 is 0 or 1;

[0443] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0444] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5 (e.g., 2 to 5);

[0445] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0446] L A4 Selected from:

[0447] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R aReplacement; and

[0448] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace.

[0449] In some embodiments of Formula (IA) or (IB), a3 is 1. In some embodiments, L A3 In some embodiments of Formula (IA) or (IB), a3 is 1; and L A3 Yes -O-.

[0450] In some embodiments of Formula (IA) or (IB), a3 is 0.

[0451] In some embodiments, L is (L-2); and the compound of formula (I) is a compound of formula (IC):

[0452]

[0453] or a pharmaceutically acceptable salt thereof, wherein:

[0454] m6 is 0 or 1;

[0455] a3a is 0 or 1;

[0456] L A3a and L A3b Independently selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0457] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 7;

[0458] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0459] L A4 Selected from:

[0460] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0461] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace.

[0462] In some embodiments, L is (L-2); and the compound of formula (I) is a compound of formula (ID):

[0463]

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

[0465] m6 is 0 or 1;

[0466] a3a is 0 or 1;

[0467] L A3a and L A3b Independently selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0468] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 7;

[0469] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0470] L A4 Selected from:

[0471] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0472] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace.

[0473] In some embodiments of Formula (IC) or (ID), L A3b Is -N(H)- or -N(C 1-3 alkyl)-.

[0474] In some embodiments of Formula (IC) or (ID), a3a is 1. In some embodiments, L A3a Yes -O-.

[0475] In some embodiments of Formula (IC) or (ID), a3a is 0.

[0476] In some embodiments, L is (L-3); and the compound of formula (I) is a compound of formula (IE):

[0477]

[0478] or a pharmaceutically acceptable salt thereof, wherein:

[0479] m6 is 0 or 1;

[0480] a3 is 0 or 1;

[0481] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0482] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0483] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0484] L A4 Selected from:

[0485] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0486] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0487] m8 is 0, 1, or 2.

[0488] In some embodiments, L is (L-3a); and the compound of formula (I) is a compound of formula (I-Ea):

[0489]

[0490] or a pharmaceutically acceptable salt thereof, wherein:

[0491] m6 is 0 or 1;

[0492] a3 is 0 or 1;

[0493] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0494] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0495] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0496] L A4 Selected from:

[0497] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0498] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0499] n2 and n3 are independently 0, 1 or 2; and

[0500] m8 is 0, 1, or 2.

[0501] In some embodiments, L is (L-3b); and the compound of formula (I) is a compound of formula (I-Eb):

[0502]

[0503] or a pharmaceutically acceptable salt thereof, wherein:

[0504] m6 is 0 or 1;

[0505] a3 is 0 or 1;

[0506] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0507] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0508] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0509] L A4 Selected from:

[0510] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0511] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0512] n2 and n3 are independently 0, 1 or 2; and

[0513] m8 is 0, 1, or 2.

[0514] In some embodiments, L is (L-4); and the compound of formula (I) is a compound of formula (IF):

[0515]

[0516] or a pharmaceutically acceptable salt thereof, wherein:

[0517] m6 is 0 or 1;

[0518] a3 is 0 or 1;

[0519] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0520] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0521] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0522] L A4 Selected from:

[0523] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0524] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0525] m8 is 0, 1, or 2.

[0526] In some embodiments of Formula (IE), (I-Ea), (I-Eb) or (IF), m8 is 0. In some embodiments of Formula (IE), (I-Ea), (I-Eb) or (IF), m8 is 1. In some embodiments of Formula (IE), (I-Ea), (I-Eb) or (IF), m8 is 2.

[0527] In some embodiments of Formula (I-Ea) or (I-Eb), n2 is 1; and n3 is 1. In some embodiments of Formula (I-Ea) or (I-Eb), n2 is 0; and n3 is 1.

[0528] In some embodiments, L is (L-3) or (L-4); and the compound of formula (I) is a compound of formula (IE) or (IF), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (IE), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (IF), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (I-Ea), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (I-Eb), or a pharmaceutically acceptable salt thereof.

[0529] In some embodiments, L is (L-3); and the compound of formula (I) is a compound of formula (IG):

[0530]

[0531] or a pharmaceutically acceptable salt thereof, wherein:

[0532] m6 is 0 or 1;

[0533] a3 is 0 or 1;

[0534] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0535] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0536] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0537] L A4 Selected from:

[0538] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0539] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0540] m8 is 0, 1, or 2.

[0541] In some embodiments, L is (L-3a); and the compound of formula (I) is a compound of formula (I-Ga):

[0542]

[0543] or a pharmaceutically acceptable salt thereof, wherein:

[0544] m6 is 0 or 1;

[0545] a3 is 0 or 1;

[0546] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0547] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0548] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0549] L A4 Selected from:

[0550] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0551] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0552] n2 and n3 are independently 0, 1 or 2; and

[0553] m8 is 0, 1, or 2.

[0554] In some embodiments, L is (L-4); and the compound of formula (I) is a compound of formula (IH):

[0555]

[0556] or a pharmaceutically acceptable salt thereof, wherein:

[0557] m6 is 0 or 1;

[0558] a3 is 0 or 1;

[0559] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0560] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0561] LA1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0562] L A4 Selected from:

[0563] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0564] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0565] m8 is 0, 1, or 2.

[0566] In some embodiments, L is (L-3) or (L-4); and the compound of formula (I) is a compound of formula (IG) or (IH), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (IG), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (IH), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (I-Ga), or a pharmaceutically acceptable salt thereof.

[0567] In some embodiments of Formula (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), a3 is 1. In some embodiments, L A3 In some embodiments of Formula (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), a3 is 1; and L A3 Yes -O-.

[0568] In some embodiments of Formula (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), a3 is 0.

[0569] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), a1a+a1b is 3.

[0570] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), a1a+a1b is 4.

[0571] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), a1a+a1b is 2 or 5. For example, a1a+a1b can be 5.

[0572] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb) (IF), (IG), (I-Ga), or (IH), each occurrence of L A1a and L A1b It is -CH2-.

[0573] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb) (IF), (IG), (I-Ga), or (IH), one occurrence of L A1a Yes-CHR L -or-C(R L )2-; Each remaining L A1a is -CH2-; and each occurrence of L A1b It is -CH2-.

[0574] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb) (IF), (IG), (I-Ga), or (IH), one occurrence of L A1b Yes-CHR L -or-C(R L )2-; Each remaining L A1b is -CH2-; and each occurrence of L A1a It is -CH2-.

[0575] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), L A4 Optionally 1 to 3 R a Substituted 4- to 10-membered (eg, monocyclic or bicyclic) heterocyclylene. For example, L A4 You can choose from: Each of them is optionally substituted at one or more ring carbon atoms with 1 to 3 R a Substitution, where cc represents L A1b attachment point.

[0576] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb) (IF), (IG), (I-Ga), or (IH), each R a Independently selected from: halo, -OH, C 1-3 Alkoxy, C 1-3 haloalkoxy and optionally 1 to 3 R c Substituted C 1-3 alkyl.

[0577] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), the presence of A4 Each R on a is independently C optionally substituted with 1 to 3 F 1-3 alkyl.

[0578] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), L A4 is optionally replaced by 1 to 3 R a Substituted C 3-10 Cycloalkylene. For example, L A4 may be optionally replaced by 1 to 3 R a Substituted 1,4-cyclohexylene.

[0579] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), L A4 is phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replace. For example, L A4 may be optionally replaced by 1 to 3 R a Substituted 1,4-phenylene. For example, L A4 It may be 1,2-phenylene or 1,3-phenylene, each of which is optionally substituted by 1 to 3 R a replace.

[0580] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb) (IF), (IG), (I-Ga), or (IH), m6 is 0.

[0581] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), R present on Ring A a is C optionally substituted with 1 to 3 -F 1-3 alkyl.

[0582] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), R 1 is C(O)OH. In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), or (IH), R 1 It is C(O)OC 1-6 alkyl.

[0583] In some embodiments, L is (L-7), wherein a3a is 0; and the compound of formula (I) is a compound of formula (II-A):

[0584]

[0585] or a pharmaceutically acceptable salt thereof, wherein:

[0586] Ring A is phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0587] L T1 is a bond or CH2;

[0588] A * is H or optionally 1 to 3 R a Substituted C 3-15 Cycloalkyl;

[0589] L A3b Selected from: C(=O), -O-, N(H)- and -N(C 1-3 alkyl)-;

[0590] a3b is 1 or 2; and

[0591] a1 is an integer from 1 to 15.

[0592] In some embodiments of Formula (II-A), Ring A is optionally substituted with 1 to 2 R a In some embodiments of Formula (II-A), Ring A is selected from: Where aa represents L T1 attachment point.

[0593] In some embodiments of Formula (II-A), L T1 It's CH2.

[0594] In some embodiments of Formula (II-A), A* is H.

[0595] In some embodiments of Formula (II-A), A* is optionally replaced by 1 to 3 R a Substituted C 3-15 For example, A* can be optionally substituted with 1 to 3 R a Substituted adamantyl.

[0596] In some embodiments of Formula (II-A), a1 is an integer from 1 to 3. In some embodiments of Formula (II-A), a1 is an integer from 4 to 6. In some embodiments of Formula (II-A), a1 is an integer from 7 to 9. In some embodiments of Formula (II-A), a1 is an integer from 10 to 15.

[0597] In some embodiments of Formula (II-A), -(L A3b ) a3b -yes where bb represents the point of attachment to ring C.

[0598] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), m2 is 0. In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), m4 is 0.

[0599] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Ring C is

[0600] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Ring C is

[0601] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Ring C is

[0602] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), R aN It is C 1-3 Alkyl. For example, R aN It may be methyl.

[0603] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Ring C is R aN It is C 1-3 alkyl (eg, methyl); c1 is 0 or 1; and R a2 Selected from: halogen (eg, -F) and C optionally substituted with 1 to 3 -F 1-3 For example, ring C can be

[0604] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Ring C is R aN It is C 1-3 alkyl (eg, methyl); c1 is 0 or 1; and R a2 Selected from: halogen (eg, -F) and C optionally substituted with 1 to 3 -F 1-3 For example, ring C can be

[0605] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Ring C is In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Ring C is

[0606] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), c1 is 0.

[0607] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), L C In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), L C It is -NH-.

[0608] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), X is CH.

[0609] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Partly

[0610] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Partly

[0611] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Partly

[0612] In some embodiments of Formula (IA), (IB), (IC), (ID), (IE), (I-Ea), (I-Eb), (IF), (IG), (I-Ga), (IH), or (II-A), Partly

[0613] In some embodiments, the compound of formula (IA) is a compound of formula (IA-1):

[0614]

[0615] or a pharmaceutically acceptable salt thereof, wherein:

[0616] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0617] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0618] a3 is 0 or 1;

[0619] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0620] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5 (e.g., 2 to 5);

[0621] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0622] L A4 Selected from:

[0623] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0624] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace.

[0625] In some embodiments, the compound of formula (IA) is a compound of formula (IA-2):

[0626]

[0627] or a pharmaceutically acceptable salt thereof, wherein:

[0628] m6 is 0 or 1;

[0629] a3 is 0 or 1;

[0630] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0631] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5 (e.g., 2 to 5);

[0632] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0633] L A4 Selected from:

[0634] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0635] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0636] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[0637] In some embodiments, the compound of formula (IA) is a compound of formula (IA-3):

[0638]

[0639] or a pharmaceutically acceptable salt thereof, wherein:

[0640] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0641] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0642] a3 is 0 or 1;

[0643] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0644] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5 (e.g., 2 to 5);

[0645] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0646] L A4 Selected from:

[0647] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0648] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0649] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[0650] In some embodiments of Formula (IA-1), (IA-2) or (IA-3):

[0651] a3 is 1;

[0652] L A3 is -O-;

[0653] L A1a and L A1b are independently selected from: -CH2-, -CH(Me)-, and -CF2-; and

[0654] LA4 is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered (eg, nitrogen-containing) heterocyclylene.

[0655] In some embodiments of Formula (IA-1), (IA-2) or (IA-3):

[0656] a3 is 1;

[0657] L A3 is -O-;

[0658] a1b is 1;

[0659] L A1b It is -CH2-;

[0660] Each L A1a are independently selected from: -CH2- and -CH(Me)-, provided that 0 to 1 L A1a is -CH(Me)-; and

[0661] L A4 is a 4- to 10-membered nitrogen-containing heterocyclylene group optionally substituted by 1 to 2 substituents independently selected from the group consisting of: -F and C optionally substituted by 1 to 3 -F 1-3 alkyl.

[0662] In some embodiments of Formula (IA-1), (IA-2) or (IA-3):

[0663] a3 is 1;

[0664] L A3 is -O-;

[0665] a1b is 1;

[0666] L A1b It is -CH2-;

[0667] a1a is 1, 2, or 3;

[0668] Each L A1a are independently selected from: -CH2- and -CH(Me)-, provided that 0 to 1 L A1a is -CH(Me)-; and

[0669] L A4 Selected from:

[0670] Where cc represents L A1b attachment point.

[0671] In some embodiments of Formula (IA), (IA-1), (IA-2), or (IA-3), The moiety is selected from the groups described in Table (LIA):

[0672] Table (LIA)

[0673]

[0674]

[0675]

[0676]

[0677] where bb represents the point of attachment to ring C.

[0678] In some embodiments, the compound of formula (IB) is a compound of formula (IB-1):

[0679]

[0680] or a pharmaceutically acceptable salt thereof, wherein:

[0681] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0682] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0683] a3 is 0 or 1;

[0684] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0685] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5 (e.g., 2 to 5);

[0686] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0687] L A4 Selected from:

[0688] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0689] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace.

[0690] In some embodiments, the compound of formula (IB) is a compound of formula (IB-2):

[0691]

[0692] or a pharmaceutically acceptable salt thereof, wherein:

[0693] m6 is 0 or 1;

[0694] a3 is 0 or 1;

[0695] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0696] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5 (e.g., 2 to 5);

[0697] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0698] L A4 Selected from:

[0699] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0700] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0701] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[0702] In some embodiments, the compound of formula (IB) is a compound of formula (IB-3):

[0703]

[0704] or a pharmaceutically acceptable salt thereof, wherein:

[0705] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0706] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0707] a3 is 0 or 1;

[0708] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0709] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5 (e.g., 2 to 5);

[0710] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0711] L A4 Selected from:

[0712] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0713] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0714] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[0715] In some embodiments of Formula (IB), (IB-1), (IB-2), or (IB-3):

[0716] a3 is 1;

[0717] L A3 is -O-;

[0718] L A1a and L A1bare independently selected from: -CH2-, -CH(Me)-, and -CF2-; and

[0719] L A4 is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered (eg, nitrogen-containing) heterocyclylene.

[0720] In some embodiments of Formula (IB-1), (IB-2), or (IB-3):

[0721] a3 is 1;

[0722] L A3 is -O-;

[0723] a1b is 1;

[0724] L A1b It is -CH2-;

[0725] Each L A1a are independently selected from: -CH2- and -CH(Me)-, provided that 0 to 1 L A1a is -CH(Me)-; and

[0726] L A4 is a 4- to 10-membered nitrogen-containing heterocyclylene group optionally substituted by 1 to 2 substituents independently selected from the group consisting of: -F and C optionally substituted by 1 to 3 -F 1-3 alkyl.

[0727] In some embodiments of Formula (IB-1), (IB-2), or (IB-3):

[0728] a3 is 1;

[0729] L A3 is -O-;

[0730] a1b is 1;

[0731] L A1b It is -CH2-;

[0732] a1a is 1, 2, or 3;

[0733] Each L A1a are independently selected from: -CH2- and -CH(Me)-, provided that 0 to 1 L A1a is -CH(Me)-; and

[0734] L A4 Selected from:

[0735] Where cc represents L A1b attachment point.

[0736] In some embodiments of Formula (IB-1), (IB-2), or (IB-3), The moiety is selected from the groups described in Table (LIB):

[0737] Table (LIB)

[0738]

[0739]

[0740] where bb represents the point of attachment to ring C.

[0741] In some embodiments, the compound of formula (IE) is a compound of formula (IE-1):

[0742]

[0743] or a pharmaceutically acceptable salt thereof, wherein:

[0744] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0745] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0746] a3 is 0 or 1;

[0747] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0748] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0749] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0750] L A4 Selected from:

[0751] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0752] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R areplace; and

[0753] m8 is 0, 1, or 2.

[0754] In some embodiments, the compound of formula (IE) is a compound of formula (IE-2):

[0755]

[0756] or a pharmaceutically acceptable salt thereof, wherein:

[0757] m6 is 0 or 1;

[0758] a3 is 0 or 1;

[0759] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0760] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0761] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0762] L A4 Selected from:

[0763] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a replace; and

[0764] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0765] m8 is 0, 1, or 2; and

[0766] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[0767] In some embodiments, the compound of formula (IE) is a compound of formula (IE-3):

[0768]

[0769] or a pharmaceutically acceptable salt thereof, wherein:

[0770] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0771] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0772] a3 is 0 or 1;

[0773] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0774] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0775] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0776] L A4 Selected from:

[0777] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0778] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0779] m8 is 0, 1, or 2; and

[0780] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[0781] In some embodiments of Formula (IE-1), (IE-2) or (IE-3):

[0782] a3 is 1;

[0783] L A3 is -O-;

[0784] a1a is 0; and

[0785] L A4 Selected from:

[0786] Optionally 1 to 3 R a Substituted C 3-10 cycloalkylene; and

[0787] Optionally 1 to 3 R a Substituted phenylene.

[0788] In some embodiments of Formula (IE-1), (IE-2) or (IE-3):

[0789] a3 is 1;

[0790] L A3 is -O-;

[0791] a1a is 0;

[0792] a1b is 3 or 4;

[0793] Each L A1b are independently selected from: -CH2- and -CH(Me)-, provided that 0 to 1 L A1b is -CH(Me)-; and

[0794] L A4 Selected from: (For example )and

[0795] In some embodiments of Formula (IE-1), (IE-2) or (IE-3):

[0796] a3 is 1;

[0797] L A3 is -O-;

[0798] a1a is 2, 3, or 4; and

[0799] L A4 is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered heterocyclylene.

[0800] In some embodiments of Formula (IE-1), (IE-2) or (IE-3):

[0801] a3 is 1;

[0802] L A3 is -O-;

[0803] a1a is 2, 3, or 4;

[0804] Each LA1a It is CH2;

[0805] a1b is 0, 1, or 2;

[0806] Each L A1b is CH2; and

[0807] L A4 is optionally replaced by 1 to 3 R a A substituted 4- to 8-membered nitrogen-containing heterocyclylene group.

[0808] In some embodiments of Formula (IE-1), (IE-2) or (IE-3):

[0809] a3 is 1;

[0810] L A3 is -O-;

[0811] a1a is 2, 3, or 4;

[0812] Each L A1a It is CH2;

[0813] a1b is 0, 1, or 2;

[0814] Each L A1b is CH2; and

[0815] L A4 Selected from: Where cc represents L A1b attachment point.

[0816] In some embodiments of Formula (IE), (IE-1), (IE-2), or (IE-3), Some are selected from the groups described in the table (LIE):

[0817] Table (LIE)

[0818]

[0819]

[0820]

[0821]

[0822]

[0823] where bb represents the point of attachment to ring C.

[0824] In some embodiments, the compound of formula (I-Ea) is a compound of formula (I-Ea-1):

[0825]

[0826] or a pharmaceutically acceptable salt thereof, wherein:

[0827] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0828] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0829] a3 is 0 or 1;

[0830] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0831] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0832] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0833] L A4 Selected from:

[0834] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0835] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0836] n2 and n3 are independently 0, 1 or 2; and

[0837] m8 is 0, 1, or 2.

[0838] In some embodiments, the compound of formula (I-Ea) is a compound of formula (I-Ea-2):

[0839]

[0840] or a pharmaceutically acceptable salt thereof, wherein:

[0841] m6 is 0 or 1;

[0842] a3 is 0 or 1;

[0843] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0844] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0845] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0846] L A4 Selected from:

[0847] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0848] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0849] n2 and n3 are independently 0, 1 or 2;

[0850] m8 is 0, 1, or 2; and

[0851] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[0852] In some embodiments, the compound of formula (I-Ea) is a compound of formula (I-Ea-3):

[0853]

[0854] or a pharmaceutically acceptable salt thereof, wherein:

[0855] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0856] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0857] a3 is 0 or 1;

[0858] L A3Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0859] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0860] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0861] L A4 Selected from:

[0862] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0863] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0864] m8 is 0, 1, or 2;

[0865] n2 and n3 are independently 0, 1 or 2; and

[0866] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[0867] In some embodiments of Formula (I-Ea-1), (I-Ea-2), or (I-Ea-3):

[0868] a3 is 1;

[0869] L A3 is -O-;

[0870] a1a is 0; and

[0871] L A4 Selected from:

[0872] Optionally 1 to 3 R a Substituted C 3-10 cycloalkylene; and

[0873] Optionally 1 to 3 R a Substituted phenylene.

[0874] In some embodiments of Formula (I-Ea-1), (I-Ea-2), or (I-Ea-3):

[0875] a3 is 1;

[0876] L A3 is -O-;

[0877] a1a is 0;

[0878] a1b is 3 or 4;

[0879] Each L A1b are independently selected from: -CH2- and -CH(Me)-, provided that 0 to 1 L A1b is -CH(Me)-; and

[0880] L A4 Selected from: (For example )and

[0881] In some embodiments of Formula (I-Ea-1), (I-Ea-2), or (I-Ea-3):

[0882] a3 is 1;

[0883] L A3 is -O-;

[0884] a1a is 2, 3, or 4; and

[0885] L A4 is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered heterocyclylene.

[0886] In some embodiments of Formula (I-Ea-1), (I-Ea-2), or (I-Ea-3):

[0887] a3 is 1;

[0888] L A3 is -O-;

[0889] a1a is 2, 3, or 4;

[0890] Each L A1a It is CH2;

[0891] a1b is 0, 1, or 2;

[0892] Each L A1b is CH2; and

[0893] L A4 is optionally replaced by 1 to 3 R a A substituted 4- to 8-membered nitrogen-containing heterocyclylene group.

[0894] In some embodiments of Formula (I-Ea-1), (I-Ea-2), or (I-Ea-3):

[0895] a3 is 1;

[0896] L A3 is -O-;

[0897] a1a is 2, 3, or 4;

[0898] Each L A1a It is CH2;

[0899] a1b is 0, 1, or 2;

[0900] Each L A1b is CH2; and

[0901] L A4 Selected from:

[0902] Where cc represents L A1b attachment point.

[0903] In some embodiments of Formula (I-Ea-1), (I-Ea-2), or (I-Ea-3), n2 is 1; and n3 is 1.

[0904] In some embodiments of Formula (I-Ea-1), (I-Ea-2), or (I-Ea-3), The moiety is selected from the groups described in Table (LI-Ea):

[0905] Table (LI-Ea)

[0906]

[0907] where bb represents the point of attachment to ring C.

[0908] In some embodiments, the compound of formula (I-Eb) is a compound of formula (I-Eb-1):

[0909]

[0910] or a pharmaceutically acceptable salt thereof, wherein:

[0911] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0912] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0913] a3 is 0 or 1;

[0914] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0915] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0916] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[0917] L A4 Selected from:

[0918] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0919] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0920] n2 and n3 are independently 0, 1 or 2; and

[0921] m8 is 0, 1, or 2.

[0922] In some embodiments, the compound of formula (I-Eb) is a compound of formula (I-Eb-2):

[0923]

[0924] or a pharmaceutically acceptable salt thereof, wherein:

[0925] m6 is 0 or 1;

[0926] a3 is 0 or 1;

[0927] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0928] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0929] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0930] L A4 Selected from:

[0931] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0932] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0933] m8 is 0, 1, or 2;

[0934] n2 and n3 are independently 0, 1 or 2; and

[0935] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[0936] In some embodiments, the compound of formula (I-Eb) is a compound of formula (I-Eb-3):

[0937]

[0938] or a pharmaceutically acceptable salt thereof, wherein:

[0939] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0940] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0941] a3 is 0 or 1;

[0942] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0943] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[0944] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[0945] L A4Selected from:

[0946] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[0947] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[0948] m8 is 0, 1, or 2;

[0949] n2 and n3 are independently 0, 1 or 2; and

[0950] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[0951] In some embodiments of Formula (I-Eb-1), (I-Eb-2), or (I-Eb-3):

[0952] a3 is 1;

[0953] L A3 is -O-;

[0954] a1a is 0; and

[0955] L A4 Selected from:

[0956] Optionally 1 to 3 R a Substituted C 3-10 cycloalkylene; and

[0957] Optionally 1 to 3 R a Substituted phenylene.

[0958] In some embodiments of Formula (I-Eb-1), (I-Eb-2), or (I-Eb-3):

[0959] a3 is 1;

[0960] L A3 is -O-;

[0961] a1a is 0;

[0962] a1b is 3 or 4;

[0963] Each L A1b are independently selected from: -CH2- and -CH(Me)-, provided that 0 to 1 LA1b is -CH(Me)-; and

[0964] L A4 Selected from: (For example )and

[0965] In some embodiments of Formula (I-Eb-1), (I-Eb-2), or (I-Eb-3):

[0966] a3 is 1;

[0967] L A3 is -O-;

[0968] a1a is 2, 3, or 4; and

[0969] L A4 is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered heterocyclylene.

[0970] In some embodiments of Formula (I-Eb-1), (I-Eb-2), or (I-Eb-3):

[0971] a3 is 1;

[0972] L A3 is -O-;

[0973] a1a is 2, 3, or 4;

[0974] Each L A1a It is CH2;

[0975] a1b is 0, 1, or 2;

[0976] Each L A1b is CH2; and

[0977] L A4 is optionally replaced by 1 to 3 R a A substituted 4- to 8-membered nitrogen-containing heterocyclylene group.

[0978] In some embodiments of Formula (I-Eb-1), (I-Eb-2), or (I-Eb-3):

[0979] a3 is 1;

[0980] L A3 is -O-;

[0981] a1a is 2, 3, or 4;

[0982] Each L A1a It is CH2;

[0983] a1b is 0, 1, or 2;

[0984] Each L A1b is CH2; and

[0985] L A4 Selected from:

[0986] Where cc represents L A1b attachment point.

[0987] In some embodiments of Formula (I-Eb-1), (I-Eb-2), or (I-Eb-3), n2 is 1; and n3 is 1.

[0988] In some embodiments of Formula (I-Eb-1), (I-Eb-2), or (I-Eb-3), The moiety is selected from the groups described in Table (LI-Eb):

[0989] Table (LI-Eb) :

[0990]

[0991] where bb represents the point of attachment to ring C.

[0992] In some embodiments, the compound of formula (IF) is a compound of formula (IF-1):

[0993]

[0994] or a pharmaceutically acceptable salt thereof, wherein:

[0995] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[0996] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[0997] a3 is 0 or 1;

[0998] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[0999] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[1000] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(RL )2-; and

[1001] L A4 Selected from:

[1002] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[1003] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[1004] m8 is 0, 1, or 2.

[1005] In some embodiments, the compound of formula (IF) is a compound of formula (IF-2):

[1006]

[1007] or a pharmaceutically acceptable salt thereof, wherein:

[1008] m6 is 0 or 1;

[1009] a3 is 0 or 1;

[1010] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[1011] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[1012] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[1013] L A4 Selected from:

[1014] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[1015] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[1016] m8 is 0, 1, or 2; and

[1017] Ring C is Where c1 is 0 or 1; Ra2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[1018] In some embodiments, the compound of formula (IF) is a compound of formula (IF-3):

[1019]

[1020] or a pharmaceutically acceptable salt thereof, wherein:

[1021] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[1022] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[1023] a3 is 0 or 1;

[1024] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[1025] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[1026] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[1027] L A4 Selected from:

[1028] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[1029] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[1030] m8 is 0, 1, or 2; and

[1031] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aNIt is C 1-3 alkyl.

[1032] In some embodiments of Formula (IF-1), (IF-2), or (IF-3):

[1033] a3 is 1;

[1034] L A3 is -O-;

[1035] a1a is 0; and

[1036] L A4 Selected from:

[1037] Optionally 1 to 3 R a Substituted C 3-10 cycloalkylene; and

[1038] Optionally 1 to 3 R a Substituted phenylene.

[1039] In some embodiments of Formula (IF-1), (IF-2), or (IF-3):

[1040] a3 is 1;

[1041] L A3 is -O-;

[1042] a1a is 0;

[1043] a1b is 3 or 4;

[1044] Each L A1b are independently selected from: -CH2- and -CH(Me)-, provided that 0 to 1 L A1b is -CH(Me)-; and

[1045] L A4 Selected from: (For example )and

[1046] In some embodiments of Formula (IF-1), (IF-2), or (IF-3):

[1047] a3 is 1;

[1048] L A3 is -O-;

[1049] a1a is 2, 3, or 4; and

[1050] L A4 is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered heterocyclylene.

[1051] In some embodiments of Formula (IF-1), (IF-2), or (IF-3):

[1052] a3 is 1;

[1053] L A3 is -O-;

[1054] a1a is 2, 3, or 4;

[1055] Each L A1a It is CH2;

[1056] a1b is 0, 1, or 2;

[1057] Each L A1b is CH2; and

[1058] L A4 is optionally replaced by 1 to 3 R a A substituted 4- to 8-membered nitrogen-containing heterocyclylene group.

[1059] In some embodiments of Formula (IF-1), (IF-2), or (IF-3), The moiety is selected from the groups described in Table (LIF):

[1060] Table (LIF)

[1061]

[1062]

[1063] where bb represents the point of attachment to ring C.

[1064] In some embodiments of Formula (IG):

[1065] a3 is 1;

[1066] L A3 is -O-;

[1067] a1a is 0; and

[1068] L A4 Selected from:

[1069] Optionally 1 to 3 R a Substituted C 3-10 cycloalkylene; and

[1070] Optionally 1 to 3 R a Substituted phenylene.

[1071] In some embodiments of Formula (IG):

[1072] a3 is 1;

[1073] L A3 is -O-;

[1074] a1a is 0;

[1075] a1b is 3 or 4;

[1076] Each L A1b are independently selected from: -CH2- and -CH(Me)-, provided that 0 to 1 L A1b is -CH(Me)-; and

[1077] L A4 Selected from: (For example )and

[1078] In some embodiments of Formula (IG):

[1079] a3 is 1;

[1080] L A3 is -O-;

[1081] a1a is 2, 3, or 4; and

[1082] L A4 is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered heterocyclylene.

[1083] In some embodiments of Formula (IG-1):

[1084] a3 is 1;

[1085] L A3 is -O-;

[1086] a1a is 2, 3, or 4;

[1087] Each L A1a It is CH2;

[1088] a1b is 0, 1, or 2;

[1089] Each L A1b is CH2; and

[1090] L A4 is optionally replaced by 1 to 3 R a A substituted 4- to 8-membered nitrogen-containing heterocyclylene group.

[1091] In some embodiments of Formula (IG):

[1092] a3 is 1;

[1093] L A3 is -O-;

[1094] a1a is 2, 3, or 4;

[1095] Each L A1a It is CH2;

[1096] a1b is 0, 1, or 2;

[1097] Each L A1b is CH2; and

[1098] L A4 Selected from:

[1099] Where cc represents L A1b attachment point.

[1100] In some embodiments of Formula (IG), The moiety is selected from the group described in Table (LIG):

[1101] Table (LIG)

[1102]

[1103] where bb represents the point of attachment to ring C.

[1104] In some embodiments, the compound of formula (IH) is a compound of formula (IH-1):

[1105]

[1106] or a pharmaceutically acceptable salt thereof, wherein:

[1107] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[1108] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[1109] a3 is 0 or 1;

[1110] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[1111] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[1112] L A1a and LA1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and

[1113] L A4 Selected from:

[1114] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[1115] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[1116] m8 is 0, 1, or 2.

[1117] In some embodiments, L is (L-4); and the compound of formula (I) is a compound of formula (IH-2):

[1118]

[1119] or a pharmaceutically acceptable salt thereof, wherein:

[1120] m6 is 0 or 1;

[1121] a3 is 0 or 1;

[1122] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[1123] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[1124] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[1125] L A4 Selected from:

[1126] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[1127] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[1128] m8 is 0, 1, or 2; and

[1129] Ring C is Where c1 is 0 or 1; R a2 Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[1130] In some embodiments, L is (L-4); and the compound of formula (I) is a compound of formula (IH-3):

[1131]

[1132] or a pharmaceutically acceptable salt thereof, wherein:

[1133] R 1 Is C(O)OH or C(O)OC 1-6 alkyl;

[1134] R a1 is C optionally substituted with 1 to 3 F 1-3 alkyl;

[1135] a3 is 0 or 1;

[1136] L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-;

[1137] a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5;

[1138] L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-;

[1139] L A4 Selected from:

[1140] a)C 3-10 Cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and

[1141] b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace;

[1142] m8 is 0, 1, or 2; and

[1143] Ring C is Where c1 is 0 or 1; R a2Selected from: halo (eg -F) and C optionally substituted with 1 to 3 F 1-3 alkyl; and R aN It is C 1-3 alkyl.

[1144] In some embodiments of Formula (IH-1), (IH-2), or (IH-3):

[1145] a3 is 1;

[1146] L A3 is -O-;

[1147] a1a is 0; and

[1148] L A4 Selected from:

[1149] Optionally 1 to 3 R a Substituted C 3-10 cycloalkylene; and

[1150] Optionally 1 to 3 R a Substituted phenylene.

[1151] In some embodiments of Formula (IH-1), (IH-2), or (IH-3):

[1152] a3 is 1;

[1153] L A3 is -O-;

[1154] a1a is 0;

[1155] a1b is 3 or 4;

[1156] Each L A1b are independently selected from: -CH2- and -CH(Me)-, provided that 0 to 1 L A1b is -CH(Me)-; and

[1157] L A4 Selected from: (For example )and

[1158] In some embodiments of Formula (IH-1), (IH-2), or (IH-3):

[1159] a3 is 1;

[1160] L A3 is -O-;

[1161] a1a is 2, 3, or 4; and

[1162] L A4 is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered heterocyclylene.

[1163] In some embodiments of Formula (IH-1), (IH-2), or (IH-3):

[1164] a3 is 1;

[1165] L A3 is -O-;

[1166] a1a is 2, 3, or 4;

[1167] Each L A1a It is CH2;

[1168] a1b is 0, 1, or 2;

[1169] Each L A1b is CH2; and

[1170] L A4 is optionally replaced by 1 to 3 R a A substituted 4- to 8-membered nitrogen-containing heterocyclylene group.

[1171] In some embodiments of Formula (IH-1), (IH-2), or (IH-3), The moiety is selected from the groups described in Table (LIH):

[1172] Table (LIH)

[1173]

[1174] where bb represents the point of attachment to ring C.

[1175] In some embodiments, the compound is selected from the compounds in Table C1, or a pharmaceutically acceptable salt thereof.

[1176] Table C1

[1177]

[1178]

[1179]

[1180]

[1181]

[1182]

[1183]

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192]

[1193]

[1194]

[1195]

[1196]

[1197]

[1198]

[1199]

[1200]

[1201]

[1202]

[1203]

[1204]

[1205]

[1206]

[1207]

[1208]

[1209]

[1210]

[1211]

[1212]

[1213]

[1214]

[1215]

[1216]

[1217]

[1218]

[1219]

[1220]

[1221]

[1222]

[1223]

[1224]

[1225]

[1226]

[1227]

[1228]

[1229]

[1230]

[1231]

[1232]

[1233]

[1234]

[1235]

[1236]

[1237]

[1238]

[1239]

[1240]

[1241]

[1242]

[1243]

[1244]

[1245]

[1246]

[1247]

[1248]

[1249]

[1250]

[1251]

[1252]

[1253]

[1254]

[1255]

[1256]

[1257]

[1258] Note: For the compounds in Table C1, when the stereogenic center is represented by "or1" in the structural formula, the stereogenic center has been resolved, but the configuration at the stereogenic center has not been determined. For example, the structure represents (R)-2-methyl-3-(1-methylpiperidin-4-yl)propan-1-ol or (S)-2-methyl-3-(1-methylpiperidin-4-yl)propan-1-ol. For example, the structure It represents (R)-2-methyl-3-(1-methylpiperidin-4-yl)propan-1-ol or (S)-2-methyl-3-(1-methylpiperidin-4-yl)propan-1-ol.

[1259] Exemplary compounds of formula (I) or (II) also include those described in Table C1 of U.S. Provisional Application Serial No. 63 / 457,997, filed on April 7, 2023; Table C1 of U.S. Provisional Application Serial No. 63 / 454,545, filed on March 24, 2023; Table C1 of U.S. Provisional Application Serial No. 63 / 449,756, filed on March 3, 2023; Table C1 of U.S. Provisional Application Serial No. 63 / 429,862, filed on December 2, 2022; Table C1 of U.S. Provisional Application Serial No. 63 / 398,783, filed on August 17, 2022; and Table C1 of U.S. Provisional Application Serial No. 63 / 339,253, filed on May 6, 2022; or pharmaceutically acceptable salts thereof, wherein each Table C1 is incorporated herein by reference in its entirety.

[1260] Exemplary compounds of Formula (IA) (e.g., Formula (IA-1), (IA-2), or (IA-3)) include Compounds 101, 102, 103, 104, 105, 106, 107, 116, 116a, 117, 117a, 120, 121, 122, 124, 124a, 125, 125a, 126, 127, 128, 129, 130, 131, 131a, 132, 134, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175 58, 159, 159a, 160, 160a, 160b, 162, 162a, 162b, 164, 164a, 164b, 166, 167, 167a, 167b, 169, 169a, 169b ,170,173,173a,173b,177,177a,180,180a,180b,181,186,186a,186b,187,187a,187b,193,193a,19 3b, 196, 197, 197a, 197b, 202, 202a, 202b, 203, 207, 207a, 207b, 209, 209a, 210, 210a, 210b, 213, 216, 216a, 216b, 218, 218a, 218b, 219, 219a, 219b, 226, 229, 231, 231a, 231b, 240, 240a, 240b, 243, 245, 245 a, 245b, 246, 246a, 246b, 262, 262a, 262b, 263, 263a, 263b, 267, 268, 268a, 268b, 272, 272a, 272b, 277, 280, 286, 289, 289a, 289b, 292, 295, 302, 309, 313, 317, 343, 343a, 343b, 343c, 343d, and 357, or a pharmaceutically acceptable salt thereof.

[1261] Exemplary compounds of Formula (IB) (e.g., Formula (IB-1), (IB-2) or (IB-3)) include compounds 119, 139, 184, 236, 242, 264, 265, 266, 266a, 266b, 271, 271a, 276, 276a, 276b, 294, 344, 344a, 344b, 344c, 344d, 355 and 356 described in Table C1, or a pharmaceutically acceptable salt thereof.

[1262] Exemplary compounds of Formula (IC) include compounds 123, 133, 136, 165, and 172 described in Table C1, or pharmaceutically acceptable salts thereof.

[1263] Exemplary compounds of Formula (IE) (e.g., Formula (IE-1), (IE-2), or (IE-3)) include compounds 147, 147a, 147b, 148, 148a, 148b, 149, 150, 161, 161a, 163, 168, 168a, 175, 188, 195, 200, 201, 204, 204a, 208, 211, 211a, 212, 212a, 212b, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235 15, 215a, 220, 225, 230, 232, 233, 234, 235, 241, 273, 273a, 273b, 274, 274a, 274b, 275, 275a, 275 b, 278, 278a, 278b, 281, 281a, 281b, 282, 282a, 282b, 283, 283a, 283b, 284, 284a, 284b, 293, 293a, 296, 296a, 297, 297a, 297b, 300, 300a, 300b, 301, 301a, 301b, 307, 307a, 307b, 308, 308a, 308b, 3 10, 310a, 316, 316a, 318, 318a, 319, 319a, 322, 322a, 323, 323a, 324, 324a, 325, 325a, 328, 328a, 3 33, 333a, 334, 334a, 335, 335a, 336, 336a, 339, 339a, 339b, 340, 340a, 341, 341a, 342, 342a, 345, 345a, 346, 346a, 346b, 347, 347a, 347b, 349, 349a, 349b, 350, 350a, 354, 354a, and 354b, or a pharmaceutically acceptable salt thereof.

[1264] Exemplary compounds of Formula (I-Ea) (e.g., Formula (I-Ea-1), (I-Ea-2) or (I-Ea-3)) include compounds 189, 192, 198, 221, 223, 228, 247, 257, 258, 261, 279, 285, 287, 288, 306, 311, 311a, 311b, 312, 353, 353a and 353b described in Table C1, or a pharmaceutically acceptable salt thereof.

[1265] Exemplary compounds of Formula (I-Eb) (e.g., Formula (I-Eb-1), (I-Eb-2), or (I-Eb-3)) include compounds 248, 249, 255, 256, 269, 269a, 270, 270a, 298, 298a, 299, 299a, 320, 320a, 320b, 321, 321a, 321b, 331, 331a, 331b, 332, 332a, 332b, 351, 351a, 351b, 352, 352a, and 352b described in Table C1, or a pharmaceutically acceptable salt thereof.

[1266] Exemplary compounds of Formula (IF) (e.g., Formula (IF-1), (IF-2) or (IF-3)) include compounds 138, 138a, 138b, 140, 141, 142, 143, 144, 145, 146, 146a, 146b, 151, 171, 171a, 176, 176a, 178, 179, 179a, 182, 182a, 185, 185a, 191, 214, 214a, 227, 227a, 239, 239a and 244 described in Table C1, or a pharmaceutically acceptable salt thereof.

[1267] Exemplary compounds of Formula (IG) include Compounds 190, 199, 250, 250a, 254, and 254a described in Table C1, or pharmaceutically acceptable salts thereof.

[1268] Exemplary compounds of Formula (IH) (e.g., Formula (IH-1), (IH-2) or (IH-3)) include compounds 152, 153, 154, 154a, 183, 183a, 251, 251a, 252 and 252a described in Table C1, or pharmaceutically acceptable salts thereof.

[1269] In some embodiments, Formula (I) or (II) is selected from the compounds in Table C2, or a pharmaceutically acceptable salt thereof.

[1270] Table C2

[1271]

[1272]

[1273]

[1274]

[1275]

[1276]

[1277]

[1278]

[1279]

[1280]

[1281]

[1282]

[1283]

[1284]

[1285]

[1286]

[1287]

[1288]

[1289]

[1290]

[1291]

[1292]

[1293]

[1294]

[1295]

[1296]

[1297]

[1298]

[1299]

[1300]

[1301]

[1302]

[1303]

[1304] Some examples of compounds of formula (I) or (II) are synthesized using methods involving the splitting (e.g., SFC separation of stereoisomers) of stereoisomer mixtures. In Table C1, the stereoisomer source centers of the splits in these compounds are marked with stereochemical symbols enhanced with "or1" or "or2". In some cases, stereoisomer splitting is performed during the final step of synthesis, thereby providing a single stereoisomer of a compound of formula (I) or (II). Alternatively, in some other cases, an intermediate or starting material is split, wherein each of the stereoisomers of the composition of the intermediate or starting material can be subjected to subsequent synthesis steps, to provide a corresponding compound of formula (I) or (II) as a separate stereoisomer. The method of splitting and the correlation between the intermediate and the compound of formula I or (II) of the split are disclosed in the Examples and Table P1 herein. One of ordinary skill in the art will appreciate that, under any method for stereoisomer splitting, stereoisomers having both (R)-configuration and (S)-configuration at the stereoisomer source center of the split are provided. Referring to Table C3, compounds of Table C1 wherein the stereoisomers contain the or1 symbol are provided as diastereomeric sources, followed by the corresponding stereoisomers having the (R)-configuration and the (S)-configuration.

[1305] Table C3

[1306]

[1307]

[1308]

[1309]

[1310]

[1311]

[1312]

[1313]

[1314]

[1315]

[1316]

[1317]

[1318]

[1319] In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is expressed in a cell line expressing BCL-X. L The protein is expressed in a cell line with an EC value of less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 50 In some embodiments, the compound has an EC of 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). 50 Reduced expression of BCL-X L For example, the compound can be administered at an EC of 0.1 nM to 100 nM, 0.1 nM to 50 nM, 1 nM to 50 nM, 1 nM to 20 nM, or 0.1 nM to 1 nM. 50 Reduced expression of BCL-X L Cell viability in cell lines with proteins.

[1320] In some embodiments, the present invention relates to a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I -Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, with a DC of less than 1 μM (e.g., less than 750 nM, less than 500 nM or less than 200 nM). 50 Induction of BCL-X L Protein expression in BCL-X L In some embodiments, the protein of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), The compound of formula (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof is administered at a DC of 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) 50 Induction of BCL-X L Protein expression in BCL-X L For example, the compound can be used in a DC at a concentration of 0.1 nM to 100 nM, 0.1 nM to 50 nM, 1 nM to 50 nM, 1 nM to 20 nM, or 0.1 nM to 1 nM. 50 Induced expression of BCL-X L BCL-X protein in cell lines L Protein degradation.

[1321] In some embodiments, the present invention relates to a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I -Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof with less than 70% (e.g., less than 50%, less than 30%, less than 20% or less than 10%) of Y min Induction of BCL-X L Protein expression in BCL-X L In some embodiments, the degradation of proteins of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb -1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, induces Y with less than 50% (e.g., less than 40%, less than 30%, less than 20%, less than 10% or less than 5%). min Induction of BCL-X L Protein expression in BCL-X LIn some embodiments, the degradation of proteins of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb -1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, induces Y with less than 30% (e.g., less than 25%, less than 20%, less than 15%, less than 10% or less than 5%). min Induction of BCL-X L Protein expression in BCL-X L For example, the compound can be used to degrade the protein in a cell line at a Y of about 1% to about 70% (e.g., about 5% to about 50% or about 10% to about 30%). min Induced expression of BCL-X L BCL-X protein in cell lines L Protein degradation.

[1322] This article also provides a BCL-X L A protein that non-covalently binds to a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof.

[1323] Also provided herein is a ternary complex comprising BCL-X LA protein, a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, and a CRBN protein or a portion thereof.

[1324] Chemical definition

[1325] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[1326] The term "oxo" refers to a divalent doubly bonded oxygen atom (ie, "=0"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.

[1327] The term "alkyl" refers to a saturated acyclic hydrocarbon group which may be straight or branched and contains the specified number of carbon atoms. 1-10 "Saturated" means that there are only single bonds between the carbon atoms of the constituent groups, and other available bonds are occupied by hydrogen and / or other substituents as defined herein.

[1328] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halo groups (eg, -CF3, -CHF2, or -CH2F).

[1329] The term "alkoxy" refers to an -O-alkyl group (eg, -OCH3).

[1330] The term "alkylene" refers to a divalent alkyl group (e.g., -CH2-). Similarly, terms such as "cycloalkylene" and "heterocyclylene" refer to divalent cycloalkyl and heterocyclyl groups, respectively. For the avoidance of doubt, in "cycloalkylene" and "heterocyclylene", both groups may be on the same ring carbon atom (e.g., geminal diradicals such as ) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms)) (e.g., ).

[1331] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon double bonds. The alkenyl moiety contains the specified number of carbon atoms. For example, C 2-6 The term "alkenyl" refers to a group having from 2 to 6 carbon atoms (inclusive). An alkenyl group may be unsubstituted or substituted with one or more substituents.

[1332] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2-6 The alkynyl group may be unsubstituted or substituted with one or more substituents.

[1333] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbon atoms, wherein at least one ring in the system is aromatic (e.g., a monocyclic aromatic ring system of 6 carbon atoms, a bicyclic aromatic ring system of 10 carbon atoms, or a tricyclic aromatic ring system of 14 carbon atoms); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted with a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[1334] As used herein, the term "cycloalkyl" refers to a 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, a monocyclic, bicyclic, tricyclic or polycyclic (e.g., fused, bridged or spirocyclic bicyclic, tricyclic or polycyclic) group, wherein the cycloalkyl group may be optionally substituted. As used in this context, the term "saturated" means that there is only a single bond between the carbon atoms that form the cycloalkyl group. 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 partially unsaturated cycloalkyl groups are generally incompletely saturated. Examples of partially unsaturated cycloalkyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Non-limiting examples of fused / bridged cycloalkyl groups include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and the like. Non-limiting examples of spirocyclic cycloalkyl groups include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, and the like.

[1335] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic or polycyclic group having from 5 to 20 ring atoms, or 5, 6, 9, 10 or 15 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, S (including oxidized forms such as: ) and P (including oxidized forms such as: )(e.g., N, O, and S (including oxidized forms such as: )), and at least one ring in the system is aromatic (but not necessarily a ring containing heteroatoms, such as tetrahydroisoquinolinyl, for example, tetrahydroquinolinyl). In some embodiments, the heteroaryl group contains 1 to 4 (e.g., 1, 2, or 3) ring heteroatoms, each of which is independently selected from the group consisting of N, O, and S (including oxidized forms such as: ). A heteroaryl group may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl , thieno[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]dioxolane, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolyl, and the like. In some embodiments, the heteroaryl group is selected from thienyl, pyridinyl, furanyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof in which each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (i.e., all three valence bonds are occupied by non-hydrogen substituents), such as pyridones (e.g., ), pyrimidone (e.g., ), pyridazinones (e.g., ), pyrazinones (e.g., ) and imidazolones (e.g., ), wherein each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (ie, an oxo group (ie, "=O") herein is part of a heteroaryl ring).

[1336] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic (e.g., a fused, bridged or spirocyclic bicyclic, tricyclic or polycyclic) saturated or partially unsaturated ring system (e.g., a 5- to 8-membered monocyclic, 8- to 12-membered bicyclic or 11- to 15-membered tricyclic ring system) having from 3 to 15 ring atoms, 1 to 3 heteroatoms if a monocyclic ring system, 1 to 6 heteroatoms if a bicyclic ring system, or 1 to 9 heteroatoms if a tricyclic or polycyclic ring system, the heteroatoms being selected from O, N, S (including oxidized forms such as: ) and P (including oxidized forms such as: )(e.g., O, N, and S (including oxidized forms such as: )) (e.g., carbon atoms and, if a monocyclic, bicyclic, or tricyclic ring system, 1 to 3, 1 to 6, or 1 to 9 heteroatoms (N, O, S, or P), respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. In some embodiments, the heterocyclyl group contains 1 to 4 (e.g., 1, 2, or 3) ring heteroatoms, each of which is independently selected from the group consisting of N, O, and S (including oxidized forms such as: ). As used in this context, the term "saturated" means that there are only single bonds between the constituent ring atoms, and that the other available valence bonds are occupied by hydrogen and / or other substituents defined herein. Examples of saturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, etc. Partially unsaturated heterocyclyl groups can have any degree of unsaturation, provided that one or more double bonds are present in the heterocyclyl, none of the rings in the ring system is aromatic, and that partially unsaturated heterocyclyl groups are generally incompletely saturated. Examples of partially unsaturated heterocyclyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, 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 and the like. 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[4.5]decyl, 4-azaspiro[3.5]octyl, 1-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[4.5]decyl, 4-azaspiro[3.5]decyl, 4-azaspiro[3.5]un ... [2.2]pentyl, 4-oxaspiro[2.5]octyl, 1-oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6-oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, 1-oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl and the like.

[1337] As used herein, a nitrogen-containing heterocyclic group refers to a heterocyclic group having 1 to 2 ring nitrogen atoms and 0 to 2 ring heteroatoms selected from the group consisting of: O and S (including oxidized forms such as: ). The nitrogen-containing heterocyclic group may be a monocyclic, bicyclic, or polycyclic nitrogen-containing heterocyclic group as defined elsewhere herein. Examples of monocyclic nitrogen-containing heterocyclic groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like. Examples of bicyclic nitrogen-containing heterocyclic groups include 7-azaspiro[3.5]nonyl, 1,7-diazaspiro[4.5]decyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonanyl, 2,6-diazaspiro[3.3]heptanyl, and the like.

[1338] As used herein, when a ring is described as "partially unsaturated," it is meant 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 constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[1339] For the avoidance of doubt, unless otherwise indicated, with respect to rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc., as described herein) containing a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located: (i) on adjacent ring atoms (e.g., a [xx0] ring system where 0 represents a zero atom bridge (e.g., )); (ii) a single ring atom (spiro-fused ring system) (e.g., ), or (iii) a continuous array of ring atoms (bridged ring systems with all bridge lengths > 0) (e.g., ).

[1340] Furthermore, the atoms comprising the compounds of the present embodiments are intended to include all isotopic forms of these atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[1341] Furthermore, compounds disclosed generally or specifically herein are intended to include all tautomeric forms. Thus, for example, a compound containing the moiety: The compounds include: Similarly, a pyridinyl or pyrimidinyl moiety described as optionally substituted with hydroxy includes tautomeric forms of pyridone or pyrimidone.

[1342] The compounds provided herein can encompass various stereochemical forms. The compounds also encompass diastereomers and optical isomers (e.g., mixtures of enantiomers, including racemic mixtures) and individual enantiomers and diastereomers, which are produced due to the structural asymmetry of certain compounds. Unless otherwise indicated, when a disclosed compound is named or described by a structure that does not specify stereochemistry and has one or more chiral centers, it should be understood to represent all possible stereoisomers of the compound.

[1343] Treatment

[1344] Indications

[1345] This article provides a method for inducing BCL-X L For example, the present invention provides a method for the degradation of BCL-X that can be used to treat or prevent cancer. L Compounds that degrade proteins. See, for example, Guo et al. Aging (Albany NY) 13.15 (2021): 19750; Park et al. Proceedings of the National Academy of Sciences 112.40 (2015): 12492-12497; Zhang et al. Molecular Cancer 14.1 (2015): 1-9; Beroukhim et al. Nature 463.7283 (2010): 899-905. Evaluation of compounds with BCL-X L BCL-X L Other methods of protein inhibition are described in, for example, US Patent Publications 2007 / 027135; 2010 / 305122; and 2013 / 096120.

[1346] It will be appreciated that the effect of protein degradation generally increases over time, but the occurrence of degradation (e.g., as measured by the percentage of degradation compared to a control or by parameter Y) min 、DC 50 and / or D max Degradation is measured after a specified time period (e.g., 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, or longer). For example, degradation can be expressed as a percentage of degradation after 24 hours.

[1347] Exemplary assays for validating the degradation-inducing mechanisms of compounds provided herein are known in the art and are described, for example, in International Publication No. WO 2019 / 144117 and Wu et al. Nature Structural & Molecular Biology 27.7 (2020): 605-614.

[1348] Degradation assays can be used for on-target and off-target degradation induction of quantitative compounds (such as those provided herein). Exemplary assays include quantitative immunoblotting, other immunoassays (e.g., MesoScale Discovery (MSD) immunoassays), homogeneous time-resolved fluorescence (HTRF), and HiBiT. In some embodiments, cells can be co-cultured with Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). -2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof, incubated, and then lysates can be prepared for gel electrophoresis (e.g., SDS-PAGE), followed by immunoblotting and quantification compared to a control (e.g., a DMSO-treated control). As another example, a cell line can be engineered to express HiBiT-tagged BCL-X LThe protein, and the amount of fluorescence observed when a complementary LgBiT peptide is added can be measured using formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)). )), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or a compound of Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is compared to a control (e.g., a DMSO-treated control). See, e.g., Example B1 and Example B2. See also, e.g., International Publications WO 2020 / 163823 and WO 2019 / 144117. In some embodiments, the induction of off-target degradation of the proteins eukaryotic peptide chain release factor GTP-binding subunit ERF3A (GSPT1), Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and / or casein kinase I isoform alpha (CK1α) can be assessed.

[1349] See also International Publications WO 2023 / 044046; WO 2022 / 169780; WO 2021 / 222114; WO 2021 / 146536; WO 2021 / 078301; WO 2021 / 007307; WO 2020 / 163823; WO 2019 / 144117; WO 2017 / 184995 and the assays described in Khan et al. Nature Medicine 25.12(2019):1938-1947; Balachander et al. Clinical Cancer Research 26.24(2020):6535-6549.

[1350] A compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, as provided herein, and BCL-X L The binding affinity can be determined by, for example, binding IC 50 or K i value (e.g. using a competition assay) or by K D As determined under substantially similar conditions, a protein with a lower binding IC 50 Compounds with higher binding IC 50 Compounds with lower binding K values ​​are more effective binders. i Compounds with higher binding K i Similarly, as determined under substantially similar conditions, compounds with lower K D Compounds with higher K D Compounds with higher values ​​are more effective binders. For example, when combined with IC 50 The Ki value can be determined in a fluorescence polarization assay using a fluorescently labeled BH3-only peptide (e.g., BAD or BAX) as a competitor. As another example, the binding Ki value can be determined using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay using a fluorescently labeled BH3-only peptide (e.g., BAK) and a BCL-X LA fluorescently labeled antibody wherein the fluorophore is a FRET pair and a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)) as provided herein, or a pharmaceutically acceptable salt thereof, is used as a competitor for the BH3 peptide alone. See, for example, US Patent Publication Nos. 2007 / 0027135, 2010 / 305122, and 2013 / 096120.

[1351] A compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, as provided herein, inhibits BCL-X L The ability to use IC 50 As determined under substantially similar conditions, the 50 Compounds with higher IC 50 Compounds with higher values ​​are more effective inhibitors. BCL-X L One way to measure the inhibition of BCL-X LInterruption of the process of forming a complex with a BH3-only peptide (e.g., BIM). For example, an electrochemiluminescence-based sandwich ELISA assay (e.g., Meso Scale Discovery (MSD)-ELISA assay) can be used. See, for example, Phillips, DC et al. Blood Cancer Journal 5.11 (2015): e368-e368 and Xiao, Yu et al. Molecular Cancer Therapeutics 14.8 (2015): 1837-1847. In these assays, expression of BCL-X L Cells can be incubated with a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), for a period of time, lysed, and then evaluated in an assay. Anti-BCL-X antibodies labeled with a tag can be used. L Antibodies (e.g., biotinylated anti-BCL-X L The lysate can then be applied to the plate to precipitate BCL-X L An anti-BIM antibody (e.g., rabbit anti-BIM antibody) can be introduced, and then a detection antibody (e.g., sulfo-labeled goat anti-rabbit antibody) can be added and measured. As another example, BCL-X L Disruption of complex formation with a BH3-only peptide (e.g., BIM) can be measured using a mammalian two-hybrid assay. In such an assay, two plasmids encoding a "bait" and a "prey" fusion protein (e.g., BCL-X) can be placed in a PCR amplification assay. LA plasmid containing the DNA binding domain of GAL4 fused to the transcriptional activation domain of VP16 fused to BIM is introduced into cells stably expressing the GAL4-luciferase reporter gene (e.g., HeLa cells). A compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)) can be added to cultured cells, incubated, and luciferase activity can be measured. See, e.g., Souers, Andrew J. et al., Nature Medicine 19.2(2013):202-208.

[1352] The degradation effect produced by a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, as provided herein, can be determined by DC 50 As used herein, DC 50refers to the protein concentration compared to the protein concentration before the cell is contacted with a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or compared to the protein concentration before the cell is contacted with a compound of Formula (II) (e.g., (II-a)). (I-a)), for example, (I-H), (I-IH-1), (I-IH-2), or (I-I-3)), or a compound of formula (II) (e.g., (II-a)), resulting in a decrease in the protein (e.g., BCL-X) in the cell compared to the protein concentration when the cell is exposed to a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or a compound of formula (II) (e.g., (II-a)), resulting in a decrease in the protein (e.g., BCL-X) in the cell compared to the protein concentration when the cell is exposed to a compound of formula (I) (e.g., (IA) L The concentration of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)) in which the concentration of the compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)) is reduced by 50 50Compounds with higher DC 50 In some embodiments, the DC 50 Values ​​can be obtained in vitro or in vivo (e.g., in cells expressing BCL-X L The expression of the protein in tumor cells (e.g., cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080 and / or H929) is determined (e.g., using a HiBiT assay).

[1353] The degradation effect produced by a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, as provided herein, can be determined by EC 50 As used herein, EC 50refers to the protein concentration compared to the protein concentration before the cell is contacted with a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or compared to the protein concentration before the cell is contacted with a compound of Formula (II) (e.g., (II-a)). (I-a)), for example, (I-H), (I-IH-1), (I-IH-2), or (I-I-3)), or a compound of formula (II) (e.g., (II-a)), resulting in a decrease in the protein (e.g., BCL-X) in the cell compared to the protein concentration when the cell is exposed to a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or a compound of formula (II) (e.g., (II-a)), resulting in a decrease in the protein (e.g., BCL-X) in the cell compared to the protein concentration when the cell is exposed to a compound of formula (I) (e.g., (IA) L

[0015] The concentration of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)) in which the concentration of the compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)) 50Compounds with higher EC 50 In some embodiments, the compound with the highest value is the more effective compound. 50 Values ​​can be obtained in vitro or in vivo (e.g., in cells expressing BCL-X L The expression of the protein in tumor cells (e.g., cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080 and / or H929) is determined (e.g., using a HiBiT assay).

[1354] The degradation effect produced by a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, as provided herein, can be determined by Y min As used herein, Y min Refers to proteins in cells (such as BCL-X LThe trough concentration of the protein) is compared to the protein concentration before the cell is contacted with a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)). As used herein, D is the ratio of the protein concentration in cells not contacted with a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), the ratio being expressed as a percentage. max is 1-Y min .Y min It can be measured by the HiBiT assay as described in Example B1. As determined under substantially similar conditions, a lower Y min Compounds with higher Y min Compounds with lower Y values ​​are more effective degradation inducers. As determined under substantially similar conditions, compounds with lower Y values ​​are more effective degradation inducers. min Compounds with higher Y min In some embodiments, Y min Values ​​can be obtained in vitro or in vivo (e.g., in cells expressing BCL-X LThe expression of the protein in tumor cells (e.g., cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080 and / or H929) is determined (e.g., using a HiBiT assay).

[1355] Exemplary assays for determining the potency of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, include The effect of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, on cell proliferation and / or viability is measured. Cell proliferation assays can be performed in a variety of formats, including 2D and 3D. Similarly, cell proliferation assays can be performed using any suitable cell line, including, for example, MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929.As an illustrative example, a 3D cell proliferation assay can include growing cells in a 3D culture medium, contacting the cells with a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, using an appropriate reagent (e.g., The cell proliferation is measured by measuring cell proliferation in a 3D manner, and then the information from the experiment using a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is then added to the cell proliferation assay. The signal is compared to the signal from a control experiment (e.g., lacking a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof).As another illustrative example, a 2D cell proliferation assay can include plating cells onto a growth surface, optionally growing the cells for a period of time, and incubating the cells with a mixture of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1 ), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof, using an appropriate reagent (e.g., ) measures cell proliferation, and then the signal from an experiment using a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof The signal is compared to that from a control experiment (e.g., lacking a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof). Other cell viability assays include the MTT assay (based on the reduction of the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to an insoluble purple formazan). The present invention also provides a colorimetric assay based on tetrazolium salts (e.g., a colorimetric assay based on tetrazolium salts) and other similar assays based on related tetrazolium salts. See, for example, Example B3 and Example B4.

[1356] Cell viability assays can be used to measure the effect of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, on cell death. For example, cells expressing BCL-X L Proteins (e.g., MOLT-4 cells) can be incubated with various concentrations of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, and then exposed to a detection agent (e.g., Exemplary assays for evaluating the affinity of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, include using a 5-well plate (e.g., ... L Protein competition assays. For example, purified recombinant affinity-tagged (e.g., His-tagged) BCL-X LThe protein can be incubated with various concentrations of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, and a fixed concentration of an affinity-tagged (e.g., biotin-tagged) BAD protein. After an incubation period, FRET acceptor beads (e.g., His-acceptor beads) and FRET donor beads (e.g., streptavidin-labeled donor beads) with complementary affinity tags can be added to the mixture, and the FRET reaction can be used to determine the affinity of the protein of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or ( The inhibition constant of Formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof can be determined by measuring the inhibition constant of Formula (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof. For example, an AlphaLISA competitive assay can be performed. See, for example, International Publication WO 2019 / 144117.

[1357] Exemplary assays for determining the mechanism of cell death using a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, include measuring the expression of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, on one or more markers of a cell death (e.g., apoptosis) mechanism. Exemplary markers of apoptosis include caspase induction (e.g., caspase 3 / 7 induction) and annexin V staining. Such assays can also be used as determinants of cell viability. For example, expression of BCL-X LProteins (e.g., MOLT-4 cells) can be co-cultured with various concentrations of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., For example, (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof, and the caspase activity can be measured using a luciferase substrate activated by caspase 3 / 7 (e.g., using As another example, expression of BCL-X L Cells (e.g., MOLT-4 cells) expressing proteins can be treated with various concentrations of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof, and a dye conjugated to an activated caspase motif (e.g., Relative caspase activity was assessed using Caspase 3 / 7 Green Apoptosis Assay Reagent, followed by live cell imaging using a platform such as SX5 live cell analysis instrument) was used for analysis. As another example, the expression of BCL-X LProteins (e.g., MOLT-4 cells) can be co-cultured with various concentrations of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), ), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, and Annexin V positivity can be assessed using a phosphatidylserine dye (e.g., Annexin V dye), followed by live cell imaging using a platform for live cell imaging (e.g., SX5 live cell analysis instrument) for analysis. See, for example, Example B5.

[1358] As another example, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (I The efficacy and / or effectiveness of a compound of Formula (IH) (e.g., (IH-1), (IH-2), or (IH-3)), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, e.g., a xenograft model (e.g., using established cancer cell lines such as MOLT4, HEL, TF1, F36P, OCI-M1, OCI-M2, SET-2, CMK, M07E, or UKE-1, or a patient-derived xenograft (PDX) model). For example, a PDX model can be developed in immunodeficient mice (e.g., athymic nude mice, outbred homozygous (e.g., Crl:NU(NCr)-Foxn1) mice, or a pharmaceutically acceptable salt thereof). nu ) or Fox Chase SCID(CB17 / Icr-Prkdc scidThe study was performed in IcrIcoCrl mice. Mice were female mice aged 6 to 12 weeks at the time of tumor implantation and had free access to food and water. Approximately 70 mg of tumor was implanted subcutaneously on the right flank of each mouse. Tumors were measured weekly after implantation and were monitored once tumor volume reached 150 mm. 3 Up to 300mm 3 , that is, the mice can be randomly divided into treatment groups and control groups. In some embodiments, one or more experimental groups can be added to evaluate pharmacokinetics and / or pharmacodynamics. Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) Mice are treated with a compound of formula (e.g., (I-A), (IH), (IH-1), (IH-2), or (IH-3)), or a compound of formula (II), such as (II-a), or a pharmaceutically acceptable salt thereof (e.g., administered IP or PO (orally)) and optionally an additional therapy or therapeutic agent (e.g., any additional therapy or therapeutic agent described herein). The health status, body weight, and tumor volume of the mice can be recorded weekly throughout the study. Incubation can be performed on day 28 or when the tumor reaches 1 cm 3 Mice are euthanized at t≥10 days and tumors can be assessed (e.g., by tumor weight, by tumor volume). At the end of each study, the best response can be calculated for each treatment group. The best response is defined as the delta volume at t≥10 days. t The best response between the control and treatment groups can be compared to determine whether the treatment group is better than the control group. In some embodiments, tumor samples can also be collected at the end of each study, and relevant proteins (e.g., BCL-X L, BCL-2, MCL-1, BIM, BAX and / or BAK) to determine whether the treatment experimental group may have a better protein regulation profile compared to the control experimental group. In some embodiments, tumor samples can also be collected at the end of each study, and the signal transduction pathway activity (e.g., analyzed by phospho-ERK levels) can be analyzed. For pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples can be obtained from mice at the same or different time points as the efficacy study. For example, for pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples can be obtained from mice at 5 days and 6 hours after administration, and related proteins can be measured in tumor samples, and pharmacokinetic studies can be performed on blood samples or portions thereof (e.g., plasma).

[1359] In some embodiments, the PDX is a myeloproliferative neoplasm (MPN) (e.g., CEL, CML, CNL, essential thrombocythaemia (e.g., JAK2 mutant (e.g., JAK2V617F mutant) essential thrombocythaemia or JAK2 wild-type essential thrombocythaemia), polycythaemia vera (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) polycythaemia vera or JAK2 wild-type polycythaemia vera), or myelofibrosis (e.g., primary myelofibrosis (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) primary myelofibrosis or JAK2 wild-type primary myelofibrosis), post-essential thrombocythaemia myelofibrosis (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) post-essential thrombocythaemia myelofibrosis or JAK2 wild-type post-essential thrombocythaemia myelofibrosis) or post-polycythaemia vera myelofibrosis (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) post-polycythaemia vera myelofibrosis or JAK2 wild-type post-polycythaemia vera myelofibrosis)), CRC (e.g., BRaf mutant CRC (e.g., Braf V600E CRC) or KRas mutant CRC (e.g., KRas G12C mutant CRC or KRasG12D CRC)), SCLC (e.g., ASCL1 subtype SCLC or NEUROD1 subtype SCLC), NSCLC (e.g., BRaf mutant NSCLC (e.g., Braf V600E NSCLC), EGFR mutant NSCLC (e.g., EGFR L858R NSCLC or EGFR exon 19 deletion NSCLC), MET mutant NSCLC (e.g., MET exon 14 deletion NSCLC, MET amplified NSCLC), KRas mutant NSCLC (e.g., KRas G12C NSCLC), lung squamous cell carcinoma, malignant pleural mesothelioma (e.g., BAP1 mutant malignant pleural mesothelioma), melanoma (e.g., Braf mutant melanoma (e.g., Braf V600E melanoma)), breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2-negative breast cancer (e.g., HER2-negative breast cancer with ER expression, HER2-negative breast cancer without ER expression), triple-negative breast cancer, or HER2-low breast cancer), lymphoma (e.g., T-cell lymphoma (e.g., anaplastic large T-cell lymphoma, cutaneous T-cell lymphoma, or peripheral T-cell lymphoma) or non-Hodgkin lymphoma (e.g., DLBCL, anaplastic large T-cell lymphoma, cutaneous T-cell lymphoma, or peripheral T-cell lymphoma)), leukemia (e.g., T-cell leukemia (e.g.,Models of T-ALL (e.g., relapsed / refractory T-ALL), post-MPN leukemia, M6-AML, M7-AML), head and neck cancer, pancreatic cancer, bladder cancer, ovarian cancer (e.g., BRCA1 mutant ovarian cancer or BRCA2 mutant ovarian cancer, HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC)), cervical cancer, intrahepatic bile duct carcinoma, or mesenchymal cancer (e.g., mesenchymal breast cancer or mesenchymal renal cancer).

[1360] See, e.g., Khan et al. Nature Medicine 25.12(2019):1938-1947; Balachander et al. Clinical Cancer Research 26.24(2020):6535-6549.

[1361] Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) ) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, e.g., a mouse model, a rat model, a dog model, or a non-human primate (e.g., a cynomolgus monkey) model. Exemplary assays include the following. For example, a pharmacokinetic (PK) study can be performed on animals (e.g., male or female CD-1 mice, Sprague Dawley rats, beagle dogs, or cynomolgus monkeys) using two delivery routes: intravenous (IV) injection and oral gavage (PO). Animals in both the IV and PO groups (e.g., n=3) have free access to food and water. Compounds of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof, can be formulated as solutions for IV routes and solutions or suspensions for PO routes.On the day of the experiment, the compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) ) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof can be administered via intravenous injection (e.g., at 1 mg / kg) for the IV route or via oral gavage (e.g., at 5 mg / kg to 10 mg / kg) for the PO route. In some cases, the drug may be administered after administration of a drug comprising the formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb- The animals are orally administered a cytochrome P450 inhibitor (e.g., 1-aminobenzotriazole) prior to (e.g., 16 hours prior to) administration of a compound of formula (e.g., (I-1), (I-2), or (I-3)), (I-G), (I-G), (I-H), (I-IH), (I-IH-2), or (I-3)) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof. Blood samples can be collected by serial blood sampling (e.g., at 8 time points from 0.83 hours to 24 hours after administration). At each time point, blood can be collected by venous (e.g., saphenous vein) blood sampling (e.g., approximately 30 μL of blood / time point) in a K2EDTA tube. The blood sample can be placed on wet ice and centrifuged (e.g., at 4600 RPM for 4 minutes) to obtain a plasma sample. Plasma samples can be diluted (e.g., with an equal volume of pH 3.0 phosphate buffer) and submitted to LC-MS / MS for sample analysis. Non-compartmental models can be used to calculate pharmacokinetic parameters including clearance (IV or PO, depending on the mode of administration), area under the curve (AUC), and oral bioavailability (%F).

[1362] In some embodiments, the %F of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is at least 4%. In some embodiments, the %F of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is at least 10%. In some embodiments, the %F of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is at least 20%.In some embodiments, the %F of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is at least 30%. In some embodiments, the %F of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is at least 40%.In some embodiments, the compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I -Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, has a %F of about 4% to about 80% (e.g., 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% or about 20% to about 30%). In some embodiments, the %F of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is about 4% to about 20%.In some embodiments, the %F of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is about 20% to about 40%. In some embodiments, the %F of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is about 40% to about 60%. In some embodiments, the %F of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is about 60% to about 80%.

[1363] In some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), administered PO at 10 mg / kg in rats In some embodiments, the clearance of a compound of formula (II) (e.g., (II-a)), (I-B) (e.g., (I-C)), (I-D) (e.g., (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is less than 10 mL / min / kg (e.g., less than 5 mL / min / kg, less than 3 mL / min / kg or less than 1 mL / min / kg). In some embodiments, the clearance of a compound of formula (II) (e.g., (II-C)) (e.g., (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is less than 10 mL / min / kg (e.g., less than 5 mL / min / kg, less than 3 mL / min / kg or less than 1 mL / min / kg). Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF -2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, has a clearance of about 0.05 mL / min / kg to about 5 mL / min / kg (e.g., about 0.05 mL / min / kg to about 3 mL / min / kg, about 0.05 mL / min / kg to about 1 mL / min / kg, or about 0.05 mL / min / kg to about 0.5 mL / min / kg).

[1364] In some embodiments, an agent of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), administered PO at 10 mg / kg in rats -3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, has an AUC of about 10 μM·h to about 150 μM·h (e.g., about 10 μM·h to about 100 μM·h, about 10 μM·h to about 50 μM·h or about 30 μM·h to about 80 μM·h).

[1365] In some cases, heterobifunctional degraders can induce the degradation of off-target proteins. For heterobifunctional degraders utilizing CRBN, common off-target proteins that can be degraded include GSPT1, IKZF1, IKZF2, IKZF3 and / or CK1α. It is generally believed that this degradation is due to the E3 binding portion of the heterobifunctional degrader promoting the formation of a ternary complex between the off-target protein and CRBN. GSPT1 is a translation termination factor, and CK1α is a kinase involved in many key cellular processes (including cell cycle progression and chromosome segregation); these genes are common essential genes, so the undesirable degradation of either or both of them may lead to nonspecific cytotoxicity. IKZF protein is a zinc finger transcription factor involved in cell fate in the hematopoietic process, and the degradation of these proteins is associated with hematotoxicity. See, for example, Moreau, Kevin et al. British Journal of Pharmacology 177.8 (2020): 1709-1718.

[1366] In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, may exhibit effects on BCL-X. L In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can selectively target BCL-X. L The protein is degraded relative to an off-target protein, such as another BCL-2 family member (e.g., BCL-2 and / or MCL-1) or a non-BCL-2 family member target (e.g., GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α).

[1367] As used herein, "selective" or "selectively" refers to a protein degradation assay involving a protein of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, indicates at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) better performance in a protein degradation assay than a comparative protein in the assay. In some embodiments, the specific protein is BCL-X L protein, and the comparator protein is a BCL-2 protein. For example, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, "selectively" induces BCL-X L When the degradation of BCL-2 protein exceeds that of BCL-2 protein, the DCs of BCL-2 protein are significantly downregulated when measured by degradation assay. 50 It is BCL-X L At least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) as much protein.

[1368] In some embodiments, the compounds provided herein may exhibit anti-BCL-X LThe potency of the protein is high (e.g., nanomolar potency) and activity against BCL-2 family members (e.g., BCL-2 or MCL-1 proteins) is minimal (e.g., micromolar potency). In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, may exhibit BCL-X L Efficient degradation of proteins with minimal efficacy (e.g., by Y min 、DC 50 and / or D max In some embodiments, the induction of degradation of an off-target protein (e.g., a BCL-2 family member (e.g., BCL-2 and / or MCL-1), GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α) is achieved by using a ligand (e.g., a ligand) of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)). 3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof can be used to treat BCL-X L The degradation of proteins showed greater induction (e.g. by Y min 、DC 50 and / or Dmax In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can exhibit an effect on BCL-X. L The induction of protein degradation is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than the induction of degradation of an off-target protein. In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can exhibit effects on BCL-X. LThe induction of protein degradation was up to 1000-fold greater than the induction of off-target protein degradation. In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can exhibit effects on BCL-X. L The induction of protein degradation is about 2-fold to about 10-fold greater than the induction of degradation of off-target proteins (e.g., GSPT1, IKZF1, IKZF2 and / or IKZF3 and / or CK1α) (e.g., by Y min 、DC 50 and / or D max In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can exhibit an effect on BCL-X. LThe induction of protein degradation is about 10-fold to about 100-fold greater than the induction of off-target protein degradation. In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can exhibit effects on BCL-X. L The induction of protein degradation is about 100-fold to about 1000-fold greater than the induction of off-target protein degradation. In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can exhibit effects on BCL-X. L The induction of protein degradation is about 1000-fold to about 10,000-fold greater than the induction of off-target protein degradation.

[1369] Inhibition or induction of BCL-X LCertain agents of degradation have shown platelet toxicity, which produces dose-limiting toxicity (e.g., thrombocytopenia) in the clinic. See, for example, Adams and Cory, Cell Death & Differentiation 25.1 (2018): 27-36; Campbell and Tait. Open Biology 8.5 (2018): 180002; Pullark et al., Cancer Discovery (2021) 10.1158 / 2159-8290.CD-20-1465; Negi and Voisin-Chiret. ChemBioChem (2022) (doi: 10.1002 / cbic.202100689). Platelet viability can be monitored using any suitable assay, such as those described herein. See, for example, Example B6.

[1370] In some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof exhibits at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity) when administered to a subject. In some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)) 2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof exhibits about 30% to about 100% platelet activity (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity) when administered to a subject.

[1371] In some embodiments, a therapeutically effective amount of a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)) ) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, exhibits at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity) when administered to a subject, and has a Y of about 50% to about 70%. min In some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). 2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, exhibits at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity) when administered to a subject, and has a Y of less than about 50%. minIn some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). ) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, exhibits at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity) when administered to a subject, and has a Y min value.

[1372] In some embodiments, a therapeutically effective amount of a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)) b-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof exhibits about 30% to 100% platelet activity (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity) when administered to a subject, and has a Y of about 50% to about 70%. minIn some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I -Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof exhibits about 30% to 100% platelet activity (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity) when administered to a subject and has a Y of less than about 50% min In some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). The compound of formula (Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof exhibits about 30% to 100% platelet activity (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity) when administered to a subject, and has about 0% to about 50% Y min value.

[1373] In some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, exhibits at least about 50% platelet activity (e.g., at least about 80% platelet activity) when administered to a subject, and has a Y of about 50% to about 70%. min In some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1 ), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, exhibits at least about 50% platelet activity (e.g., at least about 80% platelet activity) when administered to a subject, and has a Y of less than about 50%. minIn some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1) , (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, exhibits at least about 50% platelet activity (e.g., at least about 80% platelet activity) when administered to a subject, and has a Y of about 0% to about 50%. min value.

[1374] In some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). b-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, exhibits about 50% to 100% platelet activity (e.g., about 80% to about 100% platelet activity) when administered to a subject, and has a Y of about 50% to about 70%. minIn some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I -Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, exhibits about 50% to 100% platelet activity (e.g., about 80% to about 100% platelet activity) when administered to a subject, and has a Y of less than about 50%. min In some embodiments, a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). The compound of formula (Ii-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof exhibits about 50% to 100% platelet activity (e.g., about 80% to about 100% platelet activity) when administered to a subject, and has a Y of about 0% to about 50%. min value.

[1375] In some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). -3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof exhibits at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability) when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6. In some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), ( A compound of formula (I) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, exhibits about 30% to about 100% platelet viability (e.g., about 50% to about 100% platelet viability or about 80% to about 100% platelet viability) when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B6.

[1376] In some embodiments, the compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (I A compound of formula (IH) (e.g., (IH-1), (IH-2), or (IH-3)), or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability), and has a Y value of about 50% to about 70% in the assay described in Example B1. min In some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., A compound of formula (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability) and has a Y value of less than about 50% in the assay described in Example B1. minIn some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., ( A compound of formula (IH) (e.g., (IH-1), (IH-2), or (IH-3)), or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits at least about 30% platelet viability (e.g., at least about 50% platelet viability, or at least about 80% platelet viability), and has a Y value of about 0% to about 50% in the assay described in Example B1. min value.

[1377] In some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), The compound of formula (IH) (e.g., (IH-1), (IH-2), or (IH-3)), or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits about 30% to 100% platelet viability (e.g., about 50% to about 100% platelet viability or about 80% to about 100% platelet viability), and has a Y value of about 50% to about 70% in the assay described in Example B1. minIn some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1 ), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits about 30% to 100% platelet viability (e.g., about 50% to about 100% platelet viability or about 80% to about 100% platelet viability) and has a Y value of less than about 50% in the assay described in Example B1. min In some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1) , (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay in Example B6, exhibits about 30% to 100% platelet viability (e.g., about 50% to about 100% platelet viability or about 80% to about 100% platelet viability) and has a Y value of about 0% to about 50% in the assay described in Example B1. min value.

[1378] In some embodiments, the compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (I The compound of formula (F) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits at least about 50% platelet viability (e.g., at least about 80% platelet viability) and has a Y of about 50% to about 70% in the assay described in Example B1. min In some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), A compound of formula (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits at least about 50% platelet viability (e.g., at least about 80% platelet viability) and has a Y value of less than about 50% in the assay described in Example B1. minIn some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), ( The compound of formula (I) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay of Example B6, exhibits at least about 50% platelet viability (e.g., at least about 80% platelet viability) and has a Y value of about 0% to about 50% in the assay described in Example B1. min value.

[1379] In some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) Compounds of formula (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)) or pharmaceutically acceptable salts thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay described in Example B6, exhibit about 50% to 100% platelet viability (e.g., about 80% to about 100% platelet viability) and have a Y value of about 50% to about 70% in the assay described in Example B1. minIn some embodiments, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), The compound of formula (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay described in Example B6, exhibits about 50% to 100% platelet viability (e.g., about 80% to about 100% platelet viability) and has Y in the assay described in Example B1. min In some embodiments, the formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) Compounds of formula (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof, when tested at a concentration of about 0.25 μM to about 3 μM in the assay described in Example B6, exhibit platelet viability of about 50% to 100% (e.g., platelet viability of about 80% to about 100%), and have a Y value of about 0% to about 50% in the assay described in Example B1. min value.

[1380] Provided herein is a method of treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject has not received treatment for the cancer.In some embodiments, the subject has received one or more lines of prior treatment for the cancer.

[1381] Also provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject as a monotherapy a therapeutically effective amount of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject has not received treatment for the cancer.In some embodiments, the subject has received one or more lines of prior treatment for the cancer.

[1382] Provided herein is a method of treating cancer in a subject in need of such treatment, the method comprising:

[1383] (a) detecting a biomarker associated with cancer (e.g., mutation, amplification, copy number gain, and / or expression (optionally including expression level) of a biomarker); and

[1384] (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy or in combination with another therapy or therapeutic agent.

[1385] Also provided herein is a method of treating cancer in a subject, wherein the subject has been identified (e.g., after administration of a drug comprising Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)). a-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or a compound of formula (II) (e.g., (II-a))) having a biomarker associated with the cancer (e.g., mutation, amplification, copy number increase of a biomarker), and / or expression (optionally including expression levels)), the method comprising administering to the subject a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I -Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[1386] Provided herein is a method of treating cancer in a subject in need of such treatment, the method comprising:

[1387] (a) detecting a biomarker associated with cancer (e.g., mutation, amplification, copy number gain, and / or expression (optionally including expression level) of a marker sensitive to a particular agent (e.g., HER2 expression, ER expression, PR expression, folate receptor expression)); and

[1388] (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy or in combination with another therapy or therapeutic agent.

[1389] Also provided herein is a method of treating cancer in a subject, wherein the subject has been identified (e.g., after administration of a drug comprising Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I -Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a))) having a biomarker associated with the cancer (e.g., mutation, amplification, copy number gain and / or expression of a marker of susceptibility to a particular agent (optionally comprising

[0015] The method comprises administering to the subject a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I -Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[1390] Provided herein are uses of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating cancer, e.g., any cancer provided herein.

[1391] Provided herein are uses of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for treating cancer, e.g., any cancer provided herein.

[1392] Provided herein are uses of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer, e.g., any cancer provided herein.

[1393] Provided herein are compounds of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as medicaments. Also provided herein are compounds of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament for treating cancer, e.g., any cancer provided herein.

[1394] Provided herein are compounds of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in treating cancer, e.g., any cancer as provided herein.

[1395] As used herein, "monotherapy" refers to a combination of the following: a) an antibody comprising a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof, means a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (I-A)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))), or a compound of Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is the only therapeutic agent or therapy (e.g., anticancer agent or therapy) administered to the subject during a treatment cycle (e.g., no additional targeted therapeutic, anticancer agent, chemotherapeutic agent or checkpoint inhibitor is administered to the subject during the treatment cycle). As will be understood by one of ordinary skill in the art, monotherapy does not preclude the co-administration of drugs for the treatment of side effects or general symptoms associated with cancer or treatment, such as pain, rash, edema, photosensitivity, itching, skin discoloration, brittle hair, hair loss, brittle nails, cracked nails, nail discoloration, epidermal swelling, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms (including nausea, diarrhea, and loss of appetite).

[1396] As used herein, "a subject has previously received one or more cancer therapeutic agents or therapies" means that during the previous treatment cycle, the subject has previously been administered a cancer therapeutic agent or therapy other than a cancer therapeutic agent of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)). In some embodiments, the subject is intolerant to one or more previously administered therapeutic agents or therapies for cancer. In some embodiments, the subject has no response to one or more previously administered therapeutic agents or therapies for cancer. In some embodiments, the subject has an inadequate response to one or more previously administered therapeutic agents or therapies for cancer. In some embodiments, the subject has ceased to respond to one or more previously administered therapeutic agents or therapies for cancer. In some embodiments, no response, inadequate response, or cessation of response can be determined by objective criteria (e.g., tumor volume, or by criteria such as RECIST 1.1). In some embodiments, no response, inadequate response, or cessation of response can be determined by the subject's physician.

[1397] As used herein, "the subject is not receiving treatment for cancer" means that the subject has not previously received administration of one or more therapeutic agents or therapies for cancer.

[1398] For any of the solid tumors described herein, the solid tumor can be a primary tumor or a metastatic (or secondary) tumor. As used herein, a "primary" tumor is one that is located at the site where the tumor begins to grow (i.e., the site where the tumor originates). As used herein, a "metastatic" (or "secondary") tumor is one that has spread from the original tumor site to other parts of the body. In some embodiments, a metastatic or secondary tumor is a cancer of the same type as the primary tumor. In some embodiments, a metastatic or secondary tumor is not genetically identical to the primary tumor.

[1399] In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal breast carcinoma), cancer of central or peripheral nervous system tissue (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligoastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, neuroblastoma, pheochromocytoma, paraganglioma), multiple neuroendocrine neoplasia type I and type II, parathyroid cancer, pituitary tumor, thyroid cancer (e.g., papillary thyroid cancer)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer), or , bile duct cancer (e.g., bile duct cancer (e.g., intrahepatic bile duct cancer)), colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), liver cancer (e.g., hepatocellular carcinoma, intrahepatic bile duct cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell cancer), small intestine cancer or stomach cancer (e.g., gastric adenocarcinoma, gastric signet ring cell carcinoma)), genitourinary tract cancer (e.g., bladder cancer (e.g., urothelial bladder carcinoma), kidney cancer (e.g., clear cell renal carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), testicular cancer (e.g., testicular reproductive cell carcinoma), cell carcinoma), or ureteral cancer), gynecological cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine corpus endometrial cancer), or vulvar cancer), head and neck cancer (e.g., ear cancer (e.g., middle ear cancer), head and neck squamous cell carcinoma, nasal cavity cancer, oral cancer, pharyngeal cancer (e.g., hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), hematological cancer (e.g., leukemia (e.g., chronic eosinophilic leukemia (CEL), chronic lymphocytic leukemia (CLL), chronic middle ear cancer), leukemia (CNL), acute lymphoblastic leukemia (ALL) (e.g., Philadelphia chromosome-positive ALL or T-cell ALL (T-ALL)), acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia (APL), post-MPN AML, post-myelodysplastic syndrome (post-MDS) AML, M6-AML (also known as pure erythroid leukemia (PEL)), or M7-AML (also known as acute promegakaryocytic leukemia (AKML)), chronic myeloid leukemia (CML)), lymphoma (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)), or 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), small lymphocytic lymphoma (SLL), T-cell lymphoma (e.g., anaplastic large T-cell lymphoma, cutaneous T-cell lymphoma, or peripheral T-cell lymphoma), essential thrombocythemia, polycythemia vera, myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis), myelodysplastic syndrome (MDS) (e.g., M6MDS or M7MDS) MDS) or myeloma (e.g., multiple myeloma)), Li-Fraumeni tumor, mesenteric cancer (e.g., omental cancer, peritoneal cancer), pleural cancer, respiratory tract cancer (e.g., laryngeal cancer, lung cancer (e.g., squamous cell lung carcinoma, adenocarcinoma, malignant pleural mesothelioma, non-small cell lung cancer (NSCLC), small cell lung cancer), tracheal cancer), sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing's sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancer (e.g., melanoma or Merkel cell carcinoma), thymic cancer (e.g., thymoma), or a combination thereof.

[1400] In some embodiments, the cancer is breast cancer, gastrointestinal cancer (e.g., bile duct cancer (e.g., bile duct cancer (e.g., intrahepatic bile duct carcinoma)), colorectal cancer (CRC), gastrointestinal stromal tumors, or pancreatic cancer), genitourinary tract cancer (e.g., bladder cancer (e.g., urothelial bladder carcinoma) or renal cancer), gynecological cancer (e.g., cervical cancer, ovarian cancer (e.g., well-differentiated serous ovarian cancer (HGSOC), poorly differentiated serous ovarian cancer (LGSOC)) or uterine cancer), head and neck cancer (e.g., head and neck squamous cell carcinoma), hematological cancer (e.g., leukemia (e.g., acute lymphoblastic leukemia (ALL) (e.g., T-ALL), acute myeloid leukemia (AML) (e.g., AP L, post-MPN AML, post-MDS AML, M6-AML, or M7-AML), chronic lymphocytic leukemia (CLL)), lymphoma (e.g., follicular lymphoma (FL), small lymphocytic lymphoma (SLL), T-cell lymphoma (e.g., anaplastic large T-cell lymphoma, cutaneous T-cell lymphoma, or peripheral T-cell lymphoma), or diffuse large B-cell lymphoma (DLBCL)), essential thrombocythemia, polycythemia vera, myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis), or myelodysplastic syndrome (MDS) (e.g., M6MDS or M7 MDS)), lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), squamous cell lung carcinoma, or malignant pleural mesothelioma (MPM)), neuroblastoma, sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing's sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), or skin cancer (e.g., melanoma or Merkel cell carcinoma).

[1401] In some embodiments, the cancer is a myeloproliferative neoplasm (MPN). In some embodiments, the myeloproliferative neoplasm is CEL, CML, CNL, essential thrombocythemia, polycythemia vera, or myelofibrosis (e.g., primary myelofibrosis, myelofibrosis after essential thrombocythemia, or myelofibrosis after polycythemia vera). In some embodiments, the MPN has a JAK2 mutation (e.g., a JAK2 V617F mutation). In some embodiments, the MPN does not have a JAK2 mutation. In some embodiments, the cancer is a low-risk myelofibrosis. In some embodiments, the cancer is an intermediate-risk (e.g., intermediate-risk-1 and / or intermediate-risk-2) or high-risk myelofibrosis (e.g., primary myelofibrosis, myelofibrosis after essential thrombocythemia, or myelofibrosis after polycythemia vera). In some embodiments, the cancer is intermediate-risk or high-risk myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis) with a JAK2 mutation (e.g., a JAK2 V617F mutation). In some embodiments, the cancer is intermediate-risk or high-risk myelofibrosis (e.g., primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis) without a JAK2 V617F mutation. In some embodiments, the subject has a platelet count of less than 50×10 9 Pieces / L.

[1402] In some embodiments, the cancer is polycythemia vera. In some embodiments, the cancer is polycythemia vera and the subject has had an inadequate response to or is intolerant to hydroxyurea.

[1403] In some embodiments, the cancer is MDS. In some embodiments, the cancer is M6 MDS. In some embodiments, the cancer is M7 MDS.

[1404] In some embodiments, the cancer is T-ALL. In some embodiments, the cancer is relapsed / refractory T-ALL.

[1405] In some embodiments, the cancer is CRC (eg, Braf mutant CRC (eg, Braf V600E CRC) or KRas mutant CRC (eg, KRas G12C CRC or KRas G12D CRC)).

[1406] In some embodiments, the cancer is SCLC (eg, ASCL1 subtype SCLC or NEUROD1 subtype SCLC).

[1407] In some embodiments, the cancer is NSCLC (e.g., Braf mutant NSCLC (e.g., Braf V600 NSCLC), EGFR mutant NSCLC (e.g., EGFR L858R NSCLC or EGFR exon 19 deletion NSCLC), MET mutant NSCLC (e.g., MET exon 14 deletion NSCLC, MET amplified NSCLC), KRas mutant NSCLC (e.g., KRasG12C NSCLC)).

[1408] In some embodiments, the cancer is squamous cell carcinoma of the lung.

[1409] In some embodiments, the cancer is malignant pleural mesothelioma (eg, BAP1 mutant malignant pleural mesothelioma). In some embodiments, the cancer is malignant pleural mesothelioma, and a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[1410] In some embodiments, the cancer is melanoma (eg, Braf mutant melanoma (eg, Braf V600E melanoma)).

[1411] In some embodiments, the cancer is breast cancer (e.g., HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), HER2-negative breast cancer (e.g., HER2-negative breast cancer with ER expression, HER2-negative breast cancer without ER expression), HER2-low breast cancer, triple-negative breast cancer, hormone receptor-positive breast cancer (ER+ and / or PR+, HER2 positive or not)).

[1412] In some embodiments, the cancer is a lymphoma. In some embodiments, the lymphoma is a T-cell lymphoma (e.g., anaplastic large T-cell lymphoma, cutaneous T-cell lymphoma, or peripheral T-cell lymphoma). In some embodiments, the lymphoma is a non-Hodgkin's lymphoma (e.g., DLBCL, anaplastic large T-cell lymphoma, cutaneous T-cell lymphoma, or peripheral T-cell lymphoma). In some embodiments, the lymphoma is a peripheral T-cell lymphoma.

[1413] In some embodiments, the cancer is a leukemia. In some embodiments, the leukemia is a T-cell leukemia (e.g., T-cell ALL). In some embodiments, the cancer is a post-MPN leukemia. In some embodiments, the cancer is a T-cell leukemia (e.g., T-cell ALL), and a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[1414] In some embodiments, the cancer is M6-AML. In some embodiments, M6-AML is post-MPN AML. In some embodiments, M6-AML is post-myelodysplastic syndrome (MDS) AML. In some embodiments, the cancer is M6-AML, and a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[1415] In some embodiments, the cancer is M7-AML. In some embodiments, the M7-AML is post-MPN AML. In some embodiments, the M7-AML is post-MDS AML. In some embodiments, the cancer is M7-AML, and a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[1416] In some embodiments, the cancer is head and neck cancer.

[1417] In some embodiments, the cancer is essential thrombocythemia.

[1418] In some embodiments, the cancer is polycythemia vera.

[1419] In some embodiments, the cancer is myelofibrosis. In some embodiments, the cancer is primary myelofibrosis. In some embodiments, the cancer is post-essential thrombocythaemia myelofibrosis. In some embodiments, the cancer is post-polycythaemia vera myelofibrosis.

[1420] In some embodiments, the cancer is MDS. In some embodiments, the MDS is M6 MDS. In some embodiments, the MDS is M7 MDS. In some embodiments, the cancer is MDS and a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[1421] In some embodiments, the cancer is pancreatic cancer.

[1422] In some embodiments, the cancer is bladder cancer (eg, bladder urothelial carcinoma).

[1423] In some embodiments, the cancer is ovarian cancer (e.g., BRCA1 mutant ovarian cancer or BRCA2 mutant ovarian cancer). In some embodiments, the cancer is HGSOC (e.g., BRCA1 mutant HGSOC or BRCA2 mutant HGSOC).

[1424] In some embodiments, the cancer is cervical cancer.

[1425] In some embodiments, the cancer is colorectal cancer.

[1426] In some embodiments, the cancer is skin cancer. In some embodiments, the skin cancer is melanoma. In some embodiments, the cancer is Merkel cell carcinoma. In some embodiments, the cancer is Merkel cell carcinoma, and a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy.

[1427] In some embodiments, the cancer is neuroblastoma.

[1428] In some embodiments, the cancer is intrahepatic bile duct carcinoma.

[1429] In some embodiments, the cancer is a mesenchymal cancer. In some embodiments, the mesenchymal cancer is mesenchymal breast cancer or mesenchymal renal cancer.

[1430] In some embodiments, BCL-X L Copy number gain or BCL-X L Amplification can be detected in a sample from a subject (eg, detecting three or more copies of the BCL2L1 gene in a sample from a subject). In some embodiments, the subject has been determined (e.g., prior to administration of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)) to have a BCL-XL Copy number gain or BCL-X L Amplified cancer.

[1431] In some embodiments, the cancer has BCL-X L Increased copy number.

[1432] In some embodiments, the cancer has BCL-X L Amplification.

[1433] BCL-X LNon-limiting examples of relationships to cancer can be found in: Wilson, Wyndham H. et al. The Lancet Oncology 11.12 (2010): 1149-1159; Keitel, Ulrike et al. Oncotarget 5.23 (2014): 11778; Chonghaile, Triona Ni et al. Cancer Discovery 4.9 (2014): 1074-1087; Zaanan, Aziz et al. Journal of Biological Chemistry 290.39 (2015): 23838-23849; Zhang, Haichao et al. Molecular Cancer 14.1 (2015): 1-9; Soderquist, Ryan S. et al. Nature Communications 9.1 (2018): 1-13; Stover, Elizabeth H. et al. Molecular Cancer Research 17.11(2019):2281-2293;Concoran,RB et al.Annals of Oncology(2019)30(suppl_5):v159-v193;Lakhani,Nehal J. et al.Journal of Clinical Oncology(2020):3509-3509doi:10.1200 / JCO.2020.38;He,Yonghan et al.Journal of Hematology&Oncology13.1(2020):1-13;Grubb,Treg et al.Clinical Cancer Research(2022)doi:10.1158 / 1078-0432.CCR-22-0669;Joly,Florence et al.Gynecologic Oncology165.1(2022):30-39;and Nanjo,Shigeki et al.The Journal of Clinical Investigation(2022)doi:10.1172 / JCI145099.

[1434] In some embodiments, the subject has been previously treated with another anticancer agent, a chemotherapeutic agent, radiation therapy, surgery, a multi-kinase inhibitor, or a combination thereof.

[1435] Provided herein is a method of treating an ocular disease or condition in a subject in need of such treatment, the method comprising administering to the subject (e.g., intravitreally or topically) a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) ( For example, (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (for example, (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (for example, (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (for example, (IH-1), (IH-2), or (IH-3))), or a compound of formula (II) (for example, (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the eye disease or condition is diabetic macular edema. In some embodiments, the eye disease or condition is age-related macular degeneration. In some embodiments, the eye disease or condition is diabetic retinopathy. See, e.g., Crespo-Garcia, Sergio et al. Cell Metabolism 33.4 (2021): 818-832; Hassan, Jannah Waled and Ashay D. Bhatwadekar, Frontiers in Pharmacology 13 (2022): 896907.

[1436] Provided herein are uses of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating an ocular disease or condition, e.g., any ocular disease or condition provided herein.

[1437] Provided herein are uses of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for treating an ocular disease or condition, e.g., any ocular disease or condition provided herein.

[1438] Provided herein are uses of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating an ocular disease or condition, e.g., any ocular disease or condition provided herein.

[1439] Also provided herein are compounds of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as a medicament for treating an ocular disease or condition, such as any of the ocular diseases or conditions provided herein.

[1440] Provided herein are compounds of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in treating an ocular disease or condition, such as any of the ocular diseases or conditions provided herein.

[1441] Also provided herein is a method of treating a fibrotic disease or condition and / or a disease or condition associated with senescent cells in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-E a) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Non-limiting examples of fibrotic diseases or disorders and / or diseases or disorders associated with senescent cells include pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, systemic fibrosis-associated lung disease, radiation therapy-associated pulmonary fibrosis), radiation therapy-associated skin fibrosis, liver fibrosis, primary sclerosing cholangitis, diabetic macular edema, age-related macular degeneration, diabetic retinopathy, geographic atrophy, ischemia and reperfusion injury, heart failure, recovery from acute myocardial infarction, pulmonary hypertension, inflammatory bowel disease, colitis, Crohn's disease, diabetes, aging skin (including photoaging-related pigmentation), donor organ graft survival and function, stem cell graft survival and function, osteoarthritis, recovery from spinal cord injury, Alzheimer's disease, tauopathies, progressive supranuclear palsy, and age-related neurodegeneration (e.g., associated with impaired neurovascular coupling). See, e.g., Zhu, YI et al. Aging Cell 14.4 (2015): 644-658; Zhu, YI et al. Aging Cell 15.3 (2016): 428-435; Chang, Jianhui et al. Nature Medicine 22.1 (2016): 78-83; Zhu, Yi et al. Aging (Albany NY) 9.3 (2017): 955; Lagares, David et al. Science Translational Medicine 9.420 (2017): eaal3765; Pan, Jin et al. International Journal of Radiation Oncology Biology Physics 99.2(2017):353-361;Bussian, Tyler J. et al. Nature 562.7728(2018):578-582;Moncsek, Anja et al. Hepatology 67.1(2018):247-259;vanWilligenburg, Hester, Peter LJ de Keizer and Ron WF de Bruin. Pharmacological Research 130(2018):322-330;Walaszczyk, Anna et al. Aging Cell 18.3(2019):e12945;Aguayo-Mazzucato, Cristina et al. Cell Metabolism 30.1(2019):129-142;Sessions, Garrett A. et al. The FASEB Journal 33.11(2019):12364;Gerdes, Erin O. Wissler et al. International Review of Neurobiology 155(2020):203-234; Sasaki, Motoko, YasunoriSato and Yasuni Nakanuma. Journal of Autoimmunity 107(2020):102377; Yabluchanskiy, Andriy et al. Geroscience 42(2020):409-428; Dookun, Emily et al. Aging Cell 19.10(2020):e13249; Jia, Kangni et al. Journal of Cardiovascular Pharmacology 76.4(2020):452-460; Sierra-Ramirez, Arantzazu et al. Aging (Albany NY) 12.12(2020):11337; Yang, Hao et al. Aging (Albany) NY) 12.13 (2020): 12750; Lawrie, Allan and Sheila E. Francis. The Journal of Clinical Investigation 131.11 (2021): e149721; Paramos-de-Carvalho, Diogo et al. Cell Reports 36.1 (2021): 109334; Tarantini, Stefano et al. GeroScience 43.5(2021):2427-2440;Park,Ji Hee et al. The British Journal of Dermatology(2021);Fielder,Edward et al. ELife 11(2022):e75492;Suzuki,Keiji et al. Mutation Research / Genetic Toxicology and Environmental Mutagenesis 876(2022):503448;He,An et al. American Journal of Transplantation 22.11(2022):2529-2547;Johnson,Laura A. et al. Inflammatory Bowel Diseases 28.2(2022):161-175;Miura,Yugo et al. Stem Cell Research&Therapy 13.1(2022):222;Cooley,Joseph C. et al. JCI Insight 8.3(2023):e163762. Watanabe, Yusuke et al. Hepatology Research 53(2023):460-472; and Takaya, Kento et al. Rejuvenation Research 26.1(2023):9-20.

[1442] Provided herein are compounds of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). -3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating a fibrotic disease or disorder and / or a disease or disorder associated with senescent cells, such as any fibrotic disease or disorder and / or a disease or disorder associated with senescent cells provided herein.

[1443] Provided herein are compounds of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3) ), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as a medicament for treating a fibrotic disease or disorder and / or a disease or disorder associated with senescent cells, such as any fibrotic disease or disorder and / or a disease or disorder associated with senescent cells provided herein.

[1444] Provided herein are compounds of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). -3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a fibrotic disease or disorder and / or a disease or disorder associated with senescent cells, such as any fibrotic disease or disorder and / or a disease or disorder associated with senescent cells provided herein.

[1445] Also provided herein are compounds of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). )), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for treating a fibrotic disease or disorder and / or a disease or disorder associated with senescent cells, such as any fibrotic disease or disorder and / or a disease or disorder associated with senescent cells provided herein.

[1446] Provided herein are compounds of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)). -3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a fibrotic disease or disorder and / or a disease or disorder associated with senescent cells, such as any fibrotic disease or disorder and / or a disease or disorder associated with senescent cells provided herein.

[1447] Also provided are methods for regulating (e.g., decreasing) BCL-X in cells. LA method for inhibiting the activity of a protein, the method comprising contacting a cell with an effective compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is performed in vivo, wherein the method comprises administering to the subject an effective amount of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), 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.

[1448] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a cell with a compound provided herein includes administering a compound provided herein to the cell in vitro or in vivo, including, for example, introducing a compound provided herein into a sample containing cells (e.g., grown in culture or derived from a patient), organoid, or organism (e.g., an animal (e.g., a tumor-bearing animal) or a human).

[1449] Also provided are methods for regulating (e.g., decreasing) BCL-X in cells.L A method for increasing the level of protein, the method comprising contacting a cell with a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof. In some embodiments, BCL-X is expressed in cells that have not been contacted with a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof. L In some embodiments, the contacting is performed in vitro. In some embodiments, the contacting is performed in vivo. In some embodiments, the contacting is performed in vivo, wherein the method comprises treating a cell having BCL-X LIn 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.

[1450] Also provided is a method for inducing BCL-X in cells L A method for ubiquitination of a protein, the method comprising contacting a cell with a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is performed in vivo, wherein the method comprises treating a BCL-X LIn 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.

[1451] Also provided is a method for forming a ternary complex in a cell, wherein the ternary complex comprises BCL-X La protein, a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, and a CRBN protein or its In some embodiments, the method comprises contacting a cell with a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is performed in vivo, wherein the method comprises treating a subject having BCL-X LIn 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.

[1452] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting the cell with an effective amount of a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)) as defined herein, or a pharmaceutically acceptable salt thereof.

[1453] Also provided herein is a method of increasing cell death in vitro or in vivo, comprising contacting the cell with an effective amount of a compound of formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or formula (II) (e.g., (II-a)), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.

[1454] When used as a pharmaceutical, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)) or a salt thereof, or a pharmaceutically acceptable salt thereof, can be administered in the form of a pharmaceutical composition described herein.

[1455] The present invention also provides a method for inducing BCL-X in mammalian cells. L A method for protein degradation, comprising contacting a mammalian cell with an effective amount of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof.

[1456] Also provided herein is a method of treating a subject having cancer, wherein the method comprises:

[1457] A therapeutically effective amount of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is administered as monotherapy or in combination with a first anticancer agent to a subject who has been administered one or more doses of the first anticancer agent for a period of time.

[1458] Also provided herein is a method of treating a subject having cancer, wherein the method comprises:

[1459] (a) administering one or more doses of a first anticancer agent to a subject for a period of time; and

[1460] (b) Following (a), a therapeutically effective amount of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy or in combination with a first anticancer agent.

[1461] Also provided herein is a method of treating a subject having cancer, wherein the method comprises:

[1462] (a) administering one or more doses of a first anticancer agent to a subject for a period of time; and

[1463] (b) Following (a), a therapeutically effective amount of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy or in combination with a second anticancer agent.

[1464] combination

[1465] In any of the indications described herein, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can be used as monotherapy. In some embodiments, a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, one or more doses of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2) or (IA-3)), (IB) (e.g., (IB-1), (IB-2) or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2) or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2) or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, can be administered to a subject in need thereof for a period of time, followed by at least partial resection of the tumor.In some embodiments, treatment with one or more doses of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, prior to at least partial resection of the tumor, reduces the size of the tumor (e.g., tumor burden).

[1466] In some embodiments, one or more doses of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))) or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, may be administered to a subject in need thereof over a period of time with one or more cycles of radiation therapy. In some embodiments, treatment with one or more doses of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, prior to one or more cycles of radiation therapy, reduces the size of the tumor (e.g., tumor burden).

[1467] In some embodiments of any of the methods described herein, Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb) or (I-Eb-1), (I-Eb-2) or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2) or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2) or (IH-3))) or a compound of formula (II) (e.g., (II-a)), or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or treatments (e.g., chemotherapeutic) agents.

[1468] Non-limiting examples of additional therapies and therapeutic agents include: RAS pathway targeted therapeutics (e.g., Ras / RAF / MEK / PI3K pathway inhibitors, (e.g., Ras inhibitors (e.g., KRas inhibitors), KRas targeted therapeutics, SOS1 inhibitors, SOS1 / Ras protein-protein interaction inhibitors, SHP2 inhibitors, PI3K-AKT-mTOR pathway inhibitors)), kinase targeted therapeutics (e.g., MEK inhibitors, ERK inhibitors, Raf inhibitors (e.g., BRaf inhibitors), PI3K inhibitors, Abl inhibitors (e.g., BCR-Abl inhibitors), ALK inhibitors, AKT inhibitors, AURKA inhibitors, mTOR inhibitors, CDK2 inhibitors, CDK4 / 5 inhibitors, CDK4 / 6 inhibitors, CDK7 inhibitors, CDK9 inhibitors, MET (also known as cMET) inhibitors, FAK inhibitors, FGFR1 inhibitors, FGFR2 inhibitors, FGFR3 inhibitors, FGFR4 inhibitors, ErbB family inhibitors agents (e.g., EGFR inhibitors, anti-EGFR antibodies or anti-EGFR antibody-drug conjugates, HER2 inhibitors, anti-HER2 antibodies or biologics utilizing anti-HER2 antibodies), JAK inhibitors (e.g., JAK inhibitors having activity against JAK1, JAK2 and / or JAK1 / 2), Src inhibitors, VEGFR inhibitors), LSD1 inhibitors, EZH2 inhibitors, BET inhibitors, STING agonists, telomerase inhibitors, mTORC1 inhibitors, YAP inhibitors, proteasome inhibitors, farnesyl transferase inhibitors, Hif2α inhibitors, HSP90 inhibitors, PTEN inhibitors, PARP inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of apoptosis pathways (e.g., BCL-2 inhibitors), chemotherapeutic agents, angiogenesis-targeted therapies, immune-targeted agents (including immunomodulatory imide drugs (sometimes referred to as "IMiDs" or "CELMoDs")) and immunotherapy (e.g., anti-PD1 therapy or anti-PD-L1 therapy) and radiation therapy.

[1469] As used herein, a biosimilar antibody refers to an antibody or antigen-binding fragment that has the same primary amino acid sequence as a reference antibody and, optionally, may have detectable differences in post-translational modifications (e.g., glycosylation and / or phosphorylation) compared to the reference antibody (e.g., a different glycoform).

[1470] In some embodiments, the additional therapy or therapeutic agent is an Abl inhibitor (e.g., a BCR-Abl inhibitor), an ALK inhibitor, an AURKA inhibitor, a BCL-2 inhibitor, a Braf inhibitor, a CDK2 inhibitor, a CDK4 / 6 inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, an EGFR inhibitor, an anti-EGFR antibody or an anti-EGFR antibody-drug conjugate, an ERK inhibitor, an EZH2 inhibitor, a FGFR1 inhibitor, a FGFR2 inhibitor, a FGFR3 inhibitor, a FGFR4 inhibitor, a HER2 inhibitor, an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate, a JAK inhibitor, a KRas inhibitor, a MEK inhibitor, a MET inhibitor, a Hif2α inhibitor, a PARP inhibitor, a VEGFR inhibitor, a LSD1 inhibitor, a BET inhibitor, a STING agonist, a telomerase inhibitor, a TORC1 / 2 inhibitor, an immunomodulatory imide drug, an immunotherapy (e.g., a PD-1 inhibitor (e.g., an anti-PD1 therapy), a PD-L1 inhibitor (e.g., an anti-PD-L1 therapy)), chemotherapy, radiation therapy, or a combination thereof.

[1471] In some embodiments, the additional therapy or therapeutic agent is an Abl degrader (e.g., a BCR-Abl degrader), an ALK degrader, an AURKA degrader, a BCL-2 degrader, a BRaf degrader, a CDK2 degrader, a CDK4 / 6 degrader, a CDK7 degrader, a CDK9 degrader, an EGFR degrader, an ERK degrader, an EZH2 degrader, a FGFR1 degrader, a FGFR2 degrader, a FGFR3 degrader, a FGFR4 degrader, a HER2 degrader, a JAK2 degrader, a KRas degrader, a MEK degrader, a MET degrader, a Hif2α degrader, a PARP degrader, a VEGFR degrader, a LSD1 degrader, a BET degrader, a telomerase degrader, a TORC1 / 2 degrader, an immunomodulatory imide drug, an immunotherapy (e.g., an anti-PD1 therapy or an anti-PD-L1 therapy), chemotherapy, radiation therapy, or a combination thereof.

[1472] In some embodiments, the Abl inhibitor (e.g., BCR-Abl inhibitor) is asciminib (e.g., asciminib hydrochloride), bafetinib, bosutinib (e.g., bosutinib monohydrate), danusertib, dasatinib (e.g., dasatinib monohydrate), flumatinib (e.g., flumatinib mesylate), imatinib (e.g., imatinib mesylate), ), nilotinib (e.g., nilotinib monochloride monohydrate), olverembatinib (e.g., orebatininib mesylate), ponatinib (e.g., ponatinib hydrochloride), radotinib (e.g., radotinib dihydrochloride), ruserontinib, vandetanib, AN-019, AT-9283, IkT-148009, NPB-001-056, or a combination thereof.

[1473] In some embodiments, the ALK inhibitor is alectinib (e.g., alectinib hydrochloride), brigatinib, ceritinib, crizotinib, ensartinib (e.g., ensartinib hydrochloride), entrectinib, fidrisertib, lorlatinib, TQ-B-3101, TQ-B-3139, or a combination thereof. In some embodiments, the ALK inhibitor is alectinib (e.g., alectinib hydrochloride), brigatinib, ceritinib, crizotinib, ensartinib (e.g., ensartinib hydrochloride), fidrisertib, lorlatinib, TQ-B-3101, TQ-B-3139, or a combination thereof.

[1474] In some embodiments, the AURKA inhibitor is alisertib, danusertib, ilorasertib, tinengotinib, AT-9283, BI-811283, ENMD-2076, or a combination thereof.

[1475] In some embodiments, the BCL-2 inhibitor is lisaftoclax, navitoclax, obatoclax, venetoclax, oblimersen (e.g., oblimersen sodium), beclanorsen, AZD-0466, BGB-11417, UBX-1325 (or a phosphate prodrug thereof), UBX-1967 (or a phosphate prodrug thereof), ZN-d5, or a combination thereof.

[1476] In some embodiments, the cancer is lung cancer (e.g., SCLC) and the additional therapy or therapeutic agent is a BCL-2 inhibitor (e.g., lisaftoclax, navitoclax, obatoclax, venetolax, oblimersen (e.g., oblimersen sodium), becloranoxan, AZD-0466, BGB-11417, UBX-1325 (or its phosphate prodrug), UBX-1967 (or its phosphate prodrug), or ZN-d5). In some embodiments, the cancer is lung cancer (e.g., SCLC) and the additional therapy or therapeutic agent is venetolax.

[1477] In some embodiments, the cancer is non-Hodgkin lymphoma and the additional therapy or therapeutic agent is a BCL-2 inhibitor (e.g., lisaftoclax, navitoclax, obatoclax, venetolax, oblimersen (e.g., oblimersen sodium), beclofosine, AZD-0466, BGB-11417, UBX-1325 (or its phosphate prodrug), UBX-1967 (or its phosphate prodrug), or ZN-d5). In some embodiments, the cancer is non-Hodgkin lymphoma and the additional therapy or therapeutic agent is venetolax.

[1478] In some embodiments, the BRaf inhibitor is avutometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), 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 a combination thereof.

[1479] In some embodiments, the BRaf V600E mutation can be detected in a sample from a subject (eg, detecting a BRAF gene having a mutation corresponding to the V600E mutation in the BRaf protein and / or detecting a BRaf protein having the V600E mutation). In some embodiments, the subject has been determined to have a cancer having a BRaf V600E mutation (e.g., prior to administration of a compound of Formula (I) (e.g., (IA) (e.g., (IA-1), (IA-2), or (IA-3)), (IB) (e.g., (IB-1), (IB-2), or (IB-3)), (IC), (ID), (IE) (e.g., (IE-1), (IE-2), or (IE-3)), (I-Ea) (e.g., (I-Ea-1), (I-Ea-2), or (I-Ea-3)), (I-Eb) (e.g., (I-Eb-1), (I-Eb-2), or (I-Eb-3)), (IF) (e.g., (IF-1), (IF-2), or (IF-3)), (IG), (I-Ga), (IH) (e.g., (IH-1), (IH-2), or (IH-3))), or Formula (II) (e.g., (II-a)).

[1480] In some embodiments, the cancer is BRaf mutant CRC (e.g., BRaf V600E mutant CRC) and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), contrafenib (e.g., BRAFTOVI TM , LGX818), naborafenib (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 or PLX-4720. In some embodiments, the cancer is BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), conafenib (e.g., BRAFTOVI TM , LGX818), naborafenib (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 or PLX-4720, and an anti-EGFR antibody or anti-EGFR antibody-drug conjugate (e.g., amivantamab (e.g., amivantamab-vmjw or a biosimilar thereof), cetuximab (e.g., (cetuximab) or its biosimilars (e.g., CMAB-009, CPGJ-602, or KL-140), cetuximab sarotalocan ( (sacetuximab) or its biosimilars), depatuxizumab, duligotuzumab, futuximab, imgatuzumab, modotuximab, necitumumab (e.g., (nexitozumab) or its biosimilars), nimotuzumab (e.g., BIOMAb (nimotuzumab) or its biosimilars), panitumumab (e.g., (panitumumab) or its biosimilars), tomozuotuximab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SI-B-001, TAS-0313 or their biosimilars). In some embodiments, the cancer is BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), connefenib (e.g., BRAFTOVI TM , LGX818), naborafenib (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, or PLX-4720), and cetuximab (e.g., (cetuximab) or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140). In some embodiments, the cancer is BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), contrafenib (e.g., BRAFTOVI TM , LGX818), naborafenib (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, or PLX-4720), and panitumumab (e.g., (panitumumab) or a biosimilar thereof). In some embodiments, the cancer is BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), conefoxim (e.g., BRAFTOVI TM , LGX818) or vemurafenib (e.g., RO5185426) and cetuximab (e.g., (cetuximab) or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140). In some embodiments, the cancer is BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), conefoxim (e.g., BRAFTOVI TM , LGX818) or vemurafenib (e.g., RO5185426) and panitumumab (e.g., (panitumumab) or a biosimilar thereof). In some embodiments, the cancer is BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and cetuximab (e.g., (cetuximab) or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140). In some embodiments, the cancer is BRaf mutant CRC (e.g., BRaf V600E mutant CRC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and panitumumab (e.g., (panitumumab) or its biosimilars).

[1481] In some embodiments, the cancer is BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC) and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), contrafenib (e.g., BRAFTOVI TM , LGX818), naborafenib (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, or PLX-4720, and MEK inhibitors (e.g., avometinib, binimetinib, cobimetinib, In some embodiments, the cancer is BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), conafenib (e.g., BRAFTOVI), or selumetinib (e.g., selumetinib sulfate). TM , LGX818) or vemurafenib (e.g., RO5185426) and bimetinib, cobimetinib (e.g., cobimetinib fumarate), selumetinib (e.g., selumetinib sulfate), or trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is vemurafenib (e.g., RO5185426) and cobimetinib (e.g., cobimetinib fumarate). In some embodiments, the cancer is BRaf mutant NSCLC (e.g., BRaf V600E mutant NSCLC), and the additional therapy or therapeutic agent is conafenib (e.g., BRAFTOVI TM , LGX818) and bimetinib.

[1482] In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRaf V600E mutant melanoma) and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), contrafenib (e.g., BRAFTOVI TM , LGX818), naborafenib (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 or PLX-4720. In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRaf V600E mutant melanoma), and the additional therapy or therapeutic agent is a BRaf inhibitor (e.g., avometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), conafenib (e.g., BRAFTOVI TM , LGX818), naborafenib (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, or PLX-4720, and MEK inhibitors (e.g., avometinib, binimetinib, cobimetinib, In some embodiments, the cancer is a BRaf mutant melanoma (e.g., a BRaf V600E mutant melanoma), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), conafenib (e.g., BRAFTOVI), or a combination thereof. TM , LGX818) or vemurafenib (e.g., In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRaf V600E mutant melanoma), and the additional therapy or therapeutic agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRaf V600E mutant melanoma), and the additional therapy or therapeutic agent is vemurafenib (e.g., vemurafenib mesylate, GSK2118436). RO5185426) and cobimetinib (e.g., cobimetinib fumarate). In some embodiments, the cancer is a BRaf mutant melanoma (e.g., BRafV600E mutant melanoma), and the additional therapy or therapeutic agent is conafenib (e.g., BRAFTOVI TM In some such embodiments, the subject was previously treated with immunotherapy.

[1483] In some embodiments, the CDK2 inhibitor is ebvaciclib, fadraciclib, milciclib, pacritinib (e.g., paritinib citrate), roniciclib, roscovitine, BLU-222, NUV-422, PF-07104091, TQB-3616, or a combination thereof.

[1484] In some embodiments, the CDK4 / 6 inhibitor is abemaciclib, birociclib, dalpiciclib, lerociclib, milciclib, palbociclib, ribociclib (e.g., ribociclib succinate), riviciclib, roniciclib, trilaciclib (e.g., trilaciclib dihydrochloride), FCN-437, TQB-3616, or a combination thereof.

[1485] In some embodiments, the CDK7 inhibitor is mircelib, roscovitine, samuraciclib, or a combination thereof.

[1486] In some embodiments, the CDK9 inhibitor is fadraciclib, rivaccilib, roniciclib, roscovitine, zotiraciclib, AZD-4573, KB-0742, or a combination thereof.

[1487] In some embodiments, the EGFR inhibitor is abivertinib, afatinib (e.g., afatinib dimaleate), alflutinib (e.g., afatinib mesylate), almonertinib (e.g., ametinib mesylate), befotertinib, brigatinib, canertinib, dacomitinib (e.g., dacomitinib monohydrate), dovitinib, erlotinib (e.g., erlotinib hydrochloride), gefitinib, icotinib, lapatinib (e.g., lapatinib ditosylate monohydrate), larotinib, lazertinib, limertinib, mobociclib, or ertinib (e.g., mobocertinib succinate), nazartinib, neratinib (e.g., neratinib maleate), olmutinib, osimertinib (e.g., osimertinib mesylate), pelitinib, poziotinib, pyrotinib (e.g., pyrotinib maleate), ruseronti nib) (SKLB-1028), sapitinib, sunvozertinib, tesevatinib, vandetanib, varlitinib, zorifertinib, BIBW-2948, BPI-7711, HA-121-28, SH-1028, an anti-EGFR antibody or an anti-EGFR antibody-drug conjugate, or a combination thereof.

[1488] In some embodiments, the anti-EGFR antibody or anti-EGFR antibody-drug conjugate is ervantamab (e.g., amivantamab-vmjw or a biosimilar thereof), cetuximab (e.g., (cetuximab) or its biosimilars (e.g., CMAB-009, CPGJ-602, or KL-140)), sacetuximab ( (sacetuximab) or its biosimilars), depertuzumab, dugotuzumab, vortuximab, ingatuzumab, zatuximab, nexituzumab (e.g., (necitumomab) or its biosimilars), Nimotuzumab (e.g., BIOMAb (nimotuzumab) or its biosimilars), panitumumab (e.g., (panitumumab) or a biosimilar thereof), tomatuximab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SI-B-001, TAS-0313, a biosimilar thereof, or a combination thereof. In some embodiments, the anti-EGFR antibody or anti-EGFR antibody-drug conjugate is ivantuzumab (e.g., amivantamab-vmjw or a biosimilar thereof), cetuximab (e.g., (cetuximab) or its biosimilars (e.g., CMAB-009, CPGJ-602, or KL-140)), sacetuximab ( (sacetuximab) or its biosimilars), depertuzumab, dugotuzumab, vortuximab, ingatuzumab, zatuximab, nexituzumab (e.g., (necitumomab) or its biosimilars), Nimotuzumab (e.g., BIOMAb (nimotuzumab) or its biosimilars), panitumumab (e.g., (panitumumab) or its biosimilars), toltuximab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SI-B-001, their biosimilars, or combinations thereof.

[1489] In some embodiments, an EGFR mutation (e.g., an EGFR exon 19 deletion or an EGFR L858R mutation (with or without an EGFR T790M mutation)) can be detected in a sample from a subject (e.g., detecting an EGFR gene with a mutation (e.g., a mutation corresponding to an EGFR exon 19 deletion or ...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from: (a)C 3-15 cycloalkylene or 3 to 15 membered heterocyclylene, each of which is optionally substituted by 1 to 6 substituents independently selected from the following: R a and R b ;as well as (b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 substituents independently selected from the following: R a and R b ; R 1 Selected from: (a) C(O)OH, (b)C(O)NR d R e ,and (c)C(O)OC 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 1 to 3 R c replace; Each R 2 , R 3 , R 4 and R 5 Independently selected from: halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH and NR d R e ; m2 is 0, 1, or 2; m3 and m4 are independently 0, 1, 2 or 3; m5 is 0, 1, 2, 3, or 4; L is -(L A ) n1 -, where L A and n1 is defined according to (AA) or (BB): (AA) n1 is an integer from 3 to 15; and Each L A Independently selected from: L A1 , L A3 and L A4 , the condition is 1 to 3 occurrences of L A YesL A4 ; (BB) n1 is an integer from 0 to 20; and Each L A Independently selected from: L A1 and L A3 ; Each L A1 Independently selected from: -CH2-, -CHR L -and-C(R L )2-; Each L A3 Independently selected from: -N(R d )-、-N(R b )-、-O-、-S(O) 0-2 - and C(=O); Each L A4 Independently selected from: (a)C 3-15 cycloalkylene or 3 to 15 membered heterocyclylene, each of which is optionally substituted by 1 to 6 substituents independently selected from the following: R a and R b ;as well as (b)C 6-15 arylene or 5 to 15 membered heteroarylene, each of which is optionally substituted by 1 to 6 substituents independently selected from the following: 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 Independently selected from: 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 to 6 R c Replace C 1-6 alkyl; Ring C is selected from: c1 is 0, 1, 2, or 3; Each R Y Independently selected from: R a and R b ; R aN is H or optionally 1 to 3 R c Substituted C 1-6 alkyl; Y 1 and Y 2 are independently N, CH or CR Y ; yy represents the attachment point to L; X is CH, C or N; is a single bond or a double bond; L C Selected from: bond, -CH2-, -CHR a -、-C(R a )2-、-N(R d )- and O, provided that when X is N, then L C Not O; Each R a Independently selected from: (a) halo; (b) cyano; (c) -OH; (d) oxo; (e)-C 1-6 Alkoxy; (f)-C 1-6 Haloalkoxy; (g)-NR d R e ; (h)C(=O)C 1-6 alkyl; (i) C(=O)C 1-6 Haloalkyl; (j) C(═O)OH; (k)C(=O)OC 1-6 alkyl; (l)C(=O)OC 1-6 Haloalkyl; (m)C(=O)N(R f )2; (n)S(O) 0-2 (C 1-6 alkyl); (o)S(O) 0-2 (C 1-6 haloalkyl); (p)S(O) 1-2 N(R f )2; and (q)C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl, each optionally substituted by 1 to 6 R c replace; Each R b Independently selected from: -(L b ) b -R b1 and -R b1 ,in: Each b is independently 1, 2 or 3; Each -L b Independently selected from: -O-; -N(H)-; -N(C 1-3 Alkyl)-; -S(O) 0-2 -; C(=O); and C 1-3 an alkylene group; and Each R b1 Independently selected from: C 3-10 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R g replace; Each R c Independently selected from: 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: 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 to 3 R h Substituted C 1-6 alkyl; Each R f Independently selected from: H and optionally 1 to 3 R h Substituted C 1-6 alkyl; Each R g Independently selected from: R h ; C 1-3 Alkyl; and C 1-3 haloalkyl; and Each R h Independently selected from: halo; cyano; -OH; -C 1-6 Alkoxy; -C 1-6 Haloalkoxy; -NH2, -N(H)(C 1-3 alkyl); and -N(C 1-3 Alkyl)2.

2. The compound according to claim 1, wherein ring A is optionally substituted with 1 to 3 R a Substituted phenylene.

3. The compound according to claim 1 or 2, wherein ring A is Where aa represents the point of attachment to L; or Ring A is Where aa represents the point of attachment to L; or Ring A is where aa represents the point of attachment to L.

4. The compound according to claim 1, wherein Ring A is optionally substituted with 1 to 3 R a Substituted 5- to 6-membered heteroarylene.

5. The compound according to any one of claims 1 to 4, wherein one R present on ring A a is C optionally substituted with 1 to 3 F 1-3 Alkyl; or An R on ring A a It is methyl or CF3.

6. A compound according to any one of claims 1 to 5, wherein R 1 It is C(O)OH.

7. The compound according to any one of claims 1 to 6, wherein m2 is 0.

8. The compound according to any one of claims 1 to 7, wherein m3 is 0.

9. The compound according to any one of claims 1 to 8, wherein m4 is 0.

10. The compound according to any one of claims 1 to 9, wherein m5 is 0.

11. The compound of any one of claims 1 to 6, wherein m2 is 0; m3 is 0; m4 is 0; and m5 is 0.

12. The compound according to any one of claims 1 to 11, wherein ring C is or Ring C is or Ring C is The compound according to claim 12 , wherein c1 is 0.

14. A compound according to any one of claims 12 or 13, wherein R aN It is C 1-3 Alkyl; or R aN It's methyl.

15. A compound according to any one of claims 12 to 14, wherein L C is the key.

16. A compound according to any one of claims 12 to 15, wherein X is CH.

17. A compound according to any one of claims 1 to 12, wherein Part is or Part is 18. A compound according to any one of claims 1 to 17, wherein L is -(L A ) n1 -;L A and n1 are defined according to (AA).

19. The compound according to any one of claims 1 to 18, wherein n1 is an integer from 3 to 5; or n1 is an integer from 5 to 9; or n1 is 6, 7 or 8; or n1 is an integer from 9 to 12.

20. A compound according to any one of claims 1 to 19, wherein 1 to 2 occurrences of L A YesL A4 ; or one occurrence of L A YesL A4 ; or two occurrences of L A YesL A4 .

21. A compound according to any one of claims 1 to 20, wherein each L A4 Independently selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace.

22. A compound according to any one of claims 1 to 21, wherein 1 to 4 occurrences of L A YesL A3 ; or 1 to 3 occurrences of L A YesL A3 .

23. A compound according to any one of claims 1 to 22, wherein 0 to 1 occurrences of L A3 is C(=O); each remaining occurrence of L A3 are independently selected from: -O-; -N(H)-; and -N(C 1-3 alkyl)-.

24. A compound according to any one of claims 1 to 23, wherein 2 to 7 occurrences of L A YesL A1 ; or 2 to 5 occurrences of L A YesL A1 .

25. A compound according to any one of claims 1 to 24, wherein 0 to 2 occurrences of L A1 Yes - CHR L -or-C(R L )2-; and each remaining occurrence of L A1 It is -CH2-.

26. A compound according to any one of claims 1 to 25, wherein each occurrence of L A1 is -CH2-; or one occurrence of L A1 Yes - CHR L -or-C(R L )2-; and each remaining occurrence of L A1 It is -CH2-.

27. A compound according to any one of claims 1 to 26, wherein each R L independently selected from: -F and -C optionally substituted with 1 to 3 F 1-3 alkyl.

28. A compound according to any one of claims 1 to 18, wherein L is -(L A ) n1 -, and L A and n1 is defined according to (AA): n1 is an integer from 5 to 9; 1 to 2 occurrences of L A YesL A4 ; 2 to 7 occurrences of L A YesL A1 ;and 1 to 3 occurrences of L A YesL A3 .

29. A compound according to any one of claims 1 to 18, wherein L is selected from: (i)-(L A3 ) 0-2 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(L A3 ) 1-2-bb ; (ii)-(L A3 ) 0-2 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A4 - bb ; (iii)-(L A3 ) 0-2 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 -L A4 - bb ;as well as (iv)-(L A3 ) 0-1 -(L A1 ) 2-3 -L A3 -L A4 -(L A1 ) 0-5 -(L A3 ) 1-2-bb ; Provided that L contains 1 to 7 L A1 ; and wherein bb represents the point of attachment to ring C.

30. A compound according to any one of claims 1 to 18, wherein L is: -(L A3 ) 0-2 -(L A1 ) 2-9 -(L A3 ) 0-1 -L A4 - bb , where bb represents the point of attachment to ring C.

31. A compound according to claims 28 to 30, wherein each L A4 Independently selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace.

32. A compound according to any one of claims 28 to 31, wherein 0 to 1 occurrences of L A1 Yes - CHR L -or-C(R L )2-; and each remaining occurrence of L A1 It is -CH2-.

33. A compound according to any one of claims 28 to 32, wherein 0 to 1 occurrences of L A3 is C(=O); each remaining occurrence of L A3 are independently selected from: -O-; -N(H)-; and -N(C 1-3 alkyl)-.

34. A compound according to any one of claims 1 to 18, wherein L is: -(L A3 ) 0-2 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(L A3 ) 1-2-bb ; Provided that L contains 1 to 7 L A1 ; and wherein bb represents the point of attachment to ring C.

35. A compound according to any one of claims 1 to 18 or 34, wherein L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(L A3 ) 2-bb ; Provided that L contains 1 to 5 L A1 ; and wherein bb represents the point of attachment to ring C.

36. A compound according to any one of claims 1 to 18 or 34 to 35, wherein L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -C(=O)-N(R d )- bb ; Provided that L contains 1 to 5 L A1 ; and wherein bb represents the point of attachment to ring C.

37. A compound according to any one of claims 34 to 36, wherein L is a divalent group of formula (L-1): in: a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is from 1 to 5; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; and bb indicates the point of attachment to ring C.

38. The compound of claim 37, wherein a3 is 1.

39. The compound according to claim 37 or 38, wherein L A3 Yes -O-.

40. The compound of claim 37, wherein a3 is 0.

41. The compound of any one of claims 37 to 40, wherein a1a+a1b is 3 or 4; or a1a+a1b is 2 or 5.

42. The compound according to any one of claims 38 to 40, wherein a1a+a1b is 2 to 5.

43. A compound according to any one of claims 1 to 18 or 34, wherein L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 - bb ; Provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C.

44. The compound according to claim 34 or 43, wherein L is a divalent group of formula (L-2): in: a3a is 0 or 1; L A3a and L A3b are independently selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 7; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; and bb indicates the point of attachment to ring C.

45. The compound of claim 44, wherein a3a is 1.

46. ​​The compound according to claim 44 or 45, wherein L A3a Yes -O-.

47. A compound according to any one of claims 44 to 46, wherein L A3b is -N(H)- or -N(C 1-3 alkyl)-.

48. A compound according to any one of claims 44 to 46, wherein L A3b Yes -O-.

49. The compound according to any one of claims 44 to 48, wherein a1a+a1b is 2, 3 or 4.

50. The compound according to any one of claims 44 to 48, wherein a1a+a1b is 5 or 6.

51. A compound according to any one of claims 1 to 18, wherein L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A4 - bb ;or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -L A3 -L A4 - bb ; Provided that L contains 2 to 7 L A1 ; and wherein bb represents the point of attachment to ring C.

52. The compound according to claim 51, wherein L is: -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(Piperazinyl)- bb ; -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -(Piperidinyl)- bb ;or -(L A3 ) 0-1 -(L A1 ) 0-5 -L A4 -(L A1 ) 0-5 -C(=O)-(piperazinylene)- bb ; Provided that L contains 2 to 5 L A1 ; wherein the piperazinylene and the piperidinylene are each optionally substituted with 1 to 3 R a Replace, and where bb represents the point of attachment to ring C.

53. The compound of claim 51, wherein L is a divalent group of formula (L-3), (L-3a), (L-3b) or (L-4): in: a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; n2 and n3 are independently 0, 1 or 2; m8 is 0, 1, or 2; L A4b is optionally replaced by 1 to 3 R a a substituted 7- to 10-membered bicyclic nitrogen-containing heterocyclylene group; and bb indicates the point of attachment to ring C.

54. The compound of claim 53, wherein a3 is 1.

55. The compound according to claim 53 or 54, wherein L A3 Yes -O-.

56. The compound according to any one of claims 53 to 55, wherein a1a+a1b is 3 or 4.

57. A compound according to any one of claims 53 to 55, wherein a1a+a1b is 2.

58. A compound according to any one of claims 37 to 42, 44 to 50 or 53 to 57, wherein each occurrence of L A1a and L A1b It is -CH2-.

59. A compound according to any one of claims 37 to 42, 44 to 50 or 53 to 57, wherein one occurrence of L A1a Yes - CHR L -or-C(R L )2-; Each remaining occurrence of L A1a is -CH2-; and each occurrence of L A1b It is -CH2-.

60. A compound according to any one of claims 37 to 42, 44 to 50 or 53 to 57, wherein one occurrence of L A1b Yes - CHR L -or-C(R L )2-; Each remaining occurrence of L A1b is -CH2-; and each occurrence of L A1a It is -CH2-.

61. according to the compound described in any one of claims 34 to 60, wherein L A4 is optionally replaced by 1 to 3 R a Substituted 4- to 10-membered heterocyclylene.

62. according to the compound described in any one of claims 34 to 60, wherein L A4 is optionally replaced by 1 to 3 R a A substituted 4- to 10-membered nitrogen-containing heterocyclylene group.

63. according to the compound described in any one of claims 34 to 62, wherein L A4 Selected from: They are each optionally substituted at one or more ring carbon atoms with 1 to 3 R a Substitution, where cc represents L A1b attachment point.

64. according to the compound of claim 62 or 63, wherein present in L A4 Each R on a is independently F or C optionally substituted with 1 to 3 F 1-3 alkyl.

65. according to the compound described in any one of claims 34 to 61, wherein L A4 is optionally replaced by 1 to 3 R a Substituted C 3-10 Cycloalkylene.

66. according to the compound described in any one of claim 34 to 61 or 65, wherein L A4 is optionally replaced by 1 to 3 R a Substituted 1,4-cyclohexylene.

67. A compound according to any one of claims 34 to 60, wherein L A4 is phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace.

68. according to the compound described in any one of claim 35 to 60 or 67, wherein L A4 yes: (a) optionally with 1 to 3 R a Substituted phenylene; (b) optionally 1 to 3 R a Substituted 1,2-phenylene; or (c) optionally 1 to 3 R a Substituted 1,4-phenylene.

69. A compound according to any one of claims 1 to 18 or 30, wherein L is: -(L A3 ) 0-1 -(L A1 ) 2-9 -(L A3 ) 0-1 -(Piperazinyl)- bb , where bb represents the point of attachment to ring C.

70. The compound according to claim 69, wherein L is a divalent group of formula (L-6): in: L A3a Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a3a is 0 or 1; a1 is an integer from 2 to 11; a3c is 0 or 1; and bb indicates the point of attachment to ring C.

71. The compound of claim 70, wherein a3a is 1.

72. The compound according to claim 70 or 71, wherein L A3a Yes -O-.

73. according to the compound described in any one of claims 70 to 72, wherein 0 to 1 occurrences of L A1 Yes - CHR L -or-C(R L )2-; and each remaining occurrence of L A1 It is -CH2-.

74. A compound according to any one of claims 1 to 18 or 34 to 37, wherein L is selected from: where bb represents the point of attachment to ring C.

75. A compound according to any one of claims 1 to 18 or 34 to 37, wherein L is selected from: where bb represents the point of attachment to ring C.

76. according to any one of claims 1 to 18, 34 or 43 to 44, wherein L is where bb represents the point of attachment to ring C.

77. A compound according to any one of claims 1 to 18 or 51 to 53, wherein L is selected from: where bb represents the point of attachment to ring C.

78. A compound according to any one of claims 1 to 18 or 51 to 53, wherein L is selected from: where bb represents the point of attachment to ring C.

79. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (IA): or a pharmaceutically acceptable salt thereof, wherein: m6 is 0 or 1; a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 1 to 5; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; or The compound of formula (I) is a compound of formula (IB): or a pharmaceutically acceptable salt thereof, wherein: m6 is 0 or 1; a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is from 1 to 5; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; or The compound of formula (I) is a compound of formula (IC) or (ID): or a pharmaceutically acceptable salt thereof, wherein: m6 is 0 or 1; a3a is 0 or 1; L A3a and L A3b are independently selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 7; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; or The compound of formula (I) is a compound of formula (IE): or a pharmaceutically acceptable salt thereof, wherein: m6 is 0 or 1; a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; and m8 is 0, 1, or 2; or The compound of formula (I) is a compound of formula (I-Ea): or a pharmaceutically acceptable salt thereof, wherein: m6 is 0 or 1; a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; n2 and n3 are independently 0, 1 or 2; and m8 is 0, 1, or 2; or The compound of formula (I) is a compound of formula (I-Eb): or a pharmaceutically acceptable salt thereof, wherein: m6 is 0 or 1; a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; n2 and n3 are independently 0, 1 or 2; and m8 is 0, 1, or 2; or The compound of formula (I) is a compound of formula (IF): or a pharmaceutically acceptable salt thereof, wherein: m6 is 0 or 1; a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; and m8 is 0, 1, or 2; or The compound of formula (I) is a compound of formula (IG): or a pharmaceutically acceptable salt thereof, wherein: m6 is 0 or 1; a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; and m8 is 0, 1, or 2; or The compound of formula (I) is a compound of formula (IH): or a pharmaceutically acceptable salt thereof, wherein: m6 is 0 or 1; a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is 2 to 5; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; and L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; and m8 is 0, 1, or 2.

80. A compound selected from the group consisting of compounds in Table C1 or pharmaceutically acceptable salts thereof.

81. according to the compound described in claim 80, wherein said compound does not show Y under the conditions described in Example B1. min (6h) ≥70% and / or Y min (24h)≥70%.

82. A pharmaceutical composition comprising a compound according to any one of claims 1 to 81 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

83. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 81 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 82.

84. The method of claim 83, wherein the method comprises administering an additional therapy or therapeutic agent.

85. The method of claim 84, wherein the additional therapy or therapeutic agent is an ALK inhibitor, a BCL-2 inhibitor, a BCR-Abl inhibitor, a BRaf inhibitor, a CDK2 inhibitor, a CDK 4 / 6 inhibitor, a CDK7 inhibitor, a CDK9 inhibitor, an EGFR inhibitor, an anti-EGFR antibody or an anti-EGFR antibody-drug conjugate, an ERK inhibitor, a FGFR1 inhibitor, a FGFR2 inhibitor, a FGFR3 inhibitor, a FGFR4 inhibitor, a HER2 inhibitor, an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate, a JAK inhibitor, a KRas inhibitor, a MEK inhibitor, a MET inhibitor, a PARP inhibitor, a LSD1 inhibitor, a BET inhibitor, a telomerase inhibitor, a TORC1 / 2 inhibitor, chemotherapy, radiotherapy, or a combination thereof.

86. The method of claim 85, wherein the additional therapy or therapeutic agent is a JAK inhibitor.

87. The method of claim 86, wherein the JAK inhibitor is fuzotinib (e.g., fuzotinib dihydrochloride monohydrate), molotinib (e.g., molotinib dihydrochloride), paclitinib (e.g., paclitinib citrate), ruxolitinib (e.g., ruxolitinib phosphate), or a combination thereof.

88. The method of any one of claims 85 to 87, wherein the cancer is breast cancer, colorectal cancer, bile duct cancer, colorectal cancer, gastrointestinal stromal tumors, pancreatic cancer, bladder cancer, kidney cancer, cervical cancer, ovarian cancer, uterine cancer, head and neck cancer, hematological cancer, lung cancer, skin cancer, or a combination thereof.

89. The method of claim 88, wherein the hematological cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), essential thrombocythemia, polycythemia vera, myelofibrosis, or a combination thereof.

90. The method of claim 89, wherein the hematological cancer is essential thrombocythemia, polycythemia vera, myelofibrosis, or a combination thereof.

91. The method of any one of claims 89 to 90, wherein the hematological cancer has a JAK2 mutation (e.g., JAK2 V617F).

92. A compound of formula (SI-A): or a salt thereof, wherein: Each R 2 and R 4 Independently selected from: halo, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, OH and NR d R e ; m2 is 0, 1, or 2; m4 is 0, 1, 2, or 3; m6 is 0 or 1; R e1 is H or C optionally substituted by 1 to 3 -F 1-6 alkyl; R e2 is H or C optionally substituted by 1 to 3 -F 1-6 alkyl; a3 is 0 or 1; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is from 1 to 5; Each R L Independently selected from: 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 to 6 R c Replace C 1-6 alkyl; Each R a Independently selected from: (a) halo; (b) cyano; (c) -OH; (d) oxo; (e)-C 1-6 Alkoxy; (f)-C 1-6 Haloalkoxy; (g)-NR d R e ; (h)C(=O)C 1-6 alkyl; (i) C(=O)C 1-6 Haloalkyl; (j) C(═O)OH; (k)C(=O)OC 1-6 alkyl; (l)C(=O)OC 1-6 Haloalkyl; (m)C(=O)N(R f )2; (n)S(O) 0-2 (C 1-6 alkyl); (o)S(O) 0-2 (C 1-6 haloalkyl); (p)S(O) 1-2 N(R f )2; and (q)C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl, each optionally substituted by 1 to 6 R c replace; Each R b Independently selected from: -(L b ) b -R b1 and -R b1 ,in: Each b is independently 1, 2 or 3; Each -L b Independently selected from: -O-; -N(H)-; -N(C 1-3 Alkyl)-; -S(O) 0-2 -; C(=O); and C 1-3 an alkylene group; and Each R b1 Independently selected from: C 3-10 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R g replace; Each R c Independently selected from: 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: 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 to 3 R h Substituted C 1-6 alkyl; Each R f Independently selected from: H and optionally 1 to 3 R h Substituted C 1-6 Alkyl; and Each R h Independently selected from: halo; cyano; -OH; -C 1-6 Alkoxy; -C 1-6 Haloalkoxy; -NH2, -N(H)(C 1-3 alkyl); and -N(C 1-3 Alkyl)2.

93. A compound of formula (IE): or a salt thereof, wherein: Each R 2 and R 4 Independently selected from: H, C 1-3 Alkyl and halo; a3 is 0 or 1; m2 is 0, 1, or 2; m4 is 0, 1, 2, or 3; m6 is 0 or 1; R e1 is H or C optionally substituted by 1 to 3 -F 1-6 alkyl; L A3 Selected from: -O-, -N(H)- and -N(C 1-3 alkyl)-; L A1a and L A1b Independently selected from: -CH2-, -CHR L -and-C(R L )2-; L A4 Selected from: a)C 3-10 cycloalkylene or 4 to 10 membered heterocyclylene, each of which is optionally substituted by 1 to 3 R a Replacement; and b) phenylene or 5- to 6-membered heteroarylene, each of which is optionally substituted by 1 to 3 R a replace; a1a is an integer from 0 to 5; a1d is an integer from 0 to 4, provided that a1a+a1d is from 1 to 4; Each R L Independently selected from: 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 to 6 R c Replace C 1-6 alkyl; Each R a Independently selected from: (a) halo; (b) cyano; (c) -OH; (d) oxo; (e)-C 1-6 Alkoxy; (f)-C 1-6 Haloalkoxy; (g)-NR d R e ; (h)C(=O)C 1-6 alkyl; (i) C(=O)C 1-6 Haloalkyl; (j) C(═O)OH; (k)C(=O)OC 1-6 alkyl; (l)C(=O)OC 1-6 Haloalkyl; (m)C(=O)N(R f )2; (n)S(O) 0-2 (C 1-6 alkyl); (o)S(O) 0-2 (C 1-6 haloalkyl); (p)S(O) 1-2 N(R f )2; and (q)C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl, each optionally substituted by 1 to 6 R c replace; Each R b Independently selected from: -(L b ) b -R b1 and -R b1 ,in: Each b is independently 1, 2 or 3; Each -L b Independently selected from: -O-; -N(H)-; -N(C 1-3 Alkyl)-; -S(O) 0-2 -; C(=O); and C 1-3 Alkylene; Each R b1 Independently selected from: C 3-10 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R g replace; Each R c Independently selected from: 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: 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 to 3 R h Substituted C 1-6 alkyl; Each R f Independently selected from: H and optionally 1 to 3 R h Substituted C 1-6 alkyl; Each R g Independently selected from: R h ; C 1-3 Alkyl; and C 1-3 haloalkyl; and Each R h Independently selected from: halo; cyano; -OH; -C 1-6 Alkoxy; -C 1-6 Haloalkoxy; -NH2, -N(H)(C 1-3 alkyl); and -N(C 1-3 Alkyl)2.

94. A compound of any one of formula (I-Ind-1), (I-Ind-2) or (I-Ind-3): or a salt thereof, wherein: Each R Y Independently selected from: R a and R b ; c1 is 0, 1, 2, or 3; n2 and n3 are independently 0, 1 or 2; R aN is H or optionally 1 to 3 R c Substituted C 1-6 alkyl; m8 is 0 to 4; Each R a Independently selected from: (a) halo; (b) cyano; (c) -OH; (d) oxo; (e)-C 1-6 Alkoxy; (f)-C 1-6 Haloalkoxy; (g)-NR d R e ; (h)C(=O)C 1-6 alkyl; (i) C(=O)C 1-6 Haloalkyl; (j) C(═O)OH; (k)C(=O)OC 1-6 alkyl; (l)C(=O)OC 1-6 Haloalkyl; (m)C(=O)N(R f )2; (n)S(O) 0-2 (C 1-6 alkyl); (o)S(O) 0-2 (C 1-6 haloalkyl); (p)S(O) 1-2 N(R f )2; and (q)C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 alkynyl, each optionally substituted by 1 to 6 R c replace; Each R b Independently selected from: -(L b ) b -R b1 and -R b1 ,in: Each b is independently 1, 2 or 3; Each -L b Independently selected from: -O-; -N(H)-; -N(C 1-3 Alkyl)-; -S(O) 0-2 -; C(=O); and C 1-3 Alkylene; Each R b1 Independently selected from: C 3-10 Cycloalkyl, 4- to 10-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted by 1 to 3 R g replace; Each R c Independently selected from: 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: 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 to 3 R h Substituted C 1-6 alkyl; Each R f Independently selected from: H and optionally 1 to 3 R h Substituted C 1-6 alkyl; Each R g Independently selected from: R h ; C 1-3 Alkyl; and C 1-3 haloalkyl; and Each R h Independently selected from: halo; cyano; -OH; -C 1-6 Alkoxy; -C 1-6 Haloalkoxy; -NH2, -N(H)(C 1-3 alkyl); and -N(C 1-3 Alkyl)2.

95. Any of the compounds, compositions, combinations, pharmaceutical compositions, methods, uses or processes provided herein.

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