Tetrahydroisoquinoline heterobifunctional bcl-xl degraders

Abstract

The present disclosure provides compounds of Formula (I) (e.g., Formula (I-1) (e.g., Formula (I-a1), Formula (I-b1), Formula (I-b3), Formula (I-c1), Formula (I-d1), Formula (I-e1), Formula (I-e3), Formula (I-f1), Formula (I-g1), Formula (I-g3), Formula (I-h1), Formula (I-i1), or Formula (I-i3)) or Formula (I-2) (e.g., Formula (I-a2), Formula (I-b2), Formula (I-b4), Formula (I-c2), Formula (I-d2), Formula (I-e2), Formula (I-e4), Formula (I-f2), Formula (I-g2), Formula (I-g4), Formula (I-h2), or Formula (I-i2))), Formula (II) (e.g., Formula (II-a1) or Formula (II-a2)), or Formula (A), or a pharmaceutically acceptable salt thereof, that induce degradation of BCL-X L proteins. These compounds are useful, for example, in treating cancer in a subject (e.g., a human). The present disclosure also provides compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, as well as methods of using and making these compositions.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application Serial No. 63 / 547,656, filed November 7, 2023; U.S. Provisional Application Serial No. 63 / 641,308, filed May 1, 2024; and U.S. Provisional Application Serial No. 63 / 704,392, filed October 7, 2024; the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] This disclosure provides information on inducing BCL-X L Protein degradation of formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I- Compounds of formula (a2), (I-b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2), (II) (e.g., (II-a1) or (II-a2)), or (A), or pharmaceutically acceptable salts thereof. These compounds may be used, for example, to treat cancer in a subject (e.g., a human). This disclosure also provides formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-i3)). Compositions of formulas (I-b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2), (II) (e.g., (II-a1) or (II-a2)) or (A), or pharmaceutically acceptable salts thereof, and methods of using and preparing them. Background Technology

[0004] The BCL-2 protein family is involved in the regulation of apoptosis and includes pro-apoptotic proteins, pro-survival proteins, and BH3-only proteins. At high levels, the binding balance of BH3-only proteins to the 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, which can be achieved by reducing the number of pro-survival proteins (e.g., BCL-X) that can compete for binding with BH3-only proteins. L This is achieved through the quantity of ). Summary of the Invention

[0005] This disclosure provides information on inducing BCL-X L Protein degradation of formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I- Compounds of formula (a2), (I-b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2), (II) (e.g., (II-a1) or (II-a2)), or (A), or pharmaceutically acceptable salts thereof. These compounds may be used, for example, to treat cancer in a subject (e.g., a human). This disclosure also provides formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1), or formula (I-i3)) or formula (I-2) (e.g., formula (I-a1), formula (I-g3), formula (I-h1), formula (I-i1), or formula (I-i3)) 2) Compositions of compounds of formula (I-b2), formula (I-b4), formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A), and methods for using and preparing them.

[0006] This article provides compounds of formula (I):

[0007]

[0008] Formula (I)

[0009] Or its pharmaceutically acceptable salt, wherein:

[0010] Z 1 Choose from the following groups: N and CH;

[0011] R 1 Choose from the following groups:

[0012] (a)C(O)OH;

[0013] (b)C(O)OC 1-6 Alkyl, wherein the C 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups. c Replace; and

[0014] (c)C(O)-(C 0-3 (alkylene)-phenyl, wherein the phenyl group is optionally surrounded by 1 to 3 R groups. a replace;

[0015] Ring A is selected from the following groups: (A1) and (A2):

[0016]

[0017] in:

[0018] m2 is 0, 1, or 2.

[0019] Each R 2 Independently select from the following groups: halogenated group, CN, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and optionally surrounded by 1 to 3 R groups c Replacement C 1-3 Alkyl, and

[0020] aa indicates the attachment point to L;

[0021] L is -(L) A ) n1 -,in:

[0022] n1 is an integer between 4 and 10.

[0023] An L A It is L A4 ,

[0024] 0 to 3 L A L is chosen independently. A3 ,and

[0025] Each remaining L A L is chosen independently.A1 ;

[0026] Each L A1 Independently select from the following groups: -CH2-, -CHR L -and-C(R) L )2-, where:

[0027] Each R L Independently select from the following groups: halogenated group, -CN, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -(C 0-3 alkylene)-(C 3-5 cycloalkyl), -(C 0-3 (alkylene)-(4- to 6-membered heterocyclic group) and optionally surrounded by 1 to 6 R c Replacement C 1-6 alkyl;

[0028] Each L A3 Independently select from the following groups: -N(R) d )-、-N(R b -、-O-、-S(O) 0-2 - and C (=O);

[0029] L A4 Choose independently from the following groups:

[0030] (a)C 3-12 Cycloalkyl or 4- to 15-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. L4 Replace; and

[0031] (b) a phenylene or a 5- to 6-membered heteroaryl group, each of which is optionally surrounded by 1 to 3 R groups. L4 replace,

[0032] Each R L4 Independently select from the following groups: R a and R b ;

[0033] Ring C can be selected from the following groups: , , and ,in:

[0034] R Ya Choose from the following groups: H, R b and optionally by 1 to 3 R c Replacement C 1-6 alkyl;

[0035] Each R Yb Independently select free R a and R b The group formed;

[0036] c1 is 0, 1, or 2; and

[0037] yy represents the attachment point to L;

[0038] Each R a Choose independently from the following groups:

[0039] (a) Halogenated group;

[0040] (b)CN;

[0041] (c)-OH;

[0042] (d) Oxide group;

[0043] (e) optionally by 1 to 6 R c Replacement C 1-6 Alkoxy;

[0044] (f)-NR d R e ;

[0045] (g)C(=O)C 1-6 alkyl;

[0046] (h)C(=O)OC 1-6 alkyl;

[0047] (i)C(=O)N(R f )2;

[0048] (j)S(O) 0-2 (C 1-6 alkyl);

[0049] (k)S(O) 0-2 (C 1-6 (halogenated alkyl); and

[0050] (l)C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne groups, each optionally surrounded by one to six R groups c replace;

[0051] Each R b Selected independently from: -(L b ) b -R b1 and -R b1 ,in:

[0052] Each b is independently 1 or 2;

[0053] Each L b Choose independently from the following groups: -O-, -N(H)-, -N(C)-. 1-3 Alkyl)-, -S(O) 0-2 - C (=O) and C 1-3 Alkylene; and

[0054] Each R b1 Choose independently from the following groups: C 3-6 Cycloalkyl and 4 to 8-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. g replace;

[0055] Each R c Independently select from the following groups: halogenated group, CN, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e C(=O)C 1-6 Alkyl, C(=O)OC 1-6 Alkyl, C(=O)N(R) f 2. S(O) 0-2 (C 1-6 Alkyl groups and S(O) 0-2 (C- 1-6 (Halogenated alkyl);

[0056] 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 groups), S(O) 1-2 (C- 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f )2 and optionally by 1 to 3 R h Replacement C 1-6 alkyl;

[0057] Each R f Independently select from the following groups: H and optionally selected by 1 to 3 Rs. h Replacement C 1-6 alkyl;

[0058] Each R g Independently select from the following groups: R h , Oxide group, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0059] Each R h Independently select from the following groups: halogenated group, CN, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl) and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

[0060] This article also provides compounds of formula (II):

[0061]

[0062] Equation (II)

[0063] Or its pharmaceutically acceptable salt, wherein:

[0064] Z 1 Choose from the following groups: N and CH;

[0065] R 1 Choose from the following groups:

[0066] (a)C(O)OH;

[0067] (b)C(O)OC 1-6 Alkyl, wherein the C 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups. c Replace; and

[0068] (c)C(O)-(C 0-3 (alkylene)-phenyl, wherein the phenyl group is optionally surrounded by 1 to 3 R groups. g replace;

[0069] Ring A is selected from the following groups: (A1) and (A2):

[0070]

[0071] in:

[0072] m2 is 0, 1, or 2.

[0073] Each R 2 Independently select from the following groups: halogenated group, CN, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and optionally surrounded by 1 to 3 R groups c Replacement C 1-3 Alkyl, and

[0074] aa represents -(L) A3a ) a3a - Attachment point;

[0075] L A3a Choose from the following groups: -N(R) d -、-O-、-S(O) 0-2 - and C (=O);

[0076] a3a is 0 or 1;

[0077] Each L A1a L A1b and L A1c Independently select from the following groups: -CH2-, -CHR L -and-C(R) L )2-, where:

[0078] Each R L Independently select from the following groups: halogenated group, -CN, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -(C 0-3 alkylene)-(C 3-5 cycloalkyl), -(C 0-3 (alkylene)-(4- to 6-membered heterocyclic group) and optionally surrounded by 1 to 6 R c Replacement C 1-6 alkyl;

[0079] a1a, a1b, and a1c are each independently 0, 1, or 2;

[0080] L A4a and L A4b Choose independently from the following groups: C 3-8 Cycloalkylene groups and 4- to 12-membered heterocyclic alkylene groups, each of which is optionally surrounded by 1 to 3 R groups. L4 replace;

[0081] Each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and optionally 1 to 3 R groups c Replacement C 1-3 alkyl;

[0082] R d1 Is it -H or C? 1-3 alkyl;

[0083] Ring C can be selected from the following groups: , , and ,in:

[0084] R Ya Choose from the following groups: H and optionally 1 to 3 Rs. c Replacement C 1-6 alkyl;

[0085] Each R Yb Choose independently from the following groups: F, C 1-3 Alkyl groups or optionally alkoxy groups, with one to three R groups c Replacement C 1-3 alkyl;

[0086] c1 is 0, 1, or 2; and

[0087] yy represents -N(R) d1 )- Attachment point;

[0088] Each R c Independently select from the following groups: halogenated group, CN, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e C(=O)C 1-6 Alkyl, C(=O)OC 1-6 Alkyl, C(=O)N(R) f 2. S(O) 0-2 (C 1-6 Alkyl groups and S(O) 0-2 (C- 1-6 (Halogenated alkyl);

[0089] 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 groups), S(O) 1-2 (C- 1-6Halogenated alkyl groups), S(O) 1-2 N(R f )2 and optionally by 1 to 3 R h Replacement C 1-6 alkyl;

[0090] Each R f Independently select from the following groups: H and optionally selected by 1 to 3 Rs. h Replacement C 1-6 alkyl;

[0091] Each R g Selected independently from: R h C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0092] Each R h Independently select from the following groups: halogenated group, CN, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl) and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

[0093] This document also provides pharmaceutical compositions comprising formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a1), formula (I-b1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) Compounds of formula (I-a2), (I-b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2)), (II) (e.g., (II-a1) or (II-a2)) or (A), or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.

[0094] This article provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1), or formula (I-i3)) or formula (I- 2) (e.g., compounds of formula (I-a2), formula (I-b2), formula (I-b4), formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2))), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as provided herein.

[0095] This document also provides equation (I) (e.g., equation (I-1) (e.g., equation (I-a1), equation (I-b1), equation (I-b3), equation (I-c1), equation (I-d1), equation (I-e1), equation (I-e3), equation (I-f1), equation (I-g1), equation (I-g3), equation (I-h1), equation (I-i1) or equation (I-i3)) or equation (I-2) (e.g., equation (I-a2), equation (I-i3)). Compounds of formula (I-b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2)), (II) (e.g., (II-a1) or (II-a2)) or (A), or pharmaceutically acceptable salts of these compounds non-covalently bound to BCL-X. L protein.

[0096] This article also provides a ternary complex containing BCL-X. LProtein; Formula (I) (e.g., Formula (I-1) (e.g., Formula (I-a1), Formula (I-b1), Formula (I-b3), Formula (I-c1), Formula (I-d1), Formula (I-e1), Formula (I-e3), Formula (I-f1), Formula (I-g1), Formula (I-g3), Formula (I-h1), Formula (I-i1) or Formula (I-i3)) or Formula (I-2) (e.g., Formula (I-a2), Formula (I- Compounds of formula (b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2), (II) (e.g., (II-a1) or (II-a2)) or (A), or pharmaceutically acceptable salts thereof; and CRBN protein or a portion thereof.

[0097] To facilitate understanding of the disclosure set forth herein, numerous additional terms are provided. Generally, the nomenclature used herein, and the laboratory procedures described in organic chemistry, medicinal chemistry, and pharmacology, are those well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Every patent, patent application, published application, and other publication mentioned throughout this specification and its appendices is incorporated herein by reference in its entirety. In the event of any conflict between this disclosure and any content incorporated herein by reference, this disclosure shall prevail.

[0098] Details of one or more embodiments of the present invention are set forth in the following drawings and description. Further features and advantages of the invention will be understood from these descriptions and drawings, as well as the claims. Detailed Implementation

[0099] This disclosure provides information on inducing BCL-X LDegradation of the protein (also referred to herein as Bcl-xL) of formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) For example, compounds of formula (I-a2), formula (I-b2), formula (I-b4), formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A), or their pharmaceutically acceptable salts. These compounds can be used, for example, to treat cancer. This disclosure also provides formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1), or formula (I-i3)) or formula (I-2) (e.g., formula (I-a1), formula (I-g3), formula (I-h1), formula (I-i1), or formula (I-i3)) 2) Compositions of compounds of formula (I-b2), formula (I-b4), formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A), and methods for using and preparing them.

[0100] Unbound 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 outer mitochondrial membrane (MOM), where voltage-dependent anion channel 2 (VDAC2) can act as a receptor. Pro-survival BCL-2 family members (e.g., BCL-2, BCL-X) LBCL-2 and MCL-1 can retrotransport BAX back into the cytosol. Only BH3 proteins (e.g., BIM) can bind to the posterior site on pro-apoptotic effectors (e.g., BAX or BAK) and release the C-terminal transmembrane domain (α9) of the effector, enabling binding to the MOM. Binding of BIM to the canonical BH3 binding groove of BAX or BAK releases the N-terminus and α1 of BAX or BAK, followed by the unfolding of the "latch" domain, releasing BIM from the BH3 binding groove. If a pro-survival BCL-2 family member subsequently binds to BAX or BAK, apoptosis signaling is usually stopped. However, if BAX or BAK is allowed to dimerize and then oligomerize, the MOM can be permeabilized, inducing apoptosis.

[0101] Numerous pro-survival BCL-2 family members are sometimes thought to “induce” cell death (e.g., through cytotoxic therapies, including BH3 mimics). Oncogenic mutations and stress are believed to cause upregulation of BH3-only proteins, thus exerting selective pressure on cancer cells to upregulate pro-survival BCL-2 family proteins. Therefore, it is believed that the more BH3-only proteins are present in the vicinity, the more sensitive the cell is to further manipulation of the BCL-2 family homeostasis. See, for example, Adams and Cory, Cell Death & Differentiation 25.1 (2018): 27-36, doi: 10.1038 / cdd.2017.161.

[0102] Compounds that induce the degradation of target proteins are sometimes referred to as heterobifunctional compounds, PROTACs, or degrading agents. These compounds typically consist of a moiety that binds to the target protein and a moiety that binds to a ubiquitin E3 ligase (sometimes called an E3 ligase or simply E3), these two moieties optionally separated by a linker. It is believed that, in order to induce degradation, heterobifunctional compounds induce the formation of a ternary complex between the target protein, the compound, and the E3 ligase. Following the formation of the ternary complex is the ubiquitination of the target protein and its degradation by the proteasome. Several E3 ligases have been used as partner E3 ligases of heterobifunctional degrading agents. In this paper, the cereblon (CRBN) E3 ligase (also referred to herein as the CRBN protein) is used.

[0103] Degradation of target proteins can have potential advantages over small-molecule inhibition, such as that of the target protein. One potential advantage is that the duration of action of heterobifunctional compounds is often based on the rate of resynthesis of the target protein. Another potential advantage is that many heterobifunctional compounds are believed to be released from ubiquitinated target protein-E3 ligase complexes and can be used to form additional ternary complexes; this is sometimes referred to as the “catalytic” conversion of heterobifunctional compounds. In some cases, degradation of target proteins can also be more advantageous than small-molecule inhibition because degradation can attenuate the scaffold function of the target protein, which small molecules cannot. It is also generally accepted that a high affinity for the target protein is not always required for the formation of ternary complexes.

[0104] The heterobifunctional compounds are further described in, for example, the following publications: International Publication Nos. WO 2017 / 184995, WO2019 / 144117, WO 2020 / 163823, WO 2021 / 078301, WO 2021 / 146536, WO 2021 / 007307, WO2021 / 222114, WO 2022 / 169780, WO 2023 / 044046, WO 2023 / 185986, WO 2024 / 027706, WO2024 / 179577, WO 2024 / 169976, WO 2024 / 078581, WO 2024 / 077023, WO 2024 / 067818, WO2024 / 051741, WO 2024 / 012449, WO 2024 / 012557; Chamberlain and Hamann, Nature ChemicalBiology 15.10 (2019): 937-944, doi: 10.1038 / s41589-019-0362-y; Li and Song, Journal of Hematology & Oncology 13 (2020): 1-14, doi: 10.1186 / s13045-020-00885-3; Wu et al. Nature Structural & Molecular Biology 27.7 (2020): 605-614,doi: 10.1038 / s41594-020-0438-0; Dong et al., Journal of Medicinal Chemistry 64.15(2021): 10606-10620, doi: 10.1021 / acs.jmedchem.1c00895; Yang et al., Targeted Oncology 16.1 (2021): 1-12, doi: 10.1007 / s11523-020-00782-2; Lv et al., Nature Communications 12.1 (2021): 6896, doi: 10.1038 / s41467-021-27210-x.

[0105] Compound implementation plan

[0106] This article provides compounds of formula (I):

[0107]

[0108] Formula (I)

[0109] Or its pharmaceutically acceptable salt, wherein:

[0110] Z 1 Choose from the following groups: N and CH;

[0111] R 1 Choose from the following groups:

[0112] (a)-C(O)OH;

[0113] (b)-C(O)OC 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups. c Replace; and

[0114] (c)-C(O)-(C 0-3 (alkylene)-phenyl, wherein the phenyl group is optionally surrounded by 1 to 3 R groups. a replace;

[0115] Ring A is selected from the following groups: (A1) and (A2):

[0116]

[0117] in:

[0118] m2 is 0, 1, or 2.

[0119] Each R 2 Independently select from the following groups: halogenated group, -CN, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and optionally surrounded by 1 to 3 R groups c Replacement C 1-3 Alkyl, and

[0120] aa indicates the attachment point to L;

[0121] L is -(L) A ) n1 -,in:

[0122] n1 is an integer between 4 and 10.

[0123] An L A It is L A4 ,

[0124] 0 to 3 L A L is chosen independently. A3 ,and

[0125] Each remaining L A L is chosen independently. A1 ;

[0126] Each L A1 Independently select from the following groups: -CH2-, -CHR L -and-C(R) L )2-, where:

[0127] Each R L Independently select from the following groups: halogenated group, -CN, -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 0-3 alkylene)-(C 3-5 cycloalkyl), -(C 0-3 (alkylene)-(4- to 6-membered heterocyclic group) and optionally surrounded by 1 to 6 R c Replacement C 1-6 alkyl;

[0128] Each L A3 Independently select from the following groups: -N(R) d )-、-N(R b -、-O-、-S(O) 0-2 -and-C(=O)-;

[0129] L A4 Choose independently from the following groups:

[0130] (a)C 3-12 Cycloalkyl or 4- to 15-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. L4 Replace; and

[0131] (b) a phenylene or a 5- to 6-membered heteroaryl group, each of which is optionally surrounded by 1 to 3 R groups. L4 replace,

[0132] Each R L4 Independently select from the following groups: R a and R b ;

[0133] Ring C can be selected from the following groups: , , and ,in:

[0134] R Ya Choose from the following groups: -H, R b and optionally by 1 to 3 R c Replacement C 1-6 alkyl;

[0135] Each R YbIndependently select free R a and R b The group formed;

[0136] c1 is 0, 1, or 2; and

[0137] yy represents the attachment point to L;

[0138] Each R a Choose independently from the following groups:

[0139] (a) Halogenated group;

[0140] (b)-CN;

[0141] (c)-OH;

[0142] (d) Oxide group;

[0143] (e) optionally by 1 to 6 R c Replacement C 1-6 Alkoxy;

[0144] (f)-NR d R e ;

[0145] (g)-C(=O)C 1-6 alkyl;

[0146] (h)-C(=O)OC 1-6 alkyl;

[0147] (i)-C(=O)N(R f )2;

[0148] (j)-S(O) 0-2 (C 1-6 alkyl);

[0149] (k)-S(O) 0-2 (C- 1-6 (halogenated alkyl); and

[0150] (l)C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne groups, each optionally surrounded by one to six R groups c replace;

[0151] Each R b Independently select from the following groups: -(L b ) b -R b1 and R b1 ,in:

[0152] Each b is independently 1 or 2;

[0153] Each L b Choose independently from the following groups: -O-, -N(H)-, -N(C)-. 1-3 Alkyl)-, -S(O) 0-2 -、-C(=O)- and C 1-3 Alkylene; and

[0154] Each R b1 Choose independently from the following groups: C 3-6 Cycloalkyl and 4 to 8-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. g replace;

[0155] Each R c Independently select from the following groups: halogenated group, -CN, -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR d R e -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl, -C(=O)N(R) f )2、-S(O) 0-2 (C 1-6 Alkyl groups and -S(O) 0-2 (C- 1-6 (Halogenated alkyl);

[0156] Each R d and R e Choose independently from the following groups: -H, -C (=O)C 1-6 Alkyl group, -C(=O)C 1-6 Haloalkyl, -C(=O)OC 1-6 Alkyl group, -C(=O)OC 1-6 Haloalkyl, -C(=O)N(R) f )2、-S(O) 1-2 (C 1-6 Alkyl groups, -S(O) 1-2 (C- 1-6 Halogenated alkyl groups), -S(O) 1-2 N(R f )2 and optionally by 1 to 3 R h Replacement C 1-6 alkyl;

[0157] Each R f Independently selected from: -H and optionally by 1 to 3 R h Replacement C 1-6 alkyl;

[0158] Each R g Independently select from the following groups: R h , Oxide group, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0159] Each R h Independently select from the following groups: halogenated group, -CN, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl) and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

[0160] In some implementations of formula (I), Z 1 It is N.

[0161] In some implementations of formula (I), Z 1 It is CH.

[0162] In some implementations of formula (I), ring A is (A1).

[0163] In some implementations of formula (I), ring A is (A2).

[0164] In some implementations of equation (I), m2 is 1.

[0165] In some implementations of equation (I), ring A is .

[0166] In some implementations of equation (I), ring A is .

[0167] In some implementations of formula (I), R 2 It can be arbitrarily divided by 1 to 3 Rs c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 F- atoms) 1-3 Alkyl groups). For example, R 2 It can be CH3. For example, R 2 It can be CF3. In some implementations of equation (I), R 2 Yes, it is -F.

[0168] In some implementations of equation (I), ring A is: .

[0169] In some implementations of equation (I), ring A is .

[0170] In some implementations of equation (I), ring A is .

[0171] In some implementations of equation (I), ring A is: .

[0172] In some implementations of equation (I), ring A is: .

[0173] In some implementations of equation (I), ring A is: .

[0174] In some implementations of equation (I), n1 is an integer from 5 to 9 (e.g., 5, 6, 7 or 8).

[0175] In some implementations of equation (I), n1 is an integer from 5 to 9; and L is:

[0176] -(L A3 ) 0-1 -(L A1 ) 0-5 -(L A4 )-(L A1 ) 0-5 -(L A3 ) 0-2 - bb ,

[0177] Where bb represents the attachment point to ring C.

[0178] In some implementations of equation (I), n1 is an integer from 5 to 9; and L is selected from the group consisting of the following:

[0179] -L A3 -(L A1 ) 0-4 -(L A4 )-L A1 -C(=O)N(R d1 )- bb ;

[0180] -L A3 -(L A1 ) 0-4 -(L A4 )-(L A1 ) 1-3 -O- bb ;

[0181] -L A3-(L A1 ) 0-4 -(L A4 )-(L A1 ) 1-3 -N(R d1 )- bb ;and

[0182] -L A3 -(L A1 ) 0-4 -(L A4 )-(L A1 ) 1-4 - bb ;

[0183] Where bb represents the attachment point to ring C; and R d1 Is it H or C? 1-3 alkyl.

[0184] In some implementations of equation (I), n1 is an integer from 5 to 9; and L is:

[0185] -L A3 -(L A1 ) 0-4 -(L A4 )-L A1 -C(=O)N(R d1 )- bb ;

[0186] Where bb represents the attachment point to ring C; and R d1 Is it H or C? 1-3 alkyl.

[0187] In some implementations of equation (I), n1 is an integer from 5 to 9; and L is:

[0188] -O-(L A1 ) 0-4 -(L A4 )-CH2-C(=O)N(H)- bb ,

[0189] Where bb represents the attachment point to ring C.

[0190] In some implementations of equation (I), n1 is an integer from 5 to 9; and L is:

[0191] -N(R d2 )-(L A1 ) 0-4 -(L A4 )-CH2-C(=O)N(H)- bb ;

[0192] Where bb represents the attachment point to ring C; and R d2 Is it H or C? 1-3 Alkyl group. For example, R d2 It can be H or methyl.

[0193] In some implementations of formula (I), L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted 5- to 12-membered nitrogen-containing heterocyclic sub-groups.

[0194] In some implementations of equation (I), each R L4 R is chosen independently. a .

[0195] In some implementations of equation (I), each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0196] In some implementations of formula (I), L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted monocyclic 5- to 6-membered nitrogen-containing heterocyclic groups, wherein each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0197] In some implementations of formula (I), L A4 yes .

[0198] In some implementations of formula (I), L A4 yes , where R L4 It is -F or -OH (e.g., -OH).

[0199] In some implementations of formula (I), L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted bicyclic 7- to 12-membered nitrogen-containing subheterocyclic groups, wherein each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0200] In some implementations of formula (I), L A4 It can be arbitrarily divided by 1 to 3 Rs L4Substituted spirocyclic bicyclic 7- to 12-membered nitrogen-containing subheterocyclic groups, wherein each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0201] In some implementations of formula (I), L A4 Choose from the following groups: , and Each of these groups is optionally surrounded by one to three R groups. L4 Replace, where each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl group. For example, L A4 It can be .

[0202] In some implementations of formula (I), L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted bridging or fused bicyclic 7- to 12-membered nitrogen-containing heterocyclic groups, wherein each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0203] In some implementations of formula (I), L A4 Choose from the following groups: , and Each of these groups is optionally surrounded by one to three R groups. L4 Replace, where each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0204] In some implementations of equation (I), each L A1 It is CH2.

[0205] In some implementations of formula (I), an L A1 It is CHR L or C(R) L )2, where each R L C is independently -F or optionally replaced by one to three Fs. 1-3Alkyl groups; and each remaining L A1 It is CH2. For example, an L A1 It can be CHMe; and each remaining L A1 It could be CH2.

[0206] In some implementations of equation (I), ring C is .

[0207] In some implementations of equation (I), ring C is .

[0208] In some implementations of equation (I), ring C is .

[0209] In some implementations of equation (I), ring C is .

[0210] In some implementations of formula (I), R Ya Choose from the following groups: H and optionally 1 to 3 Rs. c Replacement C 1-6 alkyl.

[0211] In some implementations of formula (I), R Ya It can be arbitrarily divided by 1 to 3 Rs c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 F- atoms) 1-3 Alkyl groups). For example, R Ya It can be methyl.

[0212] In some implementations of equation (I), each R Yb R is chosen independently. a .

[0213] In some implementations of equation (I), each R Yb Choose independently from the following groups: -F, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0214] In some implementations of equation (I), each R Yb Choose independently from the following groups: -F, OMe, CH3, CHF2, CH2F, and CF3.

[0215] In some embodiments of formula (I), at least one R Yb It is C 1-3 Alkyl groups (e.g., OMe).

[0216] In some implementations of equation (I), ring C is , where R Ya It can be arbitrarily divided by 1 to 3 Rs c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 F- atoms) 1-3 alkyl).

[0217] In some implementations of equation (I), ring C is , where R Ya It can be arbitrarily divided by 1 to 3 Rs c Replacement C 1-3 Alkyl groups (e.g., C-shaped groups optionally substituted with 1 to 3 F- atoms) 1-3 Alkyl); and

[0218] R Yb Choose independently from the following groups: -F, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl group. In some embodiments, when the ring C is... At that time, R Yb It is C 1-3 Alkyl groups (e.g., methoxy groups).

[0219] In some embodiments, the compound of formula (I) is a compound of formula (I-1) or formula (I-2):

[0220]

[0221] Formula (I-1)

[0222]

[0223] Formula (I-2)

[0224] Or its pharmaceutically acceptable salt, wherein:

[0225] m2 is 0 or 1;

[0226] Each L A3a and L A3b L is chosen independently. A3 ;

[0227] a3a is 0 or 1;

[0228] a3b is 0, 1, or 2;

[0229] Each L A1a and L A1b L is chosen independently. A1 ;

[0230] a1a and a1b are independent integers from 0 to 4;

[0231] The condition is that a3a + a1a + a1b + a3b is between 4 and 8; and

[0232] L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted 5- to 12-membered nitrogen-containing heterocyclic sub-groups.

[0233] In some embodiments, the compound is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof; and one or more of (1) to (4) are applicable:

[0234] (1)Z 1 It is N;

[0235] (2) Ring C is or ;

[0236] (3) c1 is 1 or 2, where at least one R Yb It is C 1-3 Alkoxy groups (e.g., OMe); and

[0237] (4) a3a is 1, and L A3a Is it -N(H)- or -N(C)-? 1-3 alkyl)-.

[0238] In some embodiments, the compound is a compound of formula (I-2) or a pharmaceutically acceptable salt thereof; and one or more of (1)-(5) are applicable:

[0239] (1)Z 1 It is N;

[0240] (2) Ring C is or ;

[0241] (3) c1 is 1 or 2, where at least one R Yb It is C 1-3 Alkoxy;

[0242] (4) m2 is 1; and R 2 It is CF3; and

[0243] (5) a3a is 1, and L A3a Is it -N(H)- or -N(C)-? 1-3 alkyl)-.

[0244] In some embodiments, the compound of formula (I-1) or formula (I-2) is a compound of formula (I-a1) or formula (I-a2):

[0245]

[0246] Equation (I-a1)

[0247]

[0248] Equation (I-a2)

[0249] Or its pharmaceutically acceptable salt.

[0250] In some embodiments, the compound of formula (I-1) or (I-2) is a compound of formula (I-b1) or (I-b2):

[0251]

[0252] Equation (I-b1)

[0253]

[0254] Formula (I-b2)

[0255] Or its pharmaceutically acceptable salt.

[0256] In some embodiments, the compound of formula (I-1) or (I-2) is a compound of formula (I-b3) or (I-b4):

[0257]

[0258] Equation (I-b3)

[0259]

[0260] Equation (I-b4)

[0261] Or its pharmaceutically acceptable salt.

[0262] In some embodiments of formula (I-b1) or formula (I-b2), these compounds are different from compounds numbered R126 or R313 as depicted in Table R1, or their pharmaceutically acceptable salts.

[0263] In some embodiments, the compound is a compound of formula (I-b2) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (I-b3) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (I-b4) or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, the compound is a compound of formula (I-b1) or a pharmaceutically acceptable salt thereof; and one or more of (1)-(5) are applicable:

[0265] (1) c1 is 1 or 2;

[0266] (2)L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted bicyclic 7- to 12-membered nitrogen-containing heterocyclic groups;

[0267] (3)L A4 It is by 1 to 3 Rs L4 Substituted 5- to 12-membered nitrogen-containing heterocyclic groups;

[0268] (4) At least one L A1a Choose from the following groups: CHR L and C(R) L )2; and

[0269] (5) a1a is 0 or 1.

[0270] In some embodiments, the compound of formula (I-1) or formula (I-2) is a compound of formula (I-c1) or formula (I-c2):

[0271]

[0272] Equation (I-c1)

[0273]

[0274] Equation (I-c2)

[0275] Or its pharmaceutically acceptable salt, wherein:

[0276] R Yb It is F, C 1-3 Alkoxy or C-substituted with 1 to 3 -F groups 1-3 alkyl.

[0277] In some embodiments of formula (I-c1) or formula (I-c2), these compounds are different from compounds numbered R302 or R356 as depicted in Table R1, or their pharmaceutically acceptable salts.

[0278] In some implementations of formula (I-c1) or formula (I-c2), R Yb It is F; and one or more of (1)-(5) apply:

[0279] (1) m2 is 1, and R 2 It's CF3;

[0280] (2)L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted bicyclic 7- to 12-membered nitrogen-containing heterocyclic groups;

[0281] (3)L A4It is by 1 to 3 Rs L4 Substituted 5- to 12-membered nitrogen-containing heterocyclic groups;

[0282] (4) At least one L A1a Choose from the following groups: CHR L and C(R) L )2; and

[0283] (5) a1a is 0, 1 or 2.

[0284] In some implementations of formula (I-c1) or formula (I-c2), R Yb It is C 1-3 Alkyl groups (e.g., OMe).

[0285] In some embodiments, the compound of formula (I-1) or formula (I-2) is a compound of formula (I-d1) or formula (I-d2):

[0286]

[0287] Equation (I-d1)

[0288]

[0289] Equation (I-d2)

[0290] Or its pharmaceutically acceptable salt, wherein:

[0291] L A4 yes , where cc represents -(L A1a ) a1a - Attachment point.

[0292] In some embodiments of formula (I-d1) or formula (I-d2), these compounds are different from compounds numbered R156 or R226 as depicted in Table R1, or their pharmaceutically acceptable salts.

[0293] In some embodiments, the compound is a compound of formula (I-d1) or a pharmaceutically acceptable salt thereof; and one or more of (1)-(5) are applicable:

[0294] (1) m2 is 1, and R 2 It's CF3;

[0295] (2) a1a is 0;

[0296] (3) a1a is 2 or 3;

[0297] (4) c1 is 1 or 2; and

[0298] (5) At least one LA1a Choose from the following groups: CHR L and C(R) L )2.

[0299] In some embodiments, the compound is a compound of formula (I-d2) or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments of equations (I-a1), (I-b1), (I-c1), (I-d1), (I-a2), (I-b2), (I-b3), (I-b4), (I-c2), and (I-d2), a1b is 1; and L A1b It is -CH2-.

[0301] In some implementations of equations (I-a1), (I-b1), (I-c1), (I-d1), (I-a2), (I-b2), (I-b3), (I-b4), (I-c2), and (I-d2), a3a is 1; L A3a It is -O-; a3b is 2; and -(L A3b ) a3b - is -C(=O)NH- which is attached to the ring C at the nitrogen atom.

[0302] In some implementations of equations (I-a1), (I-b1), (I-c1), (I-d1), (I-a2), (I-b2), (I-b3), (I-b4), (I-c2), and (I-d2), a3a is 1; L A3a It is -N(R) d2 )-, where R d2 Is it -H or C? 1-3 Alkyl; a3b is 2; and -(L A3b ) a3b - is -C(=O)NH- which is attached to the ring C at the nitrogen atom.

[0303] In some embodiments, the compound of formula (I-1) or (I-2) is a compound of formula (I-e1) or (I-e2):

[0304]

[0305] Formula (I-e1)

[0306]

[0307] Equation (I-e2)

[0308] Or its pharmaceutically acceptable salt, wherein:

[0309] a1a is an integer from 0 to 4;

[0310] m2 is 0 or 1; and

[0311] R 2 It is CH3 or CF3.

[0312] In some embodiments, the compound is a compound of formula (I-e1) or a pharmaceutically acceptable salt thereof; and one or more of (1)-(3) are applicable:

[0313] (1)Z 1 It is N;

[0314] (2) Ring C is or ;and

[0315] (3) c1 is 1 or 2, where at least one R Yb It is C 1-3 Alkyl group.

[0316] In some embodiments, the compound is a compound of formula (I-e2) or a pharmaceutically acceptable salt thereof; and one or more of (1) to (4) are applicable:

[0317] (1)Z 1 It is N;

[0318] (2) Ring C is or ;

[0319] (3) c1 is 1 or 2, where at least one R Yb It is C 1-3 alkoxy groups; and

[0320] (4) m2 is 1; and R 2 It's CF3.

[0321] In some embodiments, the compound of formula (I-1) or (I-2) is a compound of formula (I-e3) or (I-e4):

[0322]

[0323] Equation (I-e3)

[0324]

[0325] Formula (I-e4)

[0326] Or its pharmaceutically acceptable salt, wherein:

[0327] a1a is an integer from 0 to 4;

[0328] m2 is 0 or 1;

[0329] R 2 It is CH3, CF3, or -F; and

[0330] R d2 Is it H or C? 1-3 Alkyl (e.g., H or methyl).

[0331] In some embodiments, the compound of formula (I-1) or formula (I-2) (e.g., formula (I-a1) or formula (I-a2)) is a compound of formula (I-f1) or formula (I-f2):

[0332]

[0333] Formula (I-f1)

[0334]

[0335] Formula (I-f2)

[0336] Or its pharmaceutically acceptable salt, wherein:

[0337] a1a is an integer from 0 to 4;

[0338] m2 is 0 or 1; and

[0339] R 2 It is CH3 or CF3.

[0340] In some embodiments, the compound of formula (I-1) or formula (I-2) (e.g., formula (I-b1) or formula (I-b2)) is a compound of formula (I-g1) or formula (I-g2):

[0341]

[0342] Formula (I-g1)

[0343]

[0344] Formula (I-g2)

[0345] Or its pharmaceutically acceptable salt, wherein:

[0346] a1a is an integer from 0 to 4;

[0347] m2 is 0 or 1; and

[0348] R 2 It is CH3 or CF3.

[0349] In some embodiments of formula (I-g1) or formula (I-g2), these compounds are different from compounds numbered R126 or R313 as depicted in Table R1, or their pharmaceutically acceptable salts.

[0350] In some embodiments, the compound is a compound of formula (I-g2) or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the compound is a compound of formula (I-g1) or a pharmaceutically acceptable salt thereof; and one or more of (1)-(5) are applicable:

[0352] (1) c1 is 1 or 2;

[0353] (2)L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted bicyclic 7- to 12-membered nitrogen-containing heterocyclic groups;

[0354] (3)L A4 It is by 1 to 3 Rs L4 Substituted 5- to 12-membered nitrogen-containing heterocyclic groups;

[0355] (4) At least one L A1a Choose from the following groups: CHR L and C(R) L )2; and

[0356] (5) a1a is 0 or 1.

[0357] In some embodiments, the compound of formula (I-1) or formula (I-2) (e.g., formula (I-b3) or formula (I-b4)) is a compound of formula (I-g3) or formula (I-g4):

[0358]

[0359] Formula (I-g3)

[0360]

[0361] Formula (I-g4)

[0362] Or its pharmaceutically acceptable salt, wherein:

[0363] a1a is an integer from 0 to 4; and

[0364] m2 is 0 or 1.

[0365] In some embodiments, the compound of formula (I-1) or formula (I-2) (e.g., formula (I-c1) or formula (I-c2)) is a compound of formula (I-h1) or formula (I-h2):

[0366]

[0367] Equation (I-h1)

[0368]

[0369] Equation (I-h2)

[0370] Or its pharmaceutically acceptable salt, wherein:

[0371] a1a is an integer from 0 to 4;

[0372] m2 is 0 or 1;

[0373] R 2 It is CH3 or CF3; and

[0374] R Yb It is F, C 1-3 Alkoxy or C-substituted with 1 to 3 -F groups 1-3 alkyl.

[0375] In some embodiments of formula (I-h1) or formula (I-h2), these compounds are different from compounds numbered R302 or R356 as depicted in Table R1, or their pharmaceutically acceptable salts.

[0376] In some implementations of formula (I-h1) or formula (I-h2), R Yb It is F; and one or more of (1)-(5) apply:

[0377] (1) m2 is 1, and R 2 It's CF3;

[0378] (2)L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted bicyclic 7- to 12-membered nitrogen-containing heterocyclic groups;

[0379] (3)L A4 It is by 1 to 3 Rs L4 Substituted 5- to 12-membered nitrogen-containing heterocyclic groups;

[0380] (4) At least one L A1a Choose from the following groups: CHR L and C(R) L )2; and

[0381] (5) a1a is 0, 1 or 2.

[0382] In some implementations of formula (I-h1) or formula (I-h2), R Yb It is C 1-3Alkyl groups. For example, R Yb It could be OMe.

[0383] In some embodiments, the compound of formula (I-1) or formula (I-2) (e.g., formula (I-d1) or formula (I-d2)) is a compound of formula (I-i1) or formula (I-i2):

[0384]

[0385] Equation (I-i1)

[0386]

[0387] Equation (I-i2)

[0388] Or its pharmaceutically acceptable salt, wherein:

[0389] a1a is an integer from 0 to 4;

[0390] L A4 yes , where cc represents -(L A1a ) a1a - Attachment point.

[0391] m2 is 0 or 1; and

[0392] R 2 It is CH3 or CF3.

[0393] In some embodiments of formula (I-i1) or formula (I-i2), these compounds are different from compound numbers R156 or R226 as depicted in Table R1, or their pharmaceutically acceptable salts.

[0394] In some embodiments, the compound is a compound of formula (I-i1) or a pharmaceutically acceptable salt thereof; and one or more of (1)-(5) are applicable:

[0395] (1) m2 is 1, and R 2 It's CF3;

[0396] (2) a1a is 0;

[0397] (3) a1a is 2 or 3;

[0398] (4) c1 is 1 or 2; and

[0399] (5) At least one L A1a Choose from the following groups: CHR L and C(R) L )2.

[0400] In some embodiments, the compound is a compound of formula (I-i2) or a pharmaceutically acceptable salt thereof.

[0401] In some embodiments, the compound of formula (I-1) (e.g., formula (I-d1)) is a compound of formula (I-i3):

[0402]

[0403] Formula (I-i3)

[0404] Or its pharmaceutically acceptable salt, wherein:

[0405] a1a is an integer from 0 to 4;

[0406] L A4 yes , where cc represents -(L A1a ) a1a - Attachment point.

[0407] m2 is 0 or 1; and

[0408] R 2 It is CH3 or CF3.

[0409] In some embodiments of equation (I-i3), c1 is 0. In some embodiments of equation (I-i3), R... Ya It is a methyl group.

[0410] In (I-a1), (I-b1), (I-b3), (I-c1), (I-d1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-i1), (I-i3), (I-a 2) In some embodiments of (I-b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2), a1a is 0 or 1.

[0411] In (I-a1), (I-b1), (I-b3), (I-c1), (I-d1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-i1), (I-i3), (I-a2), (I -b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2) In some embodiments, a1a is 2, 3 or 4 (e.g., 2 or 3).

[0412] In (I-a1), (I-b1), (I-b3), (I-c1), (I-d1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-i1), (I-i3), ( In some embodiments of I-a2), (I-b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2), each L A1a It is CH2.

[0413] In (I-a1), (I-b1), (I-b3), (I-c1), (I-d1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-i1), (I-i3), ( In some embodiments of I-a2), (I-b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2), an L A1a It is CHR L , where R L It is a C with -F or optionally replaced by one to three -F. 1-3 Alkyl groups; and each remaining L A1a It is CH2. For example, an L A1a It can be CHMe; and each remaining L A1a It could be CH2.

[0414] In (I-a1), (I-b1), (I-b3), (I-c1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-a 2), in some embodiments of (I-b2), (I-b4), (I-c2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4) or (I-h2), L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted monocyclic 5- to 6-membered nitrogen-containing heterocyclic groups, wherein each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0415] In (I-a1), (I-b1), (I-b3), (I-c1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-a 2), in some embodiments of (I-b2), (I-b4), (I-c2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4) or (I-h2), L A4 yes , where cc represents -(L A1a ) a1a - Attachment point.

[0416] In (I-a1), (I-b1), (I-b3), (I-c1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-a 2), in some embodiments of (I-b2), (I-b4), (I-c2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4) or (I-h2), L A4 yes , where R L4 It is -F or -OH (e.g., -OH); and cc indicates the relationship with -(L A1a ) a1a - Attachment point.

[0417] In (I-a1), (I-b1), (I-b3), (I-c1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-a 2), in some embodiments of (I-b2), (I-b4), (I-c2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4) or (I-h2), L A4 yes , where R L4 C is a C that can be arbitrarily replaced by one to three Fs. 1-3 Alkyl; and cc indicates -(L A1a ) a1a - Attachment point.

[0418] In (I-a1), (I-b1), (I-b3), (I-c1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-a 2), in some embodiments of (I-b2), (I-b4), (I-c2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4) or (I-h2), L A4 It can be arbitrarily divided by 1 to 3 RsL4 Substituted spirocyclic bicyclic 7- to 12-membered nitrogen-containing subheterocyclic groups, wherein each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0419] In (I-a1), (I-b1), (I-b3), (I-c1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-a 2), in some embodiments of (I-b2), (I-b4), (I-c2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4) or (I-h2), L A4 Choose from the following groups: , and Each of these groups is optionally surrounded by one to three R groups. L4 Replace, where each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl, and wherein cc represents -(L A1a ) a1a - Attachment point.

[0420] In (I-a1), (I-b1), (I-b3), (I-c1), (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-h1), (I-a 2), in some embodiments of (I-b2), (I-b4), (I-c2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4) or (I-h2), L A4 yes , where cc represents -(L A1a ) a1a - Attachment point.

[0421] In some implementations of (I-a1), (I-c1), (I-d1), (I-e1), (I-e3), (I-f1), (I-h1), (I-i1), (I-a2), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-h2), or (I-i2), m2 is 1; and R 2 It's CF3.

[0422] In some implementations of (I-a1), (I-c1), (I-d1), (I-e1), (I-e3), (I-f1), (I-h1), (I-i1), (I-i3), (I-a2), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-h2), or (I-i2), this Part of it is ;and

[0423] Should Part of it is .

[0424] In some implementations of (I-a1), (I-c1), (I-d1), (I-e1), (I-e3), (I-f1), (I-h1), (I-i1), (I-i3), (I-a2), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-h2), or (I-i2), m2 is 1; and R 2 It is CH3.

[0425] In some implementations of (I-a1), (I-c1), (I-d1), (I-e1), (I-e3), (I-f1), (I-h1), (I-i1), (I-i3), (I-a2), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-h2), or (I-i2), this Part of it is ;and

[0426] Should Part of it is .

[0427] In (I-b1), (I-b3), (I-d1), (I-e1), (I-e3), (I-g1), (I-g3), (I-h1), (I-i1), (I-i3), In some embodiments of (I-b2), (I-b4), (I-d2), (I-e2), (I-e4), (I-g2), (I-g4), (I-h2) or (I-i2), Z 1 It is CH.

[0428] In some implementations of (I-b1), (I-b3), (I-c1), (I-d1), (I-e1), (I-g1), (I-g3), (I-h1), (I-i1), (I-i3), (I-b2), (I-b4), (I-d2), (I-e2), (I-g2), (I-g4), (I-h2), or (I-i2), Z 1It is N.

[0429] In some implementations of (I-a1), (I-b1), (I-b3), (I-d1), (I-e1), (I-g1), (I-g3), (I-h1), (I-i1), (I-i3), (I-a2), (I-b2), (I-b4), (I-d2), (I-e2), (I-g2), (I-g4), (I-h2), or (I-i2), each R Yb R is chosen independently. a .

[0430] In some implementations of (I-a1), (I-b1), (I-b3), (I-d1), (I-e1), (I-g1), (I-g3), (I-h1), (I-i1), (I-i3), (I-a2), (I-b2), (I-b4), (I-d2), (I-e2), (I-g2), (I-g4), (I-h2), or (I-i2), each R Yb Choose independently from the following groups: -F, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl groups. For example, each R Yb It can be independently selected from the following groups: -F, OMe, CH3, CHF2, CH2F, and CF3.

[0431] In some embodiments of (I-a1), (I-b1), (I-b3), (I-d1), (I-e1), (I-g1), (I-g3), (I-i1), (I-i3), (I-a2), (I-b2), (I-b4), (I-d2), (I-e2), (I-g2), (I-g4), or (I-i2), c1 is 1. In some embodiments of (I-a1), (I-b1), (I-b3), (I-d1), (I-e1), (I-g1), (I-g3), (I-i1), (I-i3), (I-a2), (I-b2), (I-b4), (I-d2), (I-e2), (I-g2), (I-g4), or (I-i2), c1 is 0.

[0432] In some implementations of (I-a1), (I-b1), (I-b3), (I-d1), (I-a2), (I-b2), (I-b4), or (I-d2), ring C is , where R Ya It can be arbitrarily divided by 1 to 3 Rs c Replacement C 1-3 Alkyl; and yy indicates -(L A3b )a3b - Attachment point. In some implementations, R Ya It is a methyl group.

[0433] In some implementations of (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-i1), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), or (I-i2), this Part of it is , where R Ya It can be arbitrarily divided by 1 to 3 Rs c Replacement C 1-3 Alkyl group. In some embodiments, R Ya It is a methyl group.

[0434] In some implementations of (I-a1), (I-b1), (I-b3), (I-d1), (I-a2), (I-b2), (I-b4), or (I-d2), ring C is , where R Ya It can be arbitrarily divided by 1 to 3 Rs c Replacement C 1-3 alkyl;

[0435] R Yb Choose from the following groups: -F, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl; and

[0436] yy represents -(L) A3b ) a3b - Attachment point. In some implementations, R Ya It is methyl. In some embodiments, R Yb It is C 1-3 Alkyl group. In some embodiments, R Yb Choose from the following groups: -F, CH3, and OMe. For example, R Yb It could be OMe.

[0437] In some implementations of (I-e1), (I-e3), (I-f1), (I-g1), (I-g3), (I-i1), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), or (I-i2), this Part of it is , where R Ya It can be arbitrarily divided by 1 to 3 Rs c Replacement C 1-3 Alkyl; and

[0438] RYb Choose from the following groups: -F, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl group. In some embodiments, R Ya It is methyl. In some embodiments, R Yb It is C 1-3 Alkyl group. In some embodiments, R Yb Choose from the following groups: -F, CH3, and OMe. For example, R Yb It could be OMe.

[0439] In some embodiments of formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b4), formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2))), R 1 It is C(O)OH.

[0440] In some embodiments, the compound of formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b4), formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2)) is selected from the group consisting of the compounds depicted in Table C1 or pharmaceutically acceptable salts thereof.

[0441] Table C1

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465] Note For the compounds in Table C1, when "or1" indicates the stereoisomer source center in the structural formula, the stereoisomer source center has been resolved, but the configuration at the stereoisomer source center is not yet determined. For example, the structure... This represents (R)-2-methyl-3-(1-methylpiperidin-4-yl)prop-1-ol or (S)-2-methyl-3-(1-methylpiperidin-4-yl)prop-1-ol. For example, the structure... It represents (R)-2-methyl-3-(1-methylpiperidin-4-yl)prop-1-ol or (S)-2-methyl-3-(1-methylpiperidin-4-yl)prop-1-ol.

[0466] In some embodiments, the compounds of formula (I) are selected from the group consisting of:

[0467]

[0468]

[0469] Or its pharmaceutically acceptable salt.

[0470] In some embodiments, the compounds of formula (I) are selected from the group consisting of: the compounds depicted in Table C1 of U.S. Provisional Application Serial No. 63 / 547,656, filed November 7, 2023; the compounds depicted in Table C1 of U.S. Provisional Application Serial No. 63 / 641,308, filed May 1, 2024; and the compounds depicted in Table C1 of U.S. Provisional Application Serial No. 63 / 704,392, filed October 7, 2024; the full text of each of these Table C1s is incorporated herein by reference.

[0471] In some embodiments, the compounds of formula (I) are different from the compounds depicted in Tables C1, C2 and / or C3 of International Patent Application No. PCT / US2023 / 021010, or their pharmaceutically acceptable salts.

[0472] In some embodiments, the compound of formula (I) is different from the compound depicted in Table R1 or its pharmaceutically acceptable salt.

[0473] Table R1

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500] This article also provides compounds of formula (II):

[0501]

[0502] Equation (II)

[0503] Or its pharmaceutically acceptable salt, wherein:

[0504] Z 1 Choose from the following groups: N and CH;

[0505] R 1 Choose from the following groups:

[0506] (a)C(O)OH;

[0507] (b)C(O)OC 1-6 Alkyl, wherein the C 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups. c Replace; and

[0508] (c)C(O)-(C 0-3 (alkylene)-phenyl, wherein the phenyl group is optionally surrounded by 1 to 3 R groups. g replace;

[0509] Ring A is selected from the following groups: (A1) and (A2):

[0510]

[0511] in:

[0512] m2 is 0, 1, or 2.

[0513] Each R 2 Independently select from the following groups: halogenated group, CN, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and optionally surrounded by 1 to 3 R groups c Replacement C 1-3 Alkyl, and

[0514] aa represents -(L) A3a ) a3a - Attachment point;

[0515] L A3a Choose from the following groups: -N(R) d -、-O-、-S(O) 0-2 - and C (=O);

[0516] a3a is 0 or 1;

[0517] Each L A1a L A1b and L A1c Independently select from the following groups: -CH2-, -CHR L -and-C(R) L )2-, where:

[0518] Each R L Independently select from the following groups: halogenated group, -CN, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -(C 0-3 alkylene)-(C 3-5 cycloalkyl), -(C 0-3 (alkylene)-(4- to 6-membered heterocyclic group) and optionally surrounded by 1 to 6 R c Replacement C 1-6 alkyl;

[0519] a1a, a1b, and a1c are each independently 0, 1, or 2;

[0520] L A4a and L A4b Choose independently from the following groups: C 3-8 Cycloalkylene groups and 4- to 12-membered heterocyclic alkylene groups, each of which is optionally surrounded by 1 to 3 R groups. L4 replace;

[0521] Each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and optionally 1 to 3 R groups c Replacement C 1-3 alkyl;

[0522] R d1 Is it -H or C? 1-3 alkyl;

[0523] Ring C can be selected from the following groups: , , and ,in:

[0524] R Ya Choose from the following groups: H and optionally 1 to 3 Rs. c Replacement C 1-6 alkyl;

[0525] Each R Yb Choose independently from the following groups: F, C 1-3 Alkyl groups or optionally alkoxy groups, with one to three R groups c Replacement C 1-3 alkyl;

[0526] c1 is 0, 1, or 2; and

[0527] yy represents -N(R) d1 )- Attachment point;

[0528] Each R c Independently select from the following groups: halogenated group, CN, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e C(=O)C 1-6 Alkyl, C(=O)OC 1-6 Alkyl, C(=O)N(R) f 2. S(O) 0-2 (C 1-6 Alkyl groups and S(O) 0-2 (C- 1-6 (Halogenated alkyl);

[0529] 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 groups), S(O) 1-2 (C- 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f )2 and optionally by 1 to 3 R h Replacement C 1-6 alkyl;

[0530] Each R f Independently select from the following groups: H and optionally selected by 1 to 3 Rs. h Replacement C 1-6 alkyl;

[0531] Each R g Selected independently from: R h C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0532] Each R h Independently select from the following groups: halogenated group, CN, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl) and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

[0533] In some implementations of formula (II), Z 1 It is CH.

[0534] In some implementations of formula (II), ring A is or .

[0535] In some implementations of formula (II), ring A is or .

[0536] In some implementations of formula (II), a3a is 1.

[0537] In some implementations of formula (II), L A3a Yes -O-.

[0538] In some implementations of formula (II), a1a is 1.

[0539] In some implementations of formula (II), L A1a It is -CH2-.

[0540] In some implementations of formula (II), a1c is 0 or 1.

[0541] In some implementations of formula (II), L A1c It is -CH2-.

[0542] In some implementations of formula (II), a1b is 1.

[0543] In some implementations of formula (II), L A1b It is -CH2-.

[0544] In some implementations of formula (II), R d1 Yes, it's -H.

[0545] In some implementations of formula (II), L A4b It can be arbitrarily divided by 1 to 3 Rs L4 The substituted 5- to 12-membered nitrogen-containing heterocyclic groups. In some embodiments, L A4b It can be arbitrarily divided by 1 to 3 Rs L4 Substituted monocyclic 5- to 6-membered nitrogen-containing subheterocyclic groups.

[0546] In some implementations of formula (II), L A4a It is optional to be 1 to 2 R L4 Replacement C 3-6 Cycloalkylene.

[0547] In some implementations of formula (II), each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0548] In some implementations of formula (II), L A4b yes , where bb represents -(L A1b ) a1b - Attachment point.

[0549] In some implementations of formula (II), L A4a yes .

[0550] In some implementations of equation (II), ring C is .

[0551] In some implementations of formula (II), c1 is 0.

[0552] In some implementations of formula (II), R Ya C is a C that can be optionally replaced by one to three -F. 1-6 Alkyl group. For example, R Ya It can be methyl.

[0553] In some implementations of formula (II), R 1 It is C(O)OH.

[0554] In some embodiments, the compound of formula (II) is a compound of formula (II-a1) or (II-a2):

[0555]

[0556] Formula (II-a1)

[0557]

[0558] Equation (II-a2)

[0559] Or its pharmaceutically acceptable salt, wherein:

[0560] Z 1 It is CH or N;

[0561] L A3a Choose from the following groups: -N(R) d - and -O-;

[0562] Each L A1a and L A1c Independently select from the following groups: -CH2-, -CHR L -and-C(R) L )2-, where:

[0563] Each R L Independently select from the following groups: halogenated groups and C groups optionally substituted with 1 to 3 -F groups. 1-3 alkyl;

[0564] a1a and a1c are each independently 0, 1 or 2;

[0565] L A4aIt is optional to be 1 to 2 R L4 Replacement C 3-6 Cycloalkylene;

[0566] L A4b It can be arbitrarily divided by 1 to 3 Rs L4 Substituted monocyclic 5- to 6-membered nitrogen-containing heterocyclic groups; and

[0567] Each R L4 Choose independently from the following groups: -F, CN, OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 alkyl.

[0568] In some embodiments of formula (II-a1) or formula (II-a2), a1a is 1; and L A1a It is -CH2-.

[0569] In some embodiments of formula (II-a1) or formula (II-a2), a1c is 0 or 1.

[0570] In some embodiments of formula (II-a1) or formula (II-a2), L A1c It is -CH2-.

[0571] In some embodiments of formula (II-a1) or formula (II-a2), L A4a yes L A4b yes , where bb represents and Attachment point.

[0572] In some embodiments of formula (II-a1) or formula (II-a2), c1 is 0; and R Ya It is C 1-3 Alkyl (e.g., methyl).

[0573] In some embodiments of formula (II-a1) or formula (II-a2), m2 is 1; and R 2 It is CH3 or CF3.

[0574] In some embodiments of formula (II-a1) or formula (II-a2), Z 1 It is CH.

[0575] In some embodiments of formula (II-a1) or formula (II-a2), R 1 It is C(O)OH.

[0576] In some embodiments, the compounds of formula (II) (e.g., formula (II-a1) or formula (II-a2)) are selected from the group consisting of the compounds depicted in Table C2 or their pharmaceutically acceptable salts.

[0577] Table C2

[0578]

[0579]

[0580]

[0581] This article also provides compounds of formula (A):

[0582]

[0583] Formula (A)

[0584] Or its pharmaceutically acceptable salt, wherein:

[0585] Z 1 Z 2 and Z 3 Choose independently from the following groups: CH, CR 4 and N (e.g., CH);

[0586] R 1 Choose from the following groups:

[0587] (a)-C(O)OH;

[0588] (b)-C(O)OC 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups. c replace;

[0589] (c)-C(O)-(C 0-3 (alkylene)-phenyl, wherein the phenyl group is optionally surrounded by 1 to 3 R groups. a replace;

[0590] (d)-P(=O)(OH)2; and

[0591] (e)-P(=O)(OC 1-6 alkyl)2, wherein the C 1-6 Each C in the alkyl group 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups. c replace;

[0592] Ring A can be selected from the following groups: C 4-10 Cycloalkylene, C 6-10arylene and 5- to 10-membered heteroarylene groups, each of which is optionally surrounded by 1 to 2 R groups. 2 replace;

[0593] Ring B can be selected from the following groups: C 6-10 Aryl and 5- to 10-membered heteroaryl groups, each of which is optionally surrounded by 1 to 3 R groups. 3 replace;

[0594] Each R 2 R 3 and R 4 Independently select from the following groups: halogenated group, -CN, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups and optionally surrounded by 1 to 3 R groups c Replacement C 1-3 alkyl;

[0595] L is -(L) A ) n1 -,in:

[0596] n1 is an integer between 4 and 10.

[0597] An L A It is L A4 ,

[0598] 0 to 3 L A L is chosen independently. A3 ,and

[0599] Each remaining L A L is chosen independently. A1 ;

[0600] Each L A1 Independently select from the following groups: -CH2-, -CHR L -and-C(R) L )2-, where:

[0601] Each R L Independently select from the following groups: halogenated group, -CN, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -(C 0-3 alkylene)-(C 3-5 cycloalkyl), -(C 0-3 (alkylene)-(4- to 6-membered heterocyclic group) and optionally surrounded by 1 to 6 R c Replacement C 1-6 alkyl;

[0602] Each L A3Independently select from the following groups: -N(R) d )-、-N(R b -、-O-、-S(O) 0-2 - and C (=O);

[0603] L A4 Choose independently from the following groups:

[0604] (a)C 3-12 Cycloalkyl or 4- to 15-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. L4 Replace; and

[0605] (b) a phenylene or a 5- to 6-membered heteroaryl group, each of which is optionally surrounded by 1 to 3 R groups. L4 replace,

[0606] Each R L4 Independently select from the following groups: R a and R b ;

[0607] The ring C is selected from the group consisting of phenylene and 5- to 15-membered heteroaryl groups, each of which is optionally surrounded by 1 to 4 R groups. Yb replace;

[0608] Each R Yb Independently select from the following groups: R a and R b ;

[0609] Each R a Choose independently from the following groups:

[0610] (a) Halogenated group;

[0611] (b)-CN;

[0612] (c)-OH;

[0613] (d) Oxide group;

[0614] (e) optionally by 1 to 6 R c Replacement C 1-6 Alkoxy;

[0615] (f)-NR d R e ;

[0616] (g)-C(=O)C 1-6 alkyl;

[0617] (h)-C(=O)OC 1-6 alkyl;

[0618] (i)-C(=O)N(R f )2;

[0619] (j)-S(O) 0-2 (C 1-6 alkyl);

[0620] (k)-S(O) 0-2 (C- 1-6 (halogenated alkyl); and

[0621] (l)C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne groups, each optionally surrounded by one to six R groups c replace;

[0622] Each R b Independently select from the following groups: -(L b ) b -R b1 and R b1 ,in:

[0623] Each b is independently 1 or 2;

[0624] Each L b Choose independently from the following groups: -O-, -N(H)-, -N(C)-. 1-3 Alkyl)-, -S(O) 0-2 -、-C(=O)- and C 1-3 Alkylene; and

[0625] Each R b1 Choose independently from the following groups: C 3-6 Cycloalkyl and 4 to 8-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. g replace;

[0626] Each R c Independently select from the following groups: halogenated group, -CN, -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR d R e -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl, -C(=O)N(R) f )2、-S(O) 0-2 (C 1-6 Alkyl groups and -S(O) 0-2 (C- 1-6 (Halogenated alkyl);

[0627] Each R d and R e Choose independently from the following groups: -H, -C (=O)C 1-6 Alkyl group, -C(=O)C 1-6 Haloalkyl, -C(=O)OC 1-6 Alkyl group, -C(=O)OC 1-6 Haloalkyl, -C(=O)N(R) f )2、-S(O) 1-2 (C 1-6 Alkyl groups, -S(O) 1-2 (C- 1-6 Halogenated alkyl groups), -S(O) 1-2 N(R f )2 and optionally by 1 to 3 R h Replacement C 1-6 alkyl;

[0628] Each R f Independently selected from: -H and optionally by 1 to 3 R h Replacement C 1-6 alkyl;

[0629] Each R g Independently select from the following groups: R h , Oxide group, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and

[0630] Each R h Independently select from the following groups: halogenated group, -CN, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl) and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

[0631] In some implementations of formula (A), Z 1 It is CH or N.

[0632] In some implementations of formula (A), Z 2 It is CH.

[0633] In some implementations of formula (A), Z 3 It is CH.

[0634] In some implementations of formula (A), ring B Optionally by 1 to 2 R 3 Replacement (e.g., ring B is) ).

[0635] In some implementations of equation (A), ring B is optionally surrounded by one to two R. 3 Substituted phenyl groups (e.g., ring B is a phenyl group).

[0636] In some implementations of equation (A), ring B is optionally surrounded by one to two R. 3 Replaced 5- to 6-membered heteroaryl groups.

[0637] In some implementations of formula (A), ring A is selected from the group consisting of: C 6-10 Cycloalkylene (e.g., cyclohexene), phenylene, and 5- to 6-membered heteroaryl groups, each of which is optionally surrounded by 1 to 2 R groups. 2 Replacement. In some embodiments of formula (A), ring A is optionally replaced by one to two R. 2 Substituted phenylene. In some embodiments of formula (A), ring A is as defined herein by formula (I).

[0638] In some implementations of formula (A), R 1 It is -C(O)OH.

[0639] In some implementations of formula (A), R 1 It is -C(O)O t Bu.

[0640] In some implementations of formula (A), R 1 It is -P(=O)(OH)2.

[0641] In some implementations of equation (A), ring C is as defined in equation (I) of this paper.

[0642] In some implementations of equation (A), ring C is optionally surrounded by one to three R. Yb Replaces 9 to 15 yuan (e.g., 9 yuan) heteroaryl compounds. In some embodiments, each R Yb Choose independently from the following groups: -F, C 1-3 Alkoxy groups and optionally 1 to 3 R groups c Replacement C 1-3 alkyl.

[0643] In some implementations of formula (A), ring C is selected from the group consisting of:

[0644] , , , , and Where yy represents the attachment point to L; R Ya It is -H or optionally by 1 to 3 Rs c Replacement C 1-3 Alkyl; c1 is 0, 1, or 2; and each R Yb Choose independently from the following groups: -F, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 -F groups 1-3 Alkyl groups (e.g., each R) Yb Independently selected from the following groups: -F, -OMe, -CH3, -CHF2, -CH2F, and -CF3). In some implementations, R Ya It is -H or methyl.

[0645] In some implementations of formula (A), L is as defined in formula (I) herein.

[0646] In some implementations of equation (A), n1 is an integer from 5 to 9; and L is selected from the group consisting of:

[0647] -L A3 -(L A1 ) 0-4 -(L A4 )-L A1 -C(=O)N(R d1 )- bb ;

[0648] -L A3 -(L A1 ) 0-4 -(L A4 )-(L A1 ) 1-3 -O- bb ;

[0649] -L A3 -(L A1 ) 0-4 -(L A4 )-(L A1 ) 1-3 -N(R d1 )- bb ;and

[0650] -L A3 -(L A1 ) 0-4 -(L A4 )-(L A1 ) 1-4- bb ;

[0651] Where bb represents the attachment point to ring C; and R d1 Is it -H or C? 1-3 alkyl.

[0652] In some implementations of equation (A), n1 is an integer from 5 to 9; and L is:

[0653] -L A3 -(L A1 ) 0-4 -(L A4 )-L A1 -C(=O)N(R d1 )- bb ;

[0654] Where bb represents the attachment point to ring C; and R d1 Is it -H or C? 1-3 alkyl.

[0655] In some implementations of equation (A), n1 is an integer from 5 to 9; and L is:

[0656] -O-(L A1 ) 0-4 -(L A4 )-CH2-C(=O)N(H)- bb ,

[0657] Where bb represents the attachment point to ring C.

[0658] In some implementations of equation (A), n1 is an integer from 5 to 9; and L is:

[0659] -N(R d2 )-(L A1 ) 0-4 -(L A4 )-CH2-C(=O)N(H)- bb ;

[0660] Where bb represents the attachment point to ring C; and R d2 Is it -H or C? 1-3 Alkyl group. For example, R d 2 can be -H or methyl.

[0661] In some implementations of formula (A), L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted 5- to 12-membered nitrogen-containing heterocyclic sub-groups.

[0662] In some implementations of equation (A), each R L4 R is chosen independently.a .

[0663] In some implementations of equation (B), each R L4 Choose independently from the following groups: -F, -CN, -OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 -F groups 1-3 alkyl.

[0664] In some implementations of formula (A), L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted monocyclic 5- to 6-membered nitrogen-containing heterocyclic groups, wherein each R L4 Choose independently from the following groups: -F, -CN, -OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 -F groups 1-3 alkyl.

[0665] In some implementations of formula (A), L A4 yes .

[0666] In some implementations of formula (A), L A4 yes , where R L4 It is -F or -OH (e.g., -OH).

[0667] In some implementations of formula (A), L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted bicyclic 7- to 12-membered nitrogen-containing subheterocyclic groups, wherein each R L4 Choose independently from the following groups: -F, -CN, -OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 -F groups 1-3 alkyl.

[0668] In some implementations of formula (A), L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted spirocyclic bicyclic 7- to 12-membered nitrogen-containing subheterocyclic groups, wherein each R L4 Choose independently from the following groups: -F, -CN, -OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 -F groups 1-3 alkyl.

[0669] In some implementations of formula (A), L A4 Choose from the following groups: and Each of these groups is optionally surrounded by one to three R groups. L4Replace, where each R L4 Choose independently from the following groups: -F, -CN, -OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 F groups 1-3 Alkyl group. For example, L A4 It can be

[0670] In some implementations of formula (A), L A4 It can be arbitrarily divided by 1 to 3 Rs L4 Substituted bridging or fused bicyclic 7- to 12-membered nitrogen-containing heterocyclic groups, wherein each R L4 Choose independently from the following groups: -F, -CN, -OH, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 -F groups 1-3 alkyl.

[0671] In some implementations of equation (A), each L A1 It is -CH2-.

[0672] In some implementations of formula (A), an L A1 Yes - CHR L -or-C(R) L )2-, where each R L C is independently -F or optionally replaced by one to three -F. 1-3 Alkyl groups; and each remaining L A1 It is -CH2-. For example, an L A1 It can be -CHMe-; and each remaining L A1 It can be -CH2-.

[0673] In some embodiments, the compound of formula (A) is selected from the group consisting of the compounds described in Table C3 or their pharmaceutically acceptable salts.

[0674] Table C3

[0675]

[0676] Some examples of compounds of formula (I), (II), or (A) are synthesized using methods involving the resolution of stereoisomer mixtures (e.g., SFC separation of stereoisomers). In Tables C1, C2, or C3, the resolved stereoisomer source centers in these compounds are labeled with "or1" or "or2" enhanced stereochemical symbols. In some cases, stereoisomer resolution is performed during the final step of the synthesis, thereby providing a single stereoisomer of the compound of formula (I), (II), or (A). Alternatively, in some other cases, an intermediate or starting material is resolved, wherein each of the stereoisomers of the composition of the intermediate or starting material can be subjected to subsequent synthetic steps separately to obtain the corresponding compound of formula (I), (II), or (A) as a separate stereoisomer. Resolution methods and the correlation between the resolved intermediates and the compound of formula (I), (II), or (A) are disclosed in the examples herein. Those skilled in the art will understand that, under any method used for stereoisomer resolution, stereoisomers having both (R)- and (S)-configurations at the center of the resolved stereoisomer source are provided. See Table C4, where the stereoisomers containing the symbol or1 of Tables C1, C2, and C3 are obtained as non-stereoisomer sources, subsequently yielding the corresponding stereoisomers having both (R)- and (S)-configurations.

[0677] Table C4

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684] In some implementations, formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b... 4) Compounds of formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A), or their pharmaceutically acceptable salts, in EC50 at less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 50 Reduce BCL-X expression L Cell viability of the protein in cell lines. In some embodiments, formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b4) Compounds of formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2) are expressed in EC50 values ​​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 Reduce BCL-X expression L Cell viability of the protein in cell lines. For example, the compound can be expressed in EC50 concentrations 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 Reduce BCL-X expression L Cell viability in protein cell lines.

[0685] In some implementations, formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b... 4) Compounds of formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A), or their pharmaceutically acceptable salts, in DC at less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 50 Induced expression of BCL-X L BCL-X in cell lines containing proteins L Protein degradation. In some embodiments, formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b4), formula (I- c2), compounds of formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A), or pharmaceutically acceptable salts thereof, at DC values ​​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 Induced expression of BCL-X L BCL-X in cell lines containing proteins L Protein degradation. For example, compounds can be expressed in DC concentrations 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 in protein cell lines L Protein degradation.

[0686] In some implementations, formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b... 4) Compounds of formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A), or their pharmaceutically acceptable salts, in EC50 at less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 50 Induced expression of BCL-X L BCL-X in cell lines containing proteins L Protein degradation. In some embodiments, formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b4), formula (I- c2), compounds of formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2)), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A), or pharmaceutically acceptable salts thereof, in EC50 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 Induced expression of BCL-X L BCL-X in cell lines containing proteins L Protein degradation. For example, compounds can be expressed in EC50 concentrations 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 in cell lines containing proteins L Protein degradation.

[0687] In some implementations, formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b... 4) Compounds of formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A), or their pharmaceutically acceptable salts, in less than 70% (e.g., less than 50%, less than 30%, less than 20%, or less than 10%) of Y. min Induced expression of BCL-X L BCL-X in cell lines containing proteins L Protein degradation. In some embodiments, formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b4)) Compounds of formula (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2), (II) (e.g., (II-a1) or (II-a2)) or (A), or pharmaceutically acceptable salts thereof, in a concentration of less than 50% (e.g., less than 40%, less than 30%, less than 20%, less than 10%, or less than 5%) of Y. min Induced expression of BCL-X L BCL-X in cell lines containing proteins LProtein degradation. In some embodiments, formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) or formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b4)) Compounds of formula (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2), (II) (e.g., (II-a1) or (II-a2)) or (A), or pharmaceutically acceptable salts thereof, in a concentration of less than 30% (e.g., less than 25%, less than 20%, less than 15%, less than 10%, or less than 5%) of Y. min Induced expression of BCL-X L BCL-X in cell lines containing proteins L Protein degradation. For example, the compound can be present in a concentration of about 1% to about 70% (e.g., about 5% to about 50% or about 10% to about 30%) of Y. min Induced expression of BCL-X L BCL-X in protein cell lines L Protein degradation.

[0688] This document also provides equation (I) (e.g., equation (I-1) (e.g., equation (I-a1), equation (I-b1), equation (I-b3), equation (I-c1), equation (I-d1), equation (I-e1), equation (I-e3), equation (I-f1), equation (I-g1), equation (I-g3), equation (I-h1), equation (I-i1) or equation (I-i3)) or equation (I-2) (e.g., equation (I-a2), equation (I-i3)). Compounds of formula (I-b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2)), (II) (e.g., (II-a1) or (II-a2)) or (A), or pharmaceutically acceptable salts of these compounds non-covalently bound to BCL-X. L protein.

[0689] This article also provides a ternary complex containing BCL-X. LProtein; Formula (I) (e.g., Formula (I-1) (e.g., Formula (I-a1), Formula (I-b1), Formula (I-b3), Formula (I-c1), Formula (I-d1), Formula (I-e1), Formula (I-e3), Formula (I-f1), Formula (I-g1), Formula (I-g3), Formula (I-h1), Formula (I-i1) or Formula (I-i3)) or Formula (I-2) (e.g., Formula (I-a2), Formula (I- Compounds of formula (b2), (I-b4), (I-c2), (I-d2), (I-e2), (I-e4), (I-f2), (I-g2), (I-g4), (I-h2) or (I-i2), (II) (e.g., (II-a1) or (II-a2)) or (A), or pharmaceutically acceptable salts thereof; and CRBN protein or a portion thereof.

[0690] Chemical definition

[0691] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0692] The term "oxo group" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.

[0693] The term "alkyl" refers to a saturated acyclic hydrocarbon group, which can be straight-chain or branched and contains a specified number of carbon atoms. For example, C 1-10 This indicates that the group may have 1 to 10 carbon atoms (including the terminal number). The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. As used in this context, the term "saturated" means that only single bonds exist between the carbon atoms in the composition, and other available valence bonds are occupied by hydrogen and / or other substituents as defined herein.

[0694] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halogens (e.g., -CF3, -CHF2, or -CH2F).

[0695] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH3).

[0696] The term "alkylene" refers to a divalent alkyl group (e.g., -CH2-). Similarly, terms such as "cycloalkylene" and "heterocyclic alkylene" refer to divalent cycloalkyl and heterocyclic groups, respectively. To avoid confusion, in "cycloalkylene" and "heterocyclic alkylene," the two groups can be on the same ring carbon atom (e.g., gemini, such as...). or Or on different ring atoms (e.g., cyclic carbon and / or nitrogen atoms (e.g., adjacent cyclic carbon and / or nitrogen atoms)) (e.g., , , , ).

[0697] The term "alkenyl" refers to an acyclic hydrocarbon chain that can be straight-chain or branched, having one or more carbon-carbon double bonds. The alkenyl moiety contains a specified number of carbon atoms. For example, C 2-6 This indicates that the group can have 2 to 6 carbon atoms (including the terminal number). The alkenyl group can be unsubstituted or substituted by one or more substituents.

[0698] The term "alkynyl" refers to an acyclic hydrocarbon chain that can be straight-chain or branched, having one or more carbon-carbon triple bonds. The alkynyl moiety contains a specified number of carbon atoms. For example, C 2-6 This indicates that the group can have 2 to 6 carbon atoms (including the terminal number). The alkynyl group can be unsubstituted or substituted by one or more substituents.

[0699] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group with 6 to 20 carbon atoms, wherein at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic aromatic ring system, a 10-carbon bicyclic aromatic ring system, or a 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted with substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and so on.

[0700] As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic (e.g., fused, bridged, or spirocyclic bicyclic, tricyclic, or polycyclic) saturated or partially unsaturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons, 3 to 10 ring carbons, or 3 to 6 ring carbons, wherein the cycloalkyl group may optionally be substituted. As used in this context, the term "saturated" means that only single bonds exist between the constituent carbon atoms. Examples of saturated cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyl groups can have any degree of unsaturation, provided that one or more double bonds are present in the cycloalkyl group, the rings in the ring system are not aromatic, and the partially unsaturated cycloalkyl group is generally not fully saturated. Examples of partially unsaturated cycloalkyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkyl groups may include multiple fused rings and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl groups include: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and so on. Cycloalkyl groups also include spirocyclic groups (e.g., spirocyclic bicyclic groups in which the two rings are connected by only one atom). Non-limiting examples of spirocycloalkyl groups include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, etc.

[0701] As used herein, the term "heteroaryl" means a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or 5, 6, 9, 10, or 15 ring atoms; wherein at least one ring in the system contains one or more heteroatoms, which are independently selected from: N, O, S (including oxidized forms, such as: or ) and P (including oxidized forms, such as: (For example, N, O, and S (including oxidized forms, such as: or (), and at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, such as tetrahydroisoquinolinyl, for example, tetrahydroquinolinyl). In some embodiments, the heteroaryl group contains one to four (e.g., one, two, or three) cyclic heteroatoms, each independently selected from the group consisting of N, O, and S (including oxidized forms, such as: or The heteroaryl group can be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thiophene, pyridinyl, furanyl, oxazolyl, oxadiazolyl, pyrroloyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl-benzothiophene, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cenylyl, indazole, indolyl, isoquinolinyl, isothiazolyl, naphridinyl, purine, thiophene-pyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl Thiophene[2,3-c]pyridyl, pyrazolo[3,4-b]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[4,3-b]pyridyl, tetrazolyl, benzodihydropyranyl, 2,3-dihydrobenzo[b][1,4]dioxacyclohexenyl, benzo[d][1,3]m-dioxacyclopentyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindololinyl, etc. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furanyl, pyrazolyl, imidazolyl, isoindololinyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, heteroaryl groups also include aryl lactams, aryl cycloureas, or their intercalated alkene analogs, wherein each cyclic nitrogen adjacent to the carbonyl group is a tertiary nitrogen (i.e., all three valence bonds are occupied by non-hydrogen substituents), such as pyridones (e.g., , , or ), pyrimidinones (e.g., or ), pyridazinone (e.g., or ), pyrazinone (e.g., or ) and imidazolids (e.g., One or more of the following, wherein each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (i.e., the oxo group (i.e., "=O") in this text is a component of the heteroaryl ring).

[0702] The term "heterocyclic group" refers to a monocyclic, bicyclic, tricyclic, or polycyclic (e.g., fused, bridged, or spirocyclic bicyclic, tricyclic, or polycyclic) saturated or partially unsaturated cyclic system (e.g., 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 15-membered tricyclic system) having 3 to 15 ring atoms. If it is a monocyclic system, it has 1 to 3 heteroatoms; if it is a bicyclic system, it has 1 to 6 heteroatoms; or if it is a tricyclic or polycyclic system, it has 1 to 9 heteroatoms selected from O, N, and S (including oxidized forms, such as: or ) and P (including oxidized forms, such as: (For example, O, N, and S (including oxidized forms, such as: or (e.g., carbon atoms and, if they are monocyclic, bicyclic, or tricyclic ring systems, one to three, one to six, or one to nine heteroatoms (N, O, S, or P)), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by substituents. In some embodiments, the heterocyclic group contains one to four (e.g., one, two, or three) cyclic heteroatoms, each independently selected from the group consisting of N, O, and S (including oxidized forms, such as: or As used in this context, the term "saturated" means that only single bonds exist between the constituent ring atoms, and other available valence bonds are occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclic groups include piperazine, pyrrolyl, dioxane, morpholinyl, tetrahydrofuranyl, and so on. Partially unsaturated heterocyclic groups can have any degree of unsaturation, provided that one or more double bonds are present in the heterocyclic group, the rings in the ring system are not aromatic, and the partially unsaturated heterocyclic group is generally not fully saturated. Examples of partially unsaturated heterocyclic groups include, but are not limited to, tetrahydropyridinyl, dihydropyrazine, dihydropyridinyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiopheneyl. Heterocyclic groups may include multiple fused rings and / or bridged rings. Non-limiting examples of fused / bridged heterocyclic groups include: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, 3- Azabicyclo[3.2.1]octyl, 2-oxabicyclo[1.1.0]butyl, 2-oxabicyclo[2.1.0]pentyl, 2-oxabicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 7-oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1]heptyl, 7-oxabicyclo[4.2.0]octyl, 2-oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl, etc. Heterocyclic groups also include spirocyclic groups (e.g., spirocyclic bicyclic groups in which the two rings are connected by only one atom).Non-limiting examples of spirocyclic heterocyclic groups include 2-azaspiro[2.2]pentyl, 4-azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, 1,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl, 2,5-diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, and 2-oxaspiro. [2.2]pentyl, 4-oxaspiro[2.5]octyl, 1-oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6-oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, 1-oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl, etc.

[0703] As used herein, a nitrogen-containing heterocyclic group refers to a heterocyclic group having one to two cyclic nitrogen atoms and 0 to two additional cyclic heteroatoms selected from the group consisting of: O and S (including oxidized forms, such as: or Nitrogen-containing heterocyclic groups can be monocyclic, bicyclic, or polycyclic as defined elsewhere herein. Examples of monocyclic nitrogen-containing heterocyclic groups include aziridine, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like. Examples of bicyclic nitrogen-containing heterocyclic groups include 7-azaspiro[3.5]nonyl, 1,7-diazaspiro[4.5]decyl, 3-oxa-7,9-diazabicyclo[3.3.1]nonyl, 2,6-diazaspiro[3.3]heptyl, and the like.

[0704] As used herein, when a ring is described as “partially unsaturated,” it means that the ring has one or more additional degrees of unsaturation (in addition to the unsaturation attributable to the ring itself; for example, one or more double or triple bonds between the constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and so on.

[0705] To avoid confusion, unless otherwise stated, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclic, heterocyclic alkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) containing a sufficient number of ring atoms to form bicyclic or higher-order ring systems (e.g., tricyclic, polycyclic ring systems), it should be understood that such rings and cyclic groups encompass those having fused rings, including those where the fusion point is located at: (i) on adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents a zero-atom bridge (e.g., ...) (ii) Monocyclic atoms (spirofused ring systems) (e.g., , or ), or (iii) a continuous array of ring atoms (bridged ring systems with all bridge lengths > 0) (e.g., , or ).

[0706] Furthermore, the atoms constituting the compounds of this embodiment are intended to include all isotopic forms of these atoms. As used herein, isotopes include those atoms with the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0707] Furthermore, the compounds generally or specifically disclosed herein are intended to include all tautomer forms. Therefore, for example, those containing: The compounds include those containing: The tautomer form. Similarly, the tautomer form described as having a pyridyl or pyrimidinyl moiety optionally substituted with a hydroxyl group includes a pyridinone or pyrimidinone.

[0708] The compounds described herein can encompass a wide range of stereochemical forms. This also includes diastereomers and optical isomers (e.g., mixtures of enantiomers, including racemic mixtures), as well as individual enantiomers and diastereomers arising from the structural asymmetry of certain compounds. Unless otherwise specified, when a disclosed compound is named or described by not specifying its stereochemical structure and has one or more chiral centers, it should be understood to represent all possible stereoisomers of that compound.

[0709] Certain combinations of heteroatoms (e.g., N, O, S, or halogens) define compounds with lower stability under physiological conditions. Examples include (1) compounds containing acetal or acetal-amine bonds; (2) compounds containing acyclic NO, NN, or NS(O)O bonds; and (3) compounds containing OO, OS(O). 0-2 N-halogens, O-halogens, and S(O) 0-2 Compounds containing halogen bonds. Therefore, such compounds are less preferred. As used herein, "acyclic bond" means a chemical bond that is not part of a ring. Examples include... and The NO bond in the ring. To avoid confusion, acyclic NO, NN, or NS(O)0 bonds (i.e., those bonds that are not part of a ring, e.g., in...) or The middle) is a secondary preference, but the compounds provided herein may include NO, NN, or NS(O)O bonds that form part of a ring (e.g., in (NN bond in the text).

[0710] Treatment

[0711] Indications

[0712] This article provides methods for inducing BCL-X. L Methods for protein degradation. For example, this article provides methods that can induce BCL-X, which could be used to treat or prevent cancer. L Compounds that degrade proteins. See, for example, Guo et al. Aging (AlbanyNY) 13.15 (2021): 19750, doi: 10.18632 / aging.203386; Park et al. Proceedings of the National Academy of Sciences 112.40 (2015): 12492-12497, doi: 10.1073 / pnas.1507491112; Zhang et al. Molecular Cancer 14.1 (2015): 1-9, doi: 10.1186 / s12943-015-0397-y; Beroukhim et al. Nature 463.7283 (2010): 899-905, doi:10.1038 / nature08822.

[0713] The term "compound provided herein" refers to a compound of formula (I) (e.g., formula (I-1) (e.g., formula (I-a1), formula (I-b1), formula (I-b3), formula (I-c1), formula (I-d1), formula (I-e1), formula (I-e3), formula (I-f1), formula (I-g1), formula (I-g3), formula (I-h1), formula (I-i1) or formula (I-i3)) as disclosed herein. Compounds of formula (I-2) (e.g., formula (I-a2), formula (I-b2), formula (I-b4), formula (I-c2), formula (I-d2), formula (I-e2), formula (I-e4), formula (I-f2), formula (I-g2), formula (I-g4), formula (I-h2) or formula (I-i2)), formula (II) (e.g., formula (II-a1) or formula (II-a2)) or formula (A).

[0714] The effects of protein degradation typically increase over time, and degradation occurs (e.g., as indicated by the percentage of degradation compared to a control or parameter Y). min DC50 EC 50 and / or D max The degradation rate (as indicated) is affected by the rate of protein resynthesis. Therefore, degradation can be examined after a specified time period (such as 6 hours, 12 hours, 18 hours, 1 day, 2 days, 3 days, or longer). For example, degradation can be expressed as the percentage of degradation after 24 hours.

[0715] Exemplary assays for verifying the degradation-inducing mechanisms of compounds as presented herein are known in the art and are published, for example, in international publication WO 2019 / 144117 and Wu et al., Nature Structural & Molecular Biology 27.7 (2020): 605-614, doi: 10.1038 / s41594-020-0438-0.

[0716] Degradation assays can be used to quantify the on-target and off-target degradation induction of compounds, such as those provided herein. Exemplary assays include quantitative Western blotting, other immunoassays (e.g., MesoScale Discovery (MSD) immunoassay), homogeneous time-resolved fluorescence (HTRF), and HiBiT. In some embodiments, cells can be contacted with the compounds provided herein or their pharmaceutically acceptable salts, incubated, and then lysates can be prepared for gel electrophoresis (e.g., SDS-PAGE), followed by Western blotting and quantification compared to a control (e.g., a DMSO-treated control). As another example, cell lines can be engineered to express the HiBiT-tagged BCL-X. L The protein can be compared between cells treated with the compounds provided herein or their pharmaceutically acceptable salts and a control (e.g., a DMSO-treated control) upon the addition of the complementary LgBiT peptide. See, for example, Examples B1 and B2. Also see, for example, International Publications WO2020 / 163823 and WO 2019 / 144117. In some embodiments, the off-target degradation induction of protein eukaryotic peptide chain releasing factor GTP-binding subunits ERF3A (GSPT1), Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and / or casein kinase I isoform α (CK1α) can be evaluated.

[0717] See also the assays described in the following publications: International Publication Nos. WO 2023 / 044046; WO 2022 / 169780, WO2021 / 222114, WO 2021 / 146536, WO 2021 / 078301, WO 2021 / 007307, WO 2020 / 163823, WO2019 / 144117, WO 2017 / 184995, and Khan et al. Nature Medicine 25.12 (2019): 1938-1947, doi: 10.1038 / s41591-019-0668-z; Balachander et al. Clinical Cancer Research 26.24 (2020): 6535-6549, doi: 10.1158 / 1078-0432.CCR-20-0863.

[0718] The compounds or pharmaceutically acceptable salts of BCL-X described herein L Binding affinity can be achieved, for example, by binding IC. 50 or K i Values ​​(e.g., using competitive determination) or by K D The value (e.g., using a biophysical assay) is used to determine this. As measured under substantially similar conditions, a lower binding IC50 value indicates a lower IC50 value. 50 Compounds with high binding IC values ​​are relative to compounds with high binding IC values. 50 Compounds with higher binding K values ​​are more effective binders. As determined under substantially similar conditions, those with lower binding K values... i Compounds with a high binding K value are relative to compounds with a high binding K value. i Compounds with higher K values ​​are more effective conjugates. Similarly, as determined under substantially similar conditions, compounds with lower K values... D Compounds with higher K values ​​are relative to those with higher K values. D Compounds with higher values ​​are more effective conjugates. For example, conjugates with IC. 50 The value can be determined using a fluorescently labeled BH3-only peptide (e.g., BAD or BAX) as a competing agent in fluorescence polarization assays. As another example, combining K... i The value can be determined using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay, which uses fluorescently labeled BH3-only peptides (e.g., BAK) and bound to BCL-X. L The fluorescently labeled antibody (where the fluorophore is a FRET pair) and the compound provided herein or a pharmaceutically acceptable salt thereof are used as a competitor to the BH3 peptide only. See, for example, U.S. Patent Publications US 2007 / 0027135, US 2010 / 305122 and US 2013 / 096120.

[0719] Another exemplary assay for evaluating the affinity of the compounds provided herein or their pharmaceutically acceptable salts includes the use of recombinant BCL-X. L Protein competition assays. For example, purified recombinant affinity-tagged (e.g., His-tagged) BCL-X can be used. L The protein is incubated with various concentrations of the compound provided herein or its pharmaceutically acceptable salts, along with a fixed concentration of affinity-tagged (e.g., biotin-tagged) BAD protein. After a period of incubation, FRET acceptor beads (e.g., His-acceptor beads) and FRET donor beads (e.g., streptavidin-tagged donor beads) with complementary affinity tags can be added to the mixture, and the inhibition constant of the compound provided herein or its pharmaceutically acceptable salts can be determined using the FRET reaction. For example, an AlphaLISA competitive assay can be performed. See, for example, International Publication No. WO 2019 / 144117.

[0720] The compounds described herein, or their pharmaceutically acceptable salts, inhibit BCL-X. L The ability can be achieved using IC 50 The value is determined by measurement. If measured under substantially similar conditions, a lower IC50 value indicates a lower IC50. 50 Compounds with high IC values ​​are relative to those with high IC values. 50 The compound with the highest value is a more effective inhibitor. BCL-X can be measured. L One way to suppress it is to measure BCL-X. L Disruption of the process of forming a complex with BH3-only peptides (e.g., BIM). For example, this can be achieved using an electrochemiluminescence-based sandwich ELISA assay (e.g., Meso Scale Discovery (MSD)-ELISA assay). See, for example, Phillips, DC et al. BloodCancer Journal 5.11 (2015): e368-e368, doi: 10.1038 / bcj.2015.88 and Xiao, Yu et al. Molecular Cancer Therapeutics 14.8 (2015): 1837-1847, doi: 10.1158 / 1535-7163.MCT-14-0928. In such assays, expression of BCL-X can be... L Cells were incubated with the compounds provided herein or their pharmaceutically acceptable salts for a period of time, lysed, and then evaluated in this assay. Tag-tagged anti-BCL-X can be used. L Antibodies (e.g., biotin-labeled anti-BCL-X) LAntibodies are immobilized on an assay plate (e.g., a streptavidin assay plate), and the lysate can then be applied to the precipitated BCL-X. L An anti-BIM antibody (e.g., rabbit anti-BIM antibody) can be introduced, followed by the addition of a detection antibody (e.g., sulfonated goat anti-rabbit antibody), and the detection antibody can be measured. As another example, BCL-X... L Disruptions in the process of forming a complex with a BH3-only peptide (e.g., BIM) can be measured using a mammalian two-hybrid assay. In such an assay, the protein encoding the "bait" and "capture" fusion protein (e.g., with BCL-X) can be used. L A plasmid containing the DNA-binding domain of GAL4 fused with BIM and the transcriptional activation domain of VP16 fused with BIM was introduced into cells stably expressing the GAL4-luciferase reporter gene (e.g., HeLa cells). The compounds described herein or their pharmaceutically acceptable salts can be added to cultured cells, incubated, and luciferase activity can be measured. See, for example, Souers, Andrew J. et al. Nature Medicine 19.2 (2013): 202-208, doi: 10.1038 / nm.3048.

[0721] Evaluation of compounds and BCL-X L Protein binding or BCL-X L Other methods for protein inhibition are described, for example, in U.S. Patent Publications US 2007 / 027135, US 2010 / 305122, and US 2013 / 096120.

[0722] The degradation efficacy of the compounds described herein, or their pharmaceutically acceptable salts as described herein, can be obtained via DC. 50 The value is used to determine this. As used in this article, DC... 50 This refers to the protein concentration in cells that results in the loss of protein concentration (e.g., BCL-X) compared to the concentration of proteins in cells before contact with the compounds provided herein or their pharmaceutically acceptable salts, or compared to the concentration of proteins in cells not contacted with the compounds provided herein or their pharmaceutically acceptable salts. L The concentration of the protein was reduced by 50% compared to the concentration of the compound provided herein or its pharmaceutically acceptable salt. As measured under substantially similar conditions, it exhibited a lower DC... 50 Compounds with higher DC values ​​relative to those with higher DC values 50 Compounds with high degradation values ​​are more effective degradation inducers. In some embodiments, DC... 50 Values ​​can be expressed in vitro or in vivo (e.g., in the expression of BCL-X). LThe protein is identified in tumor cells (e.g., cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929) (e.g., using HiBiT detection).

[0723] The degradation efficacy of the compounds described herein, or their pharmaceutically acceptable salts as described herein, can be measured by EC. 50 The value is used to determine this. As used in this article, EC 50 This refers to the protein concentration that results in the loss of protein (e.g., BCL-X) compared to the protein concentration in cells prior to contact with the compounds provided herein or their pharmaceutically acceptable salts, or compared to the protein concentration in cells not contacted with the compounds provided herein or their pharmaceutically acceptable salts. L The concentration of the compound provided herein or its pharmaceutically acceptable salt is 50% lower than the trough concentration of the protein in the cell. As measured under substantially similar conditions, it exhibits a lower EC50. 50 Compounds with higher EC values ​​relative to those with higher EC values 50 The compound with the higher value is a more effective compound. In some implementations, EC 50 Values ​​can be expressed in vitro or in vivo (e.g., in the expression of BCL-X). L The protein is identified in tumor cells (e.g., cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929) (e.g., using HiBiT detection).

[0724] The degradation efficacy of the compounds described herein, or their pharmaceutically acceptable salts as described herein, can be obtained through Y. min The value is used to determine this. As used in this article, Y... min It refers to proteins in cells (such as BCL-X). L The trough concentration of a protein is expressed as a percentage of the protein concentration prior to contact with the compound provided herein or its pharmaceutically acceptable salt, or compared to the protein concentration in cells not contacted with the compound provided herein or its pharmaceutically acceptable salt. As used herein, D max It is 1-Y min Y min It can be measured by HiBiT determination (e.g., as described in Example B1). As measured under substantially similar conditions, it has a lower Y... min Compounds with higher Y values ​​are relative to those with higher Y values. min Compounds with this value are more effective degradation inducers. In some embodiments, Y... min Values ​​can be expressed in vitro or in vivo (e.g., in the expression of BCL-X). LThe protein is identified in tumor cells (e.g., cell lines such as MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929) (e.g., using HiBiT detection).

[0725] Exemplary assays for determining the potency of the compounds provided herein or pharmaceutically acceptable salts thereof include measuring the effect of the compounds provided herein or pharmaceutically acceptable salts thereof on cell proliferation and / or viability. Cell proliferation assays can be performed in various forms, including 2D and 3D. Similarly, cell proliferation assays can be performed using any suitable cell line, including, for example, MOLT4, RS4;11, NCI-H146, EJM, HEK293T, HT1080, and / or H929. As an illustrative example, a 3D cell proliferation assay may include growing cells in a 3D medium, contacting the cells with the compounds provided herein or pharmaceutically acceptable salts thereof, and using appropriate reagents (e.g., CELLTITER-GLO). ® 3D) Cell proliferation is measured, and then the signal from the experiment using the compound provided herein or a pharmaceutically acceptable salt thereof is compared with the signal from a control experiment (e.g., lacking the compound provided herein or a pharmaceutically acceptable salt thereof). As another illustrative example, 2D cell proliferation assays may include plating cells onto a growth surface, optionally allowing the cells to grow for a period of time, contacting the cells with the compound provided herein or a pharmaceutically acceptable salt thereof, and using appropriate reagents (e.g., CELLTITER-GLO). ®Cell proliferation is measured, and the signal from the experiment using the compound provided herein or its pharmaceutically acceptable salt is then compared with the signal from the control experiment (e.g., lacking the compound provided herein or its pharmaceutically acceptable salt). In some embodiments, CRBN knockout cells can be used in similar cell viability assays to assess degradation-mediated antiproliferative effects from the compound provided herein. CRBN knockout cells can be generated from parental cells (e.g., MOLT-4 cells) using CRISPR gene editing technology. Single guide RNA (sgRNA) targeting CRBN and the Cas9 protein are available from commercial vendors and can be electroporated into parental cells (e.g., MOLT-4 cells) using a kit (e.g., the Neon NxT electroporation kit (Invitrogen)). Cell viability of CRBN knockout cells can be assessed in the same manner as parental cells (e.g., MOLT-4 cells). Other cell viability assays include the MTT assay (a colorimetric determination based on the reduction of the tetrazolium dye MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to insoluble purple formazan) and other similar assays based on related tetrazolium salts. See, for example, Example B3.

[0726] Cell viability assays can be used to measure the effect of compounds provided herein or their pharmaceutically acceptable salts on cell death. For example, BCL-X expression can be used... L Cells containing the protein (e.g., MOLT-4 cells) were incubated with different concentrations of the compounds provided herein or their pharmaceutically acceptable salts, and then exposed to a detection reagent (e.g., CELLTITER-GLO). ® Cell viability assay kits are used to determine cell viability.

[0727] Exemplary assays for determining the mechanisms of cell death using compounds provided herein or pharmaceutically acceptable salts thereof include measuring the effect of compounds provided herein or pharmaceutically acceptable salts thereof on one or more markers of cell death (e.g., apoptosis). 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, BCL-X expression can be used... L Cellular samples containing the protein (e.g., MOLT-4 cells) can be incubated with various concentrations of the compounds provided herein or their pharmaceutically acceptable salts, and can be used with luciferase substrates activated by caspase 3 / 7 (e.g., using CASPASE-GLO). ® The relative caspase activity was assessed using a 3 / 7 assay. As another example, BCL-X expression can be used... LCellular samples containing the protein (e.g., MOLT-4 cells) were incubated with different concentrations of the compounds provided herein or their pharmaceutically acceptable salts, and could be incubated with dyes conjugated to the activated caspase motif (e.g., INCUCYTE). ® Caspase 3 / 7 Green Apoptosis Assay Reagent), followed by live-cell imaging platform (e.g., INCUCYTE). ® The SX5 live cell analyzer was used to assess relative caspase activity. As another example, BCL-X expression was analyzed. L Cellular samples containing the protein (e.g., MOLT-4 cells) were incubated with different concentrations of the compounds provided herein or their pharmaceutically acceptable salts, and could be incubated with phosphatidylserine dyes (e.g., INCUCYTE). ® Annexin V dye), followed by live-cell imaging platforms (e.g., INCUCYTE). ® The SX5 live cell analyzer was used to assess annexin V positivity.

[0728] As another example, the potency and / or efficacy of the compounds provided herein or their pharmaceutically acceptable salts can be evaluated in animal models, such as cell line-derived xenograft (CDX) models (e.g., using established cancer cell lines such as MOLT4, HEL, TF1, F36P, OCI-M1, OCI-M2, SET-2, CMK, M07E, UKE-1, or NCI-H1417), or patient-derived xenograft (PDX) models. For example, CDX or PDX models can be evaluated in immunodeficient mice (e.g., athymic nude mice, distant hybrid homozygous mice (e.g., Cr1:NU(NCr)-Foxn1)). nu ) or Fox Chase SCID (CB17 / Icr-Prkdc scid The procedure was performed on mice (IcrIcoCrl). Mice could be female mice aged 6 to 12 weeks at the time of tumor transplantation, with free access to food and water. Approximately 70 mg of tumor was transplanted subcutaneously into the right side of each mouse. Tumors were measured weekly after transplantation, and once the tumor volume reached 150 mm², the tumor was considered complete. 3 Up to 300mm 3 Mice can be randomly assigned to treatment and control groups. In some implementations, one or more experimental groups may be added to evaluate pharmacokinetics and / or pharmacodynamics. Mice can be treated with the compounds provided herein or their pharmaceutically acceptable salts (e.g., via IP or PO (oral) administration) and optional additional therapies or therapeutics (e.g., any other therapies or therapeutics described herein). Throughout the study, the health status, weight, and tumor volume of the mice can be recorded weekly. Treatment can begin after 28 days or when the tumor reaches 1 cm. 3Mice were euthanized, and tumors could be evaluated (e.g., by tumor weight, by tumor volume). At the end of each study, the optimal response for each treatment group could be calculated. The optimal response was defined as Δvolume over t ≥ 10 days. t The minimum value. The optimal response can be compared between the control and treatment groups to determine if the treatment group is better than the control group. In some implementations, tumor samples can also be collected at the end of each study, and relevant proteins (e.g., BCL-X) can be measured. L The study may use BCL-2, BCL-W, MCL-1, BIM, BAX, and / or BAK to determine whether the treatment group may have a better protein regulatory profile compared to the control group. In some embodiments, tumor samples may also be collected at the end of each study, and the activity of signal transduction pathways may be analyzed (e.g., by ERK phosphate levels). For pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples may be obtained from mice at the same or different time points as in efficacy studies. For example, for pharmacokinetic and pharmacodynamic studies, tumor and / or blood samples may be obtained from mice at 5 days and 6 hours after administration, and relevant proteins may be measured in tumor samples, and pharmacokinetic studies may be performed on blood samples or portions thereof (e.g., plasma).

[0729] In some implementations, PDX is a model of the following: myeloproliferative vegetations (MPN) (e.g., CEL, CML, CNL, essential thrombocythemia (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) essential thrombocythemia or JAK2 wild-type essential thrombocythemia), polycythemia vera (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) polycythemia vera or JAK2 wild-type polycythemia 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-esophagectomy myelofibrosis (e.g., JAK2 mutant (e.g., JAK2 V617F mutant) primary myelofibrosis), and post-esophagectomy myelofibrosis (e.g., JAK2 V617F mutant). Myelofibrosis following essential thrombocytosis (e.g., JAK2 V617F mutant) or myelofibrosis following polycythemia vera (e.g., JAK2 V617F mutant) or myelofibrosis following polycythemia vera (e.g., JAK2 V617F mutant) or myelofibrosis following polycythemia vera (e.g., JAK2 wild-type)), CRC (e.g., BRaf mutant CRC (e.g., BRaf V600E CRC) or KRas mutant CRC (e.g., KRasG12C mutant CRC or KRas G12D 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., EGFRL858R) 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), squamous cell carcinoma of the lung, malignant pleural mesothelioma (e.g., BAP1-mutant malignant pleural mesothelioma), melanoma (e.g., BRaf-mutant melanoma (e.g., BRafV600E 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., 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-mutated or BRCA2-mutated ovarian cancer, HGSOC (e.g., BRCA1-mutated or BRCA2-mutated HGSOC)), cervical cancer, intrahepatic cholangiocarcinoma, or mesenchymal carcinoma (e.g., mesenchymal breast cancer or mesenchymal renal cancer).

[0730] See, for example, Khan et al. Nature Medicine 25.12 (2019): 1938-1947, doi:10.1038 / s41591-019-0668-z; Balachander et al. Clinical Cancer Research 26.24 (2020): 6535-6549, doi: 10.1158 / 1078-0432.CCR-20-0863.

[0731] The pharmacokinetic parameters of the compounds provided herein or their pharmaceutically acceptable salts can be evaluated in animal models, such as mouse models, rat models, canine models, or non-human primate models (e.g., cynomolgus monkeys). Exemplary protocols include the following. For example, pharmacokinetic (PK) studies can be performed on animals (e.g., male or female CD-1 mice, Sprague Dawley rats, beagles, or cynomolgus monkeys) via two routes of delivery: intravenous (IV) injection and oral feeding (PO). Animals in both the IV and PO groups (e.g., n=3) can have free access to food and water, or they can be fasted. The compounds provided herein or their pharmaceutically acceptable salts can be formulated into solutions for the IV route and solutions or suspensions for the PO route. On the day of the experiment, for the IV route, the compounds provided herein or their pharmaceutically acceptable salts can be administered via intravenous injection (e.g., at 1 mg / kg), or for the PO route, via oral feeding (e.g., at 0.3 mg / kg to 100 mg / kg). Blood samples can be collected via continuous blood collection (e.g., at 8 time points from 0.83 to 24 hours post-drug administration). At each time point, blood can be collected via venous (e.g., saphenous vein) collection (e.g., approximately 30 μL blood / time point) in a K2EDTA tube. Blood samples can be placed on wet ice and centrifuged (e.g., at 4600 RPM for 4 minutes) to obtain plasma samples. Plasma samples can be diluted 1:1 (v / v) (e.g., with an equal volume of pH 3.0 phosphate buffer) and submitted for LC-MS / MS analysis. Results include clearance (IV), area under the curve (AUC), and peak concentration (C).max ), the time to reach maximum concentration (T) max Pharmacokinetic parameters, including mean residence time (MRT) and oral bioavailability (%F), can be calculated using a non-compartmental model.

[0732] In some implementations, pharmacokinetic parameters of the compounds provided herein or their pharmaceutically acceptable salts can be measured in mouse models (e.g., CD-1 (ICR) models). Exemplary implementations are as follows.

[0733] The compounds described herein or their pharmaceutically acceptable salts were administered orally (PO) (e.g., at 3 mg / kg, 10 mg / kg, 30 mg / kg, 100 mg / kg, or 300 mg / kg) or intravenously (e.g., at 1 mg / kg) to mice (e.g., male CD-1 (ICR) mice aged 7 to 9 weeks). The compounds described herein or their pharmaceutically acceptable salts were also administered to mice in solution formulations (e.g., 100% PEG400 for the PO group or 5% DMSO / 10% Solutol / 85% water for the IV group). Mice had unrestricted access to food and water.

[0734] Following administration of the dose, blood samples (e.g., 30 µL per sample) were collected from mice at predetermined intervals (such as 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 ​​hours, and 72 hours) (not every mouse will be sampled at every time point; this is also known as sparse sampling). Blood was sampled via saphenous vein puncture, and the blood samples (e.g., with K2EDTA as an anticoagulant) were temporarily placed on ice and then centrifuged over 30 minutes (e.g., at 4°C and 4600 RPM for 5 minutes). Plasma samples were acidified by dilution with an equal volume of pH 3.0 phosphate buffer and placed on dry ice. After the last sampling, all samples were stored at -80°C or analyzed shortly after collection. The concentration of the compounds described herein or their pharmaceutically acceptable salts, as measured in the acidified plasma samples, can be determined (e.g., via LC / MS / MS). For example, acidified plasma samples are prepared for analysis using protein precipitation (e.g., by adding methanol), and an internal standard is incorporated at a known concentration. The incorporated sample is mixed, centrifuged, and the supernatant is used in an LC / MS / MS method. The LC / MS / MS method uses KINETEX. ®A C18 2.6 μm 100 A (50 mm * 2.10 mm) column was used, with water (0.1% formic acid) as the first mobile phase and acetonitrile (0.1% formic acid) as the second mobile phase. Multiple reaction monitoring was used to measure the analytes of interest. The following pharmacokinetic parameters were determined by non-compartmental analysis using the concentrations of the compounds described herein or their pharmaceutically acceptable salts in plasma samples: terminal t 1 / 2 (hr), t max (hr), C max (ng / mL), AUC last (hr*ng / mL), AUC Inf (hr*ng / mL), AUC Extr (%) MRT Inf (hr), AUC Inf / D (hr*kg*ng / mL / mg) and %F.

[0735] In some implementations, pharmacokinetic parameters of the compounds provided herein or their pharmaceutically acceptable salts can be measured in rat models (e.g., the Sprague-Dawley rat model). Exemplary implementations are as follows.

[0736] The compounds described herein or their pharmaceutically acceptable salts were administered orally (PO) (e.g., at 10 mg / kg, 30 mg / kg, or 100 mg / kg) or intravenously (e.g., at 1 mg / kg) to rats (e.g., male Sprague-Dawley rats aged 7 to 9 weeks). The compounds described herein or their pharmaceutically acceptable salts were administered to rats in solution or suspension formulations (e.g., 10% 1-methyl-2-pyrrolidone (NMP) / 15% Solutol / 75% (20% (2-hydroxypropyl)-β-cyclodextrin (HPBCD) aqueous solution for the PO group; or 10% DMSO / 10% Solutol / 80% aqueous solution for the IV group). Rats had unrestricted access to food and water.

[0737] Following administration of the dose, blood samples (e.g., 150 µL per sample) were collected from rats at predetermined intervals, such as 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 ​​hours, and 72 hours. Blood was sampled via jugular vein puncture, and the blood samples (e.g., with K2EDTA as an anticoagulant) were temporarily placed on ice and then centrifuged over 30 minutes (e.g., at 4°C and 6000 RPM for 5 minutes). Plasma samples were acidified by dilution with an equal volume of pH 3.0 phosphate buffer and placed on dry ice. After the final sampling, all samples were stored at -80°C or analyzed shortly after collection. The concentration of the compounds described herein or their pharmaceutically acceptable salts can be measured in the acidified plasma samples (e.g., diluted 1:1 v / v with pH 3 phosphate buffer), and this concentration can be determined (e.g., via LC / MS / MS). For example, acidified plasma samples are prepared for analysis using protein precipitation (e.g., by adding methanol followed by the addition of a known concentration of internal standard in a 1:1 methanol / acetonitrile mixture, v / v). The incorporated sample is mixed, centrifuged, and the supernatant is used in LC / MS / MS. The LC / MS / MS method uses KINETEX. ® A C18 2.6 μm 100 Å (50 mm * 2.10 mm) column was used, with water (0.1% formic acid (FA)) as the first mobile phase and acetonitrile (0.1% FA) as the second mobile phase. Multiple reaction monitoring was used to measure the analytes of interest. The following pharmacokinetic parameters were determined by non-compartmental analysis using the concentrations of the compounds described herein or their pharmaceutically acceptable salts in plasma samples: terminal t 1 / 2 (hr), t max (hr), C max (ng / mL), AUC last (hr*ng / mL), AUC Inf (hr*ng / mL), AUC Extr (%) MRT Inf (hr), AUC Inf / D(hr*kg*ng / mL / mg)、%F、AUC 0-24 (hr*ng / mL) and AUC 48-72 (hr*ng / mL).

[0738] In some implementations, pharmacokinetic parameters of the compounds provided herein or their pharmaceutically acceptable salts can be measured in canine models (e.g., beagle models). Exemplary implementations are as follows.

[0739] The compounds described herein or their pharmaceutically acceptable salts may be administered orally (PO) to dogs (e.g., male beagles) at doses of 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg, or intravenously (IV) at doses of 0.1 mg / kg. The compounds described herein or their pharmaceutically acceptable salts may also be administered to dogs in solution or suspension formulations (e.g., 10% NMP / 15% Solutol / 75% (20% HPBCD aqueous solution)). The dog must be in a feeding state.

[0740] Following administration of the dose, blood samples (e.g., approximately 0.5 mL) are collected from the dog at predetermined intervals, such as 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 ​​hours, and 72 hours. Blood is sampled via peripheral vein puncture, and the blood sample (e.g., with K2EDTA as an anticoagulant) is temporarily placed on ice and then centrifuged over 30 minutes (e.g., at 2°C to 8°C and 3200 × g for 10 minutes). The plasma sample is acidified by dilution with an equal volume of pH 3.0 phosphate buffer and placed on dry ice. After the final sampling, all samples are stored at -60°C to -80°C or analyzed shortly after collection. The concentration of the compounds described herein or their pharmaceutically acceptable salts can be measured in the acidified plasma sample, and this concentration can be determined (e.g., via LC / MS / MS). For example, acidified plasma samples are prepared for analysis using protein precipitation (e.g., by adding acetonitrile containing a known concentration of an internal standard). The incorporated samples were mixed, centrifuged, and the supernatant was used for LC / MS / MS. The LC / MS / MS method used an ACQUITY UPLC HSS T3 1.8 μm 2.1 mm x 50 mm column (or an ACQUITY UPLC Protein BEH C4 300 Å 1.7 μm 2.1 mm x 50 mm column), with the first mobile phase being water / acetonitrile (v:v, 95:5) containing 0.1% formic acid and 2 mM ammonium formate, and the second mobile phase being acetonitrile / water (v:v, 95:5) containing 0.1% formic acid and 2 mM ammonium formate. Multiple reaction monitoring was used to measure the analytes of interest. The following pharmacokinetic parameters were determined via non-compartmental analysis using the concentrations of the compounds described herein or their pharmaceutically acceptable salts in plasma samples: terminal t 1 / 2 (hr), t max (hr), C max (ng / mL), AUC last (hr*ng / mL), AUC Inf (hr*ng / mL), AUC Extr (%) MRT Inf (hr), %F, and AUC0-24 (hr*ng / mL).

[0741] In some implementations, the pharmacokinetic parameters of the compounds provided herein or their pharmaceutically acceptable salts can be measured in non-human primate models (e.g., cynomolgus monkey models). Exemplary implementations are as follows.

[0742] The compounds described herein or their pharmaceutically acceptable salts are administered orally (PO) (e.g., at 3 mg / kg) or intravenously (IV) (e.g., at 0.5 mg / kg) to non-human primates (e.g., male cynomolgus monkeys). The compounds described herein or their pharmaceutically acceptable salts are administered to the monkeys in solution formulations (e.g., 10% NMP / 15% Solutol / 75% (20% HPBCD aqueous solution, pH 5)). The monkeys are in a feeding state.

[0743] Following administration of the dose, blood samples (e.g., approximately 0.5 mL) were collected from the monkeys at predetermined intervals, such as 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, and 48 hours. Blood was sampled via peripheral venous puncture, and the blood samples (e.g., with K2EDTA as an anticoagulant) were temporarily placed on ice and then centrifuged over 30 minutes (e.g., at 2°C to 8°C and 3200 × g for 10 minutes). The plasma samples were acidified by dilution with an equal volume of pH 3.0 phosphate buffer and placed on dry ice. After the final sampling, all samples were stored at -60°C to -80°C or analyzed shortly after collection. The concentrations of the compounds described herein or their pharmaceutically acceptable salts can be measured in the acidified plasma samples by LC / MS / MS. For example, acidified plasma samples were prepared for analysis using protein precipitation (e.g., by adding acetonitrile containing a known concentration of an internal standard). The incorporated samples were mixed, centrifuged, and the supernatant was used for LC / MS / MS. The LC / MS / MS method used an ACQUITY UPLC BEH C18 1.7 μm 2.1 mm × 50 mm column, with the first mobile phase being water / acetonitrile (v:v, 95:5) containing 0.1% formic acid and 2 mM ammonium formate, and the second mobile phase being acetonitrile / water (v:v, 95:5) containing 0.1% formic acid and 2 mM ammonium formate. Multiple reaction monitoring was used to measure the analytes of interest. The following pharmacokinetic parameters were determined via non-compartmental analysis using the concentrations of the compounds described herein or their pharmaceutically acceptable salts in plasma samples: terminal t 1 / 2 (hr), t max (hr), C max (ng / mL), AUC last (hr*ng / mL), AUC Inf(hr*ng / mL), AUC Extr (%) MRT Inf (hr), %F, and AUC 0-24 (hr*ng / mL).

[0744] In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 4%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 10%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 20%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 30%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is at least 40%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is from about 4% to about 80% (e.g., from about 4% to about 60%, from about 4% to about 40%, from about 4% to about 20%, from about 4% to about 10%, from about 20% to about 40%, or from about 20% to about 30%). In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is from about 4% to about 20% (e.g., from about 4% to about 10%). In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is from about 20% to about 40%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is from about 40% to about 60%. In some embodiments, the %F of the compound provided herein or a pharmaceutically acceptable salt thereof is from about 60% to about 80%.

[0745] In some embodiments, the oral clearance (CL / F) of the compound provided herein or a pharmaceutically acceptable salt thereof, administered to rats at 10 mg / kg PO, 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 the compound provided herein or a pharmaceutically acceptable salt thereof, administered to rats at 10 mg / kg PO, is from about 0.05 mL / min / kg to about 5 mL / min / kg (e.g., from about 0.05 mL / min / kg to about 3 mL / min / kg, from about 0.05 mL / min / kg to about 1 mL / min / kg, or from about 0.05 mL / min / kg to about 0.5 mL / min / kg).

[0746] In some embodiments, the AUC of the compound provided herein or a pharmaceutically acceptable salt thereof administered to rats at 10 mg / kg PO is about 10 μM·h to about 350 μM·h (e.g., 10 μM·h to about 150 μM·h, about 50 μM·h to about 350 μM·h, about 100 μM·h to about 350 μM·h, or about 150 μM·h to about 350 μM·h).

[0747] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are not substrates of human cytochrome P450 enzymes. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are not substrates of human cytochrome P450 enzymes, wherein ≥25% clearance is attributed to the enzyme. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are not inhibitors and / or inducers of one or more human cytochrome P450 enzymes. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are not inhibitors and / or inducers of one or more human cytochrome P450 enzymes, wherein the IC50 of the one or more human cytochrome P450 enzymes is... 50 Value and / or EC 50 The values ​​are estimated free fraction concentrations of the compounds or their pharmaceutically acceptable salts provided in this article that are significantly greater than clinically relevant doses.

[0748] Exemplary human cytochrome P450 enzymes include those from the CYP1, CYP2, and CYP3 families. Among them, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2J2, CYP2S1, CYP2E1, CYP3A4, and CYP3A5 are known drug-metabolizing enzymes. In some embodiments, no single cytochrome P450 enzyme is responsible for the elimination of 25% or more of the compounds provided herein or their pharmaceutically acceptable salts. Cytochrome P450 inhibitory and / or inducing activities can be determined using appropriate in vitro assays, such as those described in the guidance document “In Vitro Drug Interaction Studies – Drug Interactions Mediated by Cytochrome P450 Enzymes and Transporters” provided by the USFDA in January 2020, and similarly those described in the ICH M12 guidance document completed in May 2024. For example, the evaluation of cytochrome P450 inhibition can be performed in an in vitro study in a reversible and time-dependent manner. In in vitro inhibition studies, the ratio of the intrinsic clearance values ​​of the probe substrate for the enzymatic pathway in the absence and presence of the compound provided herein or its pharmaceutically acceptable salt can be calculated based on these in vitro results; for reversible inhibition, this ratio is referred to as R1, where R1 = 1 + (I max,u / Ki,u ), and I max,u This is the predicted maximum unbound plasma concentration in humans of the compound provided herein or its pharmaceutically acceptable salt, and K i,u This is the unbound inhibition constant determined in vitro. Specifically, in the case of CYP3A, although the enzyme is also expressed at significant levels in the intestine, R can be calculated. 1,肠 , where R 1,gut =1 + (I 肠 + K i,u ), and where I 肠 This is the predicted human intestinal lumen concentration of the compound or its pharmaceutically acceptable salt provided in this article, calculated as a human oral dose / 250 mL. The time-dependent inhibition ratio R² can be calculated similarly, where R² = (k... obs +k deg ) / k deg And Kobs is through k obs = (k inact *I max,u ) / (K I,u + *I max,u The observed (epistemological first-order) inactivation rate of affected cytochrome P450 was calculated, k. deg K is the apparent first-order degradation rate constant of the affected cytochrome P450. I,u It is the unbound concentration of the compound provided herein or its pharmaceutically acceptable salt that causes half-maximal inactivation, and k inact This is the maximum deactivation rate constant. Using R1 and R... 1,肠These equations, along with R2, can be used to evaluate the potential of the compounds provided herein or their pharmaceutically acceptable salts as inhibitors of cytochrome P450, and the potential for drug-drug interaction (DDI) can be further investigated using mechanistic or physiological pharmacokinetic models of the liver and intestine and / or clinical DDI studies with sensitivity index substrates. Additionally, the tendency of the compounds to activate nuclear receptors (e.g., PXR, CAR, or AhR) can be evaluated through in vitro cytochrome P450 hepatocyte induction studies, and the resulting data can be evaluated via a fold change approach, where the fold change in cytochrome P450 enzyme mRNA levels when incubated with the compounds provided herein or their pharmaceutically acceptable salts is calibrated based on cutoff values ​​determined from known positive and negative controls. For example, the compounds provided herein or their pharmaceutically acceptable salts will be identified as inducers if: (1) they increase cytochrome P450 enzyme mRNA expression in a concentration-dependent manner; and (2) at the expected hepatic concentration of the drug, the fold change in cytochrome P450 mRNA expression relative to the mediator control is ≥2-fold. In addition, the evaluation of cytochrome P450 induction can be performed using relevant methods, which are based on the relative induction score (RIS) or I of a set of known inducers of the same cytochrome P450. max,u / EC 50 The calibration curves predict the magnitude of the clinical induction effect of the compounds provided herein or their pharmaceutically acceptable salts (e.g., the AUC ratio of the index substrate in the presence and absence of an inducer). If the predicted magnitude is greater than a predetermined cutoff value (e.g., an AUC ratio ≤ 0.8), the compounds provided herein or their pharmaceutically acceptable salts are considered to have in vivo induction potential.

[0749] In some implementations, the potency of the compounds provided herein or their pharmaceutically acceptable salts to inhibit hERG potassium channels can be tested. Cardiac potassium channels (hERG) are responsible for the rapid delayed rectified current (I0.05) in the ventricles. Kr ), and I Kr Inhibition of the cardiac action potential is the most common reason why non-cardiac drugs prolong the cardiac action potential. The increased action potential duration leads to QT interval prolongation, which is associated with dangerous ventricular arrhythmias (torsius ventricular tachycardia). Several methods exist for testing the inhibitory efficacy of hERG, including Fastpatch hERG and manual patch-clamp experiments.

[0750] In some embodiments, manual patch-clamp assays are used to test the potency of the compounds provided herein or their pharmaceutically acceptable salts in inhibiting hERG potassium channels. For example, in some embodiments, solutions or suspensions of the compounds provided herein or their pharmaceutically acceptable salts may be exposed to single cells at several concentrations (e.g., 0.3 µM, 1 µM, 3 µM, and 10 µM). The inhibitory effect of the compounds provided herein or their pharmaceutically acceptable salts on hERG potassium channels can be assessed in this system using electrical pulse patterns, plotted data, and calculated IC50 values ​​for the inhibition of hERG by the compounds provided herein or their pharmaceutically acceptable salts. 50 The value is used for measurement. An example scheme is as follows.

[0751] In this experiment, hERG potassium channels were used in the absence of endogenous I... Kr Human embryonic kidney cell line (HEK-293 (ATCC 293T, CRL-3216)) ™ The expression is in the text. See, for example, Brown, Arthur M. and David Rampe. Pharmaceutical News 7.4 (2000): 15-20; Weirich, Jörg and H. Antoni, Basic Research in Cardiology 93 (1998): s125-s132, doi: 10.1007 / s003950050236; and Yap, Yee Guan and AJCamm. Clinical & Experimental Allergy 29 (1999): 174-181, doi: 10.1046 / j.1365-2222.1999.0290s3174.x.

[0752] All chemicals used in solution preparation were purchased from commercial suppliers (e.g., Sigma-Aldrich) and were of ACS reagent grade or higher purity. Stock solutions of the compounds described herein or their pharmaceutically acceptable salts, positive control compounds, and reference substances were prepared in dimethyl sulfoxide (DMSO) and stored frozen. Solutions of each compound described herein or its pharmaceutically acceptable salts, positive control compounds, and reference substances at concentrations thereof were freshly prepared daily by diluting the stock solutions to HEPES-buffered saline (HB-PS; 137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 10 mM glucose, pH 7.4). Since previous results have shown that ≤0.3% DMSO does not affect channel currents, all test and control solutions may contain 0.3% DMSO.

[0753] In some embodiments, a positive control compound may be included in the experiment. In some such embodiments, the positive control compound may be, for example, a solution of HB-PS containing terfenadine (Sigma-Aldrich) and 0.3% DMSO.

[0754] In some embodiments, a reference compound may be included in the experiment. In some such embodiments, the reference compound may be, for example, HB-PS containing E-4031 (Sigma-Aldrich) and a 0.3% DMSO solution.

[0755] If necessary, sonicate the solution to promote dissolution. Note any visible precipitation observed during formulation preparation or exposure to the test system for reference.

[0756] The effects of the compounds presented herein, or their pharmaceutically acceptable salts, were initially evaluated at concentrations ranging from 1 µM to 10 µM. Subsequent concentrations were evaluated based on the inhibition observed at these concentrations.

[0757] HEK-293 cells were transfected with hERG cDNA. Stable transfectants were selected by co-expression of the G418 resistance gene incorporated into the expression plasmid. Selection pressure was maintained by including G418 in the culture medium. Cells were cultured in Dalberg Modified Eagle Medium / Hans' Nutrient Mix F-12 (DMEM / F-12) supplemented with 10% fetal bovine serum and appropriate concentrations of penicillin G sodium, streptomycin sulfate, and G418.

[0758] All experiments were conducted at near physiological temperatures (33℃-35℃). Each cell served as its own control.

[0759] The effects of the compounds provided herein or their pharmaceutically acceptable salts thereof will be evaluated at multiple (e.g., up to four) concentrations. Each concentration will be tested in at least three cell lines (n ≥ 3). Additional concentrations may be tested due to limitations imposed by the physiological and chemical effects (e.g., solubility or cytotoxicity) of the compounds provided herein or their pharmaceutically acceptable salts thereof.

[0760] The positive control compound was tested in at least two (2) cells (n≥2).

[0761] Cells were transferred to the recording chamber and superfused with a medium control solution. The pipette (intracellular) solution for whole-cell recording consisted of 130 mM potassium aspartate, 5 mM MgCl2, 5 mM EGTA, 4 mM ATP, and 10 mM HEPES (pH 7.2). Pipette solutions were prepared in batches, aliquoted, frozen, and thawed daily with fresh aliquots. Recording was performed at temperatures ranging from 33°C to 35°C using a combination of an online solution preheater, chamber heater, and feedback temperature controller. Temperature was measured in the recording chamber using a thermistor probe. Micropipettes for patch-clamp recording were prepared from glass capillaries using a P-97 micropipette puller (Sutter Instruments). A commercial patch-clamp amplifier (Molecular Devices) was used for the entire patch-clamp cell recording. The current recording was low-pass filtered before digitization.

[0762] Cells stably expressing hERG were held at -80 mV. The initiation and steady-state inhibition of hERG potassium currents induced by the compounds provided herein or their pharmaceutically acceptable salts were measured using a pulse pattern with a fixed amplitude (a pre-pulse of +20 mV for 1 second; repeated repolarization test ramps to -80 mV at 5-second intervals (at -0.5 V / sec)). Each recording ended with the application of an ultra-high concentration of a reference substance (e.g., 500 nM E-4031) to assess the contribution of the endogenous current. The remaining uninhibited current was digitally subtracted offline from the data to determine the potency of the compounds provided herein or their pharmaceutically acceptable salts for hERG inhibition. Peak currents were measured during the test ramp. Steady-state was maintained for at least 20 seconds before application of the compounds provided herein or their pharmaceutically acceptable salts, a positive control compound, or a reference substance. Peak tail currents were measured until a new steady state was reached. If steady state was not reached within 12 minutes, the response at 12 minutes was used instead of the steady-state value and labeled.

[0763] Data acquisition and analysis were performed using the commercial suite of pCLAMP (Molecular Devices) program. Steady state was defined by a finite, constant rate of change over time (linear time dependence). The percentage of current suppressed at each concentration was calculated using steady state before and after administration of each compound or its pharmaceutically acceptable salt provided herein.

[0764] In some embodiments, the Fastpatch hERG assay is used to test the potency of the compounds provided herein or their pharmaceutically acceptable salts to inhibit hERG potassium channels (e.g., encoded by the KCNH2 gene and expressed in HEK293 cells). For example, in some embodiments, a solution or suspension of the compounds provided herein or their pharmaceutically acceptable salts may be exposed to cells in an automated parallel patch-clamp system at several concentrations (e.g., 0.3 µM, 1 µM, 3 µM, and 10 µM). The inhibitory effect of the compounds provided herein or their pharmaceutically acceptable salts on hERG potassium channels can be assessed in this system using electrical pulse patterns, plotted data, and calculated IC50 values ​​for the inhibition of hERG by the compounds provided herein or their pharmaceutically acceptable salts. 50 The value is used for measurement. An example scheme is as follows.

[0765] Using QPATCH HT ® (Sophion Bioscience A / S, Denmark) An automated parallel patch-clamp system was used to evaluate the in vitro effects of the compounds described herein or their pharmaceutically acceptable salts at room temperature. The compounds described herein or their pharmaceutically acceptable salts were exposed to hERG at 0.3 µM, 1 µM, 3 µM, and 10 µM in at least five cells (n ≥ 5). The duration of exposure to each compound concentration was at least three minutes.

[0766] Prepare solutions or suspensions of the compounds described herein or their pharmaceutically acceptable salts daily. Various concentrations are prepared by diluting the stock solutions into appropriate HEPES-buffered saline solutions (HB-PS).

[0767] Previous results have shown that 0.3% DMSO does not affect the channel current. Therefore, all test and control solutions may contain up to 0.3% DMSO.

[0768] Each formulation of the compounds provided herein or their pharmaceutically acceptable salts may be sonicated, for example, at room temperature (e.g., Model 2510 / 5510, Branson Ultrasonics, Danbury, CT) to promote dissolution.

[0769] In some embodiments, a positive control may be included in the experiment. In some such embodiments, the positive control compound may be, for example, a 0.3% DMSO solution containing cisapride (Tocris Bioscience).

[0770] During the preparation of the recording phase, glass-lined 96-well compound plates were loaded with appropriate amounts of the compounds provided herein or their pharmaceutically acceptable salts and control solutions, and placed in a QPATCH system.® In the wells of (Sophion Bioscience A / S, Denmark).

[0771] HEK293 (ATCC 293T, CRL-3216) was stably transfected with appropriate ion channel cDNA. ™ Cells. In addition to cells that have already been cryopreserved, stable transfectants are maintained in a culture medium with appropriate selective pressure and antibiotics.

[0772] All experiments were conducted at room temperature. Each cell served as its own control.

[0773] via QPATCH ® The robotic pipetting system applied the medium to immature cells at 5-10 minute exposure intervals. Following medium application, various concentrations of the compound provided herein or its pharmaceutically acceptable salts (n~3, where n = number of cells / concentration) were applied at intervals of at least three (3) minutes. ® Each solution exchange on the plate is performed multiple times, resulting in 100% replacement of the compounds in the QPlate.

[0774] Positive controls were administered in the same manner as the compounds provided herein or their pharmaceutically acceptable salts to verify sensitivity to ion channel blockade.

[0775] During the recording phase preparation, intracellular solutions (e.g., 137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 10 mM glucose, pH 7.4) are loaded into the intracellular compartment of the QPlate, and the cell suspension is pipetted into the extracellular compartment. After establishing the whole-cell configuration, the cells are processed using QPATCH. ® The system uses up to 48 parallel patch-clamp amplifiers to record membrane currents.

[0776] Valid whole-cell recordings meet the following criteria:

[0777] 1. Membrane resistance ≥ 200MΩ.

[0778] 2. Leakage current ≤ 25% of channel current or be subtracted.

[0779] The onset and blocking of hERG current were measured using a stimulation voltage pattern consisting of a 500 ms pre-pulse to -40 mV (leakage subtraction), a 2-second activation pulse to +40 mV, and a subsequent 2-second test pulse to -40 mV. The pulse pattern was repeated continuously at 10-second intervals from a hold potential of -80 mV. The peak tail current was measured during the -40 mV test pulse. The leakage current was calculated from the current amplitude induced by the -40 mV pre-pulse and subtracted from the total membrane current record.

[0780] Data acquisition and analysis were performed using standard software. Steady state was defined by a finite, constant rate of change over time (linear time dependence). Steady state before and after administration of the compound provided herein or its pharmaceutically acceptable salts was used to calculate the percentage of current inhibited at each concentration. If the current was blocked by ≥50%, the estimated IC was calculated using the following formula. 50 value:

[0781] Suppression % = {1-1 / [l+([test] / IC]} 50 ) N ]}*100

[0782] Wherein [test] refers to the concentration of the compound provided herein or its pharmaceutically acceptable salt, IC50. 50 This represents the concentration of the compound or its pharmaceutically acceptable salt provided in this paper at half-maximum inhibition, where N is the Hill coefficient, and inhibition% is the percentage of current inhibited at each test concentration. A nonlinear least-squares fit was solved using the Solver add-in of Excel (Microsoft, WA). This was achieved through QPATCH. ® The manual adjustment using the exponential compensation formula in the analysis software avoids overestimation of current suppression due to attenuation.

[0783] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are not hERG inhibitors. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts are expressed at an IC50 concentration greater than 60 nM (e.g., greater than 100 nM, 300 nM, 500 nM, 1 µM, 3 µM, 5 µM, 10 µM, 20 µM, or 30 µM). 50 Inhibition of hERG. For example, the compounds provided herein or their pharmaceutically acceptable salts can inhibit hERG at an IC50 concentration greater than 500 nM (e.g., greater than 1 µM, 3 µM, 5 µM, 10 µM, 20 µM, or 30 µM). 50 Inhibition of hERG. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used at an IC50 concentration greater than 1 µM (e.g., greater than 3 µM, 5 µM, 10 µM, 20 µM, or 30 µM). 50Inhibition of hERG. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used at an IC50 concentration greater than 10 µM (e.g., greater than 20 µM or 30 µM). 50 Inhibition of hERG. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are used at an IC50 concentration greater than 30 µM. 50 Inhibit hERG.

[0784] In some embodiments, the potential secondary pharmacology of the compounds provided herein or their pharmaceutically acceptable salts can be evaluated. For example, in some embodiments, solutions of the compounds provided herein or their pharmaceutically acceptable salts can be exposed at single or multiple concentrations to a group of primary cells, cell lines, or isolated tissues expressing known pharmacological receptors, enzymes, or transporters. The effects of the compounds provided herein or their pharmaceutically acceptable salts on secondary pharmacological targets of interest can be determined, with data initially plotted as percentages of inhibition. For secondary targets exceeding an inhibition threshold (typically ≥50%), IC50 is generated and calculated based on an 8-point concentration curve of the compounds provided herein or their pharmaceutically acceptable salts. 50 value.

[0785] An exemplary list of assays is included in Table 1 below. One or more of these assays can be used to evaluate the secondary pharmacological characteristics of the compounds provided herein. Exemplary protocols are described in Valentin, Jean-Pierre, and Tim Hammond. Journal of Pharmacological and Toxicological Methods 58.2 (2008): 77-87; doi: 10.1016 / j.vascn.2008.05.007; Wakefield, Ian D, et al. Fundamental & Clinical Pharmacology 16.3 (2002): 209-218, doi: 10.1046 / j.1472-8206.2002.00099.x; Whitebread, Steven, et al. Drug Discovery Today 10.21 (2005):1421-1433, doi: 10.1016 / S1359-6446(05)03632-9; and Lounkine, Eugen et al., Nature 486.7403 (2012): 361-367, doi: 10.1038 / nature11159.

[0786] Table 1.

[0787]

[0788]

[0789]

[0790] In some cases, heterobifunctional degraders can induce the degradation of off-target proteins. Common off-target proteins that can be degraded by heterobifunctional degraders utilizing CRBN include GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α. This degradation is generally thought to be due to the E3 binding moiety of the heterobifunctional degrader promoting the formation of a ternary complex between the off-target protein and CRBN. GSPT1 is a translation termination factor, and CK1α is a kinase involved in many key cellular processes, including cell cycle progression and chromosome segregation; these are common essential genes, and therefore unintended degradation of any one or both can lead to nonspecific cytotoxicity. IKZF proteins are zinc finger transcription factors involved in cell fate during hematopoiesis, and degradation of these proteins is associated with hematologic toxicity. See, for example, Moreau, Kevin et al., British Journal of Pharmacology 177.8 (2020): 1709-1718, doi: 10.1111 / bph.15014.

[0791] In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit activity against BCL-X. L Efficient and selective induction of protein degradation. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof can selectively target BCL-X relative to off-target proteins, such as another BCL-2 family member (e.g., BCL-2 and / or MCL-1) or non-BCL-2 family member targets (e.g., GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α). L The protein is degraded.

[0792] As used herein, when referring to the compounds provided herein or their pharmaceutically acceptable salts, in protein degradation assays, "selectively" or "selectively" indicates, relative to a comparison protein in the assay, at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) superior performance for the specific protein in the protein degradation assay. In some embodiments, the specific protein is BCL-X. L The protein, and the protein in comparison is BCL-2 protein. For example, if, as determined by degradation assays, the compounds presented herein or their pharmaceutically acceptable salts "selectively" induce BCL-X relative to BCL-2 protein. LProtein degradation, when measured by a degradation assay, indicates that the compound's effect on BCL-X... L protein DC 50 The value is at most 1 / 5 of that for the BCL-2 protein (e.g., at most 1 / 10, at most 1 / 25, at most 1 / 50, or at most 1 / 100).

[0793] In some embodiments, the compounds provided herein can exhibit targeting of BCL-X. L The activity against proteins is minimal (e.g., nanomolar activity), and the activity against BCL-2 family members (e.g., BCL-2 or MCL-1 proteins) is minimal (e.g., micromolar activity). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit BCL-X activity. L Effective degradation of proteins, and minimal efficacy in degrading off-target proteins (e.g., BCL-2 family members (e.g., BCL-2 and / or MCL-1), GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α) (e.g., via Y... min DC 50 EC 50 and / or D ma (Values ​​measured). In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts may exhibit higher BCL-X levels relative to degradation induction by off-target proteins (e.g., BCL-2 family members (e.g., BCL-2 and / or MCL-1), GSPT1, IKZF1, IKZF2, IKZF3, and / or CK1α). L Protein degradation-induced (e.g., as by Y) min DC 50 EC 50 and / or D max (Values ​​measured). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit at least 2, 3, 5, 10, 25, 50, or 100 times higher BCL-X activity relative to the degradation induction of off-target proteins. L Protein degradation induction. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof can exhibit up to 1000 times higher BCL-X degradation induction relative to off-target proteins. L Protein degradation induction. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof may exhibit approximately 2 to approximately 10 times higher degradation induction of BCL-X relative to off-target proteins (e.g., GSPT1, IKZF1, IKZF2 and / or IKZF3 and / or CK1α). L Protein degradation-induced (e.g., as by Y) min DC 50EC 50 and / or D max (Values ​​measured). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof can exhibit BCL-X degradation induction that is about 10 to about 100 times higher relative to off-target proteins. L Protein degradation induction. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof can exhibit BCL-X degradation induction that is approximately 100-fold to approximately 1000-fold higher than that of off-target proteins. L Protein degradation induction. In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof can exhibit BCL-X degradation induction that is approximately 1,000 to approximately 10,000 times higher than that of off-target proteins. L Protein degradation induction.

[0794] Inhibition or induction of BCL-X L Some degraded agents have shown platelet toxicity, producing dose-limiting toxicities (e.g., thrombocytopenia) in clinical practice. See, for example, Adams and Cory, Cell Death & Differentiation 25.1 (2018): 27-36, doi: 10.1038 / cdd.2017.161; Campbell and Tait. Open Biology 8.5 (2018): 180002, doi: 10.1098 / rsob.180002; Pullarkat et al., Cancer Discovery (2021), doi:10.1158 / 2159-8290.CD-20-1465; Negi and Voisin-Chiret. ChemBioChem (2022), doi: 10.1002 / cbic.202100689. Platelet activity can be monitored using any suitable assay, such as those described herein. See, for example, Example B4.

[0795] In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof). In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces about 30% to about 100% platelet activity (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof).

[0796] In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has approximately 50% to approximately 70% Y min Value. In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has less than about 50% Y min Value. In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has approximately 0% to approximately 50% Y min value.

[0797] In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces platelet activity between about 30% and 100% (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has approximately 50% to approximately 70% Y min Value. In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces platelet activity between about 30% and 100% (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has less than about 50% Y min Value. In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces platelet activity between about 30% and 100% (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has approximately 0% to approximately 50% Y min value.

[0798] In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces at least about 50% platelet activity (e.g., at least about 80% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has approximately 50% to approximately 70% Y min Value. In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces at least about 50% platelet activity (e.g., at least about 80% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has less than about 50% Y minValue. In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces at least about 50% platelet activity (e.g., at least about 80% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has approximately 0% to approximately 50% Y min value.

[0799] In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces platelet activity between about 50% and 100% (e.g., about 80% to about 100% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has approximately 50% to approximately 70% Y min Value. In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces platelet activity between about 50% and 100% (e.g., about 80% to about 100% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has less than about 50% Y min Value. In some embodiments, when administered to a subject, a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof produces platelet activity between about 50% and 100% (e.g., about 80% to about 100% platelet activity) (e.g., compared to the subject's platelet count prior to administration of the compound provided herein or a pharmaceutically acceptable salt thereof), and for BCL-X L The protein has approximately 0% to approximately 50% Y min value.

[0800] In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay of Example B4, the compounds provided herein or pharmaceutically acceptable salts thereof exhibit at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity). In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay of Example B4, the compounds provided herein or pharmaceutically acceptable salts thereof exhibit about 30% to about 100% platelet activity (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity).

[0801] In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity), and have about 50% to about 70% Y in the assay described in Example B1. min Value. In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity), and have less than about 50% Y in the assay described in Example B1. min Value. In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show at least about 30% platelet activity (e.g., at least about 50% platelet activity, or at least about 80% platelet activity), and have about 0% to about 50% γ in the assay described in Example B1. min value.

[0802] In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show platelet activity between about 30% and 100% (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity), and have about 50% to about 70% Y in the assay described in Example B1. min Value. In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show platelet activity between about 30% and 100% (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity), and have less than about 50% Y in the assay described in Example B1. min Value. In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show platelet activity between about 30% and 100% (e.g., about 50% to about 100% platelet activity, or about 80% to about 100% platelet activity), and have about 0% to about 50% γ in the assay described in Example B1. min value.

[0803] In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show at least about 50% platelet activity (e.g., at least about 80% platelet activity) and have about 50% to about 70% Y in the assay described in Example B1. min Value. In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show at least about 50% platelet activity (e.g., at least about 80% platelet activity), and have less than about 50% Y in the assay described in Example B1. min Value. In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show at least about 50% platelet activity (e.g., at least about 80% platelet activity) and have about 0% to about 50% γ in the assay described in Example B1. min value.

[0804] In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts exhibit platelet activity between about 50% and 100% (e.g., about 80% to about 100% platelet activity), and have about 50% to about 70% Y in the assay described in Example B1. min Value. In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show platelet activity between about 50% and 100% (e.g., about 80% to about 100% platelet activity), and have less than about 50% Y in the assay described in Example B1. min Value. In some embodiments, when tested at concentrations of about 0.25 μM to about 3 μM in the assay described in Example B4, the compounds provided herein or their pharmaceutically acceptable salts show platelet activity between about 50% and 100% (e.g., about 80% to about 100% platelet activity), and have about 0% to about 50% Y in the assay described in Example B1. min value.

[0805] This article provides a method for treating cancer in a subject requiring such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject has not received treatment for cancer. In some embodiments, the subject has received first-line or multiple-line prior therapy for cancer.

[0806] This document also provides methods for treating cancer in a subject in need, comprising administering a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy to the subject. In some embodiments, the subject has not received treatment for cancer. In some embodiments, the subject has received first-line or multiple-line prior therapy for cancer.

[0807] This article provides a method for treating cancer in a subject requiring such treatment, the method comprising:

[0808] (a) Detection of cancer-related biomarkers (e.g., mutations, amplifications, copy number increases, and / or expression of biomarkers (optionally including expression levels)); and

[0809] (b) The subject is given a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as a monotherapy or in combination with another therapy or treatment agent.

[0810] This article also provides a method for treating cancer in a subject who has been identified (e.g., identified prior to administration of the compound provided herein) as having a cancer-related biomarker (e.g., mutation, amplification, copy number increase, and / or expression (optionally including expression level) of the biomarker), the method comprising administering to the subject a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as a monotherapy or in combination with an additional therapy or therapeutic agent.

[0811] This article provides a method for treating cancer in a subject requiring such treatment, the method comprising:

[0812] (a) Detection of cancer-related biomarkers (e.g., mutations, amplifications, copy number increases, and / or expression (optionally including expression levels) of markers sensitive to specific reagents (e.g., HER2 expression, ER expression, PR expression, folate receptor expression)); and

[0813] (b) The subject is given a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as a monotherapy or in combination with another therapy or treatment agent.

[0814] This article also provides a method for treating cancer in a subject who has been identified (e.g., identified prior to administration of the compound provided herein) as having cancer-related biomarkers (e.g., mutations, amplifications, copy number increases, and / or expression (optionally including expression levels) of a marker sensitive to a specific agent (e.g., HER2 expression, ER expression, PR expression, folate receptor expression)). The method comprises administering a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to the subject as a monotherapy or in combination with other therapies or therapeutic agents.

[0815] This article provides for the use of the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of cancer (e.g., any cancer described herein).

[0816] This document provides for the use of compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of cancers, such as any cancers described herein.

[0817] This article provides for the use of the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines for the treatment of cancer (e.g., any cancers provided herein).

[0818] This article provides for the use of the compounds described herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of cancer (e.g., any cancer described herein).

[0819] This document provides for the use of compounds provided herein, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines. This document also provides for the use of compounds provided herein, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines for treating cancer (e.g., any cancers provided herein).

[0820] This article provides information on the use of compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment of cancer, such as any of the cancers described herein.

[0821] As used herein, when referring to the compounds provided herein or their pharmaceutically acceptable salts, "monotherapy" means that the compounds provided herein or their pharmaceutically acceptable salts are the only therapeutic agent or therapy (e.g., an anticancer agent or therapy) administered to the subject during a treatment cycle (e.g., without the administration of other targeted therapies, anticancer agents, chemotherapy agents, or checkpoint inhibitors to the subject during a treatment cycle). As understood by those skilled in the art, monotherapy does not exclude the co-administration of medications (sometimes referred to as supportive care measures) for treating cancer or treatment-related side effects or general symptoms such as pain, rash, edema, photosensitivity, itching, skin discoloration, brittle hair, hair loss, brittle nails, nail breakage, nail discoloration, epidermal swelling, fatigue, weight loss, malaise, shortness of breath, infection, thrombocytopenia, neutropenia, anemia, or gastrointestinal symptoms (including nausea, diarrhea, and loss of appetite).

[0822] For example, in some implementations, supportive care measures may be granulocyte colony-stimulating factor (G-CSF), thrombopoietin receptor (TpoR) agonists, or steroids.

[0823] In some implementations, the TpoR agonist is avatrombopag (e.g., avatrombopag maleate), eltrombopag (e.g., eltrombopag olamine), lusutrombopag, megapoietin (KRN-9000), pegacaristim, rafutrombopag (e.g., rafutrombopag olamine), recombinant human thrombopoietin, romiplostim, totrombopag (e.g., totrombopag choline), or a combination thereof.

[0824] As used herein, "subject previously received one or more therapeutic agents or therapies for cancer" means that the subject has previously received one or more therapeutic agents or therapies for cancer (e.g., anticancer agents or therapies) other than the compounds provided herein or their pharmaceutically acceptable salts during a previous treatment cycle. In some embodiments, the subject is intolerant to the previously administered one or more therapeutic agents or therapies for cancer. In some embodiments, the subject is unresponsive to the previously administered one or more therapeutic agents or therapies for cancer. In some embodiments, the subject's response to the previously administered one or more therapeutic agents or therapies for cancer is inadequate. In some embodiments, the subject's response to the previously administered one or more therapeutic agents or therapies for cancer has ceased. In some implementations, non-response, inadequate response, or cessation of response can be determined by objective criteria (e.g., tumor volume, or by criteria such as RECIST 1.1, Lugano 2014 criteria (Cheson, Bruce D. et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JCO.2013.54.8800) or global response criteria (Olsen, Elise A. et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057)). In some implementations, non-response, inadequate response, or cessation of response can be determined by the subject's physician.

[0825] As used in this article, “the subject has not received any treatment for cancer” means that the subject has not previously received one or more treatments or therapies for cancer.

[0826] For any of the solid tumors described herein, the solid tumor can be a primary tumor or a metastatic (or secondary) tumor. As used herein, a "primary" tumor is one located at the site where the tumor began to grow (i.e., the site of origin). As used herein, a "metastatic" (or "secondary") tumor is one that has spread from the original tumor site to other parts of the body. In some embodiments, the metastatic or secondary tumor is the same type of cancer as the primary tumor. In some embodiments, the metastatic or secondary tumor is not genetically identical to the primary tumor.

[0827] In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., invasive breast cancer, invasive ductal carcinoma of the breast), cancer of the central or peripheral nervous system tissues (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligodendroastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, neuroblastoma, pheochromocytoma, paraganglioma), type I and II polyneuroendocrine tumors, parathyroid cancer, pituitary adenoma, thyroid cancer (e.g., papillary thyroid carcinoma)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer) Biliary duct cancer (e.g., cholangiocarcinoma (e.g., intrahepatic cholangiocarcinoma)), colorectal cancer (e.g., colonic adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell carcinoma), small bowel cancer or stomach cancer (e.g., gastric adenocarcinoma, gastric signet ring cell carcinoma)), genitourinary tract cancers (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., clear cell renal carcinoma, papillary renal carcinoma, chromophobe renal carcinoma), prostate cancer (e.g., prostate adenocarcinoma), testicular cancer (e.g., testicular genital cancer). Cancers include: 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 body endometrial cancer), or vulvar cancer; head and neck cancers (e.g., ear cancers (e.g., middle ear cancer), head and neck squamous cell carcinoma, nasal cavity cancer, oral cavity cancer, pharyngeal cancers (e.g., hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer); hematologic cancers (e.g., leukemia (e.g., chronic eosinophilic leukemia (CEL), chronic lymphocytic leukemia (CLL), chronic intermediate-terminal leukemia (CLL)). Myeloid 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-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 lymphocytic-dominant 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-esophagectomy myelofibrosis, or post-polycythemia vera myelofibrosis), myelodysplastic syndromes (MDS) (e.g., M6 MDS or M7 MDS). Multiple myeloma (MDS) or other myeloma (e.g., multiple myeloma), Li-Fraumeni tumors, mesenteric cancers (e.g., omental cancer, peritoneal cancer), pleural cancers, respiratory cancers (e.g., laryngeal cancer, lung cancer (e.g., squamous cell carcinoma, adenocarcinoma, malignant pleural mesothelioma, non-small cell lung cancer (NSCLC), small cell lung cancer), tracheal cancers), sarcomas (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcomas (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancers (e.g., melanoma or Merkel cell carcinoma), thymic carcinomas (e.g., thymoma), or combinations thereof.

[0828] In some implementations, the cancer is breast cancer, gastrointestinal cancer (e.g., bile duct cancer (e.g., cholangiocarcinoma (e.g., intrahepatic bile duct cancer)), colorectal cancer (CRC), gastrointestinal stromal tumor, or pancreatic cancer), genitourinary cancer (e.g., bladder cancer (e.g., urothelial carcinoma of the bladder) or kidney 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., squamous cell carcinoma of the head and neck), hematological cancer (e.g., leukemia (e.g., acute lymphoblastic leukemia (ALL) (e.g., T-ALL), acute myeloid leukemia (AML) (e.g.) APL, 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., essential myelofibrosis, post-esophageal thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis), or myelodysplastic syndrome (MDS) (e.g., M6-AML or M7-AML), are all types of leukemia. MDS or M7 MDS), lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), squamous cell carcinoma of the lung, or malignant pleural mesothelioma (MPM)), neuroblastoma, sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), or skin cancer (e.g., melanoma or Merkel cell carcinoma).

[0829] 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, post-esophageal thrombocytosis myelofibrosis, or post-polycythemia vera myelofibrosis). In some embodiments, the MPN has a JAK2 mutation (e.g., JAK2 V617F mutation). In some embodiments, the MPN does not have a JAK2 mutation. In some embodiments, the cancer is low-risk myelofibrosis. In some embodiments, the cancer is intermediate-risk (e.g., intermediate-1 and / or intermediate-2) or high-risk myelofibrosis (e.g., primary myelofibrosis, post-esophageal thrombocytosis myelofibrosis, or post-polycythemia vera myelofibrosis). In some implementations, the cancer is an intermediate- or high-risk myelofibrosis (e.g., primary myelofibrosis, post-esophagectomy myelofibrosis, or post-polycythemia vera) with a JAK2 mutation (e.g., JAK2 V617F mutation). In some implementations, the cancer is an intermediate- or high-risk myelofibrosis without a JAK2 V617F mutation (e.g., primary myelofibrosis, post-esophagectomy myelofibrosis, or post-polycythemia vera myelofibrosis). In some implementations, the subject's platelet count is less than 50 × 10⁻⁶. 9 per L.

[0830] In some implementations, the cancer is polycythemia vera. In some implementations, the cancer is polycythemia vera, and the subject does not respond adequately to or is intolerant of hydroxyurea.

[0831] In some implementations, cancer is MDS. In some implementations, cancer is M6 MDS. In some implementations, cancer is M7 MDS.

[0832] In some implementations, the cancer is T-ALL. In other implementations, the cancer is relapsed / refractory T-ALL.

[0833] In some implementations, the cancer is a CRC (e.g., a Braf mutant CRC (e.g., Braf V600E CRC) or a KRas mutant CRC (e.g., KRas G12C CRC or KRas G12D CRC)).

[0834] In some implementations, the cancer is SCLC (e.g., ASCL1 subtype SCLC or NEUROD1 subtype SCLC).

[0835] In some implementations, the cancer is NSCLC (e.g., Braf mutant NSCLC (e.g., Braf V600 ENSCLC), 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 amplification NSCLC), KRas mutant NSCLC (e.g., KRas G12C NSCLC)).

[0836] In some implementations, the cancer is squamous cell carcinoma of the lung.

[0837] In some embodiments, the cancer is a malignant pleural mesothelioma (e.g., BAP1-mutant malignant pleural mesothelioma). In some embodiments, the cancer is a malignant pleural mesothelioma, and the compounds provided herein or their pharmaceutically acceptable salts are administered as a single therapy.

[0838] In some implementations, the cancer is melanoma (e.g., Braf mutant melanoma (e.g., Braf V600E melanoma)).

[0839] In some implementations, 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 positive)).

[0840] In some embodiments, the cancer is lymphoma. In some embodiments, the lymphoma is 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 non-Hodgkin lymphoma (e.g., DLBCL, anaplastic large T-cell lymphoma, cutaneous T-cell lymphoma, or peripheral T-cell lymphoma). In some embodiments, the lymphoma is peripheral T-cell lymphoma.

[0841] In some embodiments, the cancer is leukemia. In some embodiments, the leukemia is T-cell leukemia (e.g., T-cell ALL). In some embodiments, the cancer is post-MPN leukemia. In some embodiments, the cancer is T-cell leukemia (e.g., T-cell ALL), and the compounds provided herein or their pharmaceutically acceptable salts are administered as monotherapy.

[0842] In some embodiments, the cancer is M6-AML. In some embodiments, M6-AML is post-MPN AML. In some embodiments, M6-AML is post-MDS AML. In some embodiments, the cancer is M6-AML, and the compound provided herein or a pharmaceutically acceptable salt thereof is administered as a monotherapy.

[0843] In some embodiments, the cancer is M7-AML. In some embodiments, M7-AML is post-MPN AML. In some embodiments, M7-AML is post-MDS AML. In some embodiments, the cancer is M7-AML, and the compounds provided herein or their pharmaceutically acceptable salts are administered as monotherapy.

[0844] In some implementation schemes, the cancer is head and neck cancer.

[0845] In some implementation schemes, cancer is primary thrombocytosis.

[0846] In some implementations, the cancer is polycythemia vera.

[0847] In some implementations, the cancer is myelofibrosis. In some implementations, the cancer is primary myelofibrosis. In some implementations, the cancer is post-essential thrombocythemia myelofibrosis. In some implementations, the cancer is post-polycythemia vera myelofibrosis.

[0848] In some embodiments, the cancer is an MDS. In some embodiments, the MDS is an M6 MDS. In some embodiments, the MDS is an M7 MDS. In some embodiments, the cancer is an MDS, and the compound provided herein or a pharmaceutically acceptable salt thereof is administered as a monotherapy.

[0849] In some implementation schemes, the cancer is pancreatic cancer.

[0850] In some implementations, the cancer is bladder cancer (e.g., bladder urothelial carcinoma).

[0851] In some implementations, the cancer is ovarian cancer (e.g., BRCA1-mutated ovarian cancer or BRCA2-mutated ovarian cancer). In some implementations, the cancer is HGSOC (e.g., BRCA1-mutated HGSOC or BRCA2-mutated HGSOC).

[0852] In some implementation schemes, the cancer is cervical cancer.

[0853] In some implementation schemes, the cancer is colorectal cancer.

[0854] 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 the compound provided herein or a pharmaceutically acceptable salt thereof is administered as a monotherapy.

[0855] In some implementations, the cancer is neuroblastoma.

[0856] In some implementations, the cancer is intrahepatic bile duct cancer.

[0857] In some implementations, the cancer is a mesenchymal cancer. In other implementations, the mesenchymal cancer is mesenchymal breast cancer or mesenchymal kidney cancer.

[0858] In some implementations, BCL-X L Copy number increase or BCL-X L The amplification can be detected in a sample from the subject (e.g., detecting three or more copies of the BCL2L1 gene in a sample from the subject). In some embodiments, the subject is identified (e.g., identified prior to administration of the compounds provided herein) as having BCL-X. L Copy number increase or BCL-X L Amplified cancer.

[0859] In some implementation schemes, cancer has BCL-X L The number of copies increases.

[0860] In some implementation schemes, cancer has BCL-X L Amplification.

[0861] BCL-X LNon-limiting examples of its relationship with cancer can be found in: Wilson, Wyndham H. et al., The Lancet Oncology 11.12 (2010): 1149-1159, doi: 10.1016 / S1470-2045(10)70261-8; Keitel, Ulrike et al., Oncotarget 5.23 (2014): 11778, doi: 10.18632 / oncotarget.2634; Chonghaile, Triona Ni et al., Cancer Discovery 4.9 (2014): 1074-1087, doi: 10.1158 / 2159-8290.CD-14-0353; Zaanan, Aziz et al., Journal of Biological Chemistry 290.39 (2015): 23838-23849, doi: 10.1074 / jbc.M115.657833; Zhang, Haichao et al. Molecular Cancer 14.1 (2015): 1-9, doi: 10.1186 / s12943-015-0397-y; Soderquist, Ryan S. et al. Nature Communications 9.1 (2018): 1-13, doi: 10.1038 / s41467-018-05815-z; Stover, Elizabeth H. et al. Molecular Cancer Research 17.11(2019): 2281-2293, doi: 10.1158 / 1541-7786.MCR-18-1243; Concoran, RB et al. Annals of Oncology (2019) 30 (suppl_5): v164, doi: 10.1093 / annonc / mdz244.009; Lakhani, Nehal J. et al. Journal of Clinical Oncology (2020): 3509-3509, doi:10.1200 / JCO.2020.38; He, Yonghan et al. Journal of Hematology & Oncology 13.1(2020): 1-13, doi: 10.1186 / s13045-020-00928-9; Grubb, Treg et al. Clinical Cancer Research (2022), doi: 10.1158 / 1078-0432.CCR-22-0669; Joly, Florence et al. Gynecologic Oncology 165.1 (2022): 30-39, doi: 10.1016 / j.ygyno.2022.01.021; and Nanjo, Shigeki et al. The Journal of Clinical Investigation (2022), doi:10.1172 / JCI145099.

[0862] In some implementations, the subject has previously been treated with another anticancer agent, chemotherapy agent, radiation therapy, surgery, multikinase inhibitor, or a combination thereof.

[0863] This article provides a method for treating an ocular disease or condition in a subject requiring such treatment, the method comprising administering (e.g., intravitreal or topical) a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject. In some embodiments, the ocular disease or condition is diabetic macular edema. In some embodiments, the ocular disease or condition is age-related macular degeneration. In some embodiments, the ocular disease or condition is diabetic retinopathy. See, for example, Crespo-Garcia, Sergio et al. Cell Metabolism 33.4 (2021): 818-832, doi: 10.1016 / j.cmet.2021.01.011; Hassan, Jannah Waled and Ashay D. Bhatwadekar, Frontiers in Pharmacology 13 (2022):896907, doi: 10.3389 / fphar.2022.896907.

[0864] This document provides for the use of the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of eye diseases or conditions (e.g., any of the eye diseases or conditions provided herein).

[0865] This document provides for the use of the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as medicines for the treatment of eye diseases or conditions (e.g., any of the eye diseases or conditions provided herein).

[0866] This article provides for the use of the compounds described herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of eye diseases or conditions (e.g., any of the eye diseases or conditions described herein).

[0867] This article also provides the compounds provided herein or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof, which are used as medicines for treating eye diseases or conditions (e.g., any of the eye diseases or conditions provided herein).

[0868] This document provides for the use of compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment of eye diseases or conditions (e.g., any of the eye diseases or conditions provided herein).

[0869] This article also provides a method for treating fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells in a subject requiring such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Non-limiting examples of fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells include pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, lung diseases associated with systemic fibrosis, radiation-associated pulmonary fibrosis), radiation-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, tau proteinosis, progressive supranuclear palsy, and age-related neurodegeneration (e.g., associated with neurovascular coupling injury). See, for example, Zhu, Yi et al., Aging Cell 14.4 (2015): 644-658, doi: 10.1111 / acel.12344; Zhu, Yi et al., Aging Cell 15.3 (2016): 428-435, doi: 10.1111 / acel.12445; Chang, Jianhui et al., Nature Medicine 22.1 (2016): 78-83, doi:10.1038 / nm.4010; Zhu, Yi et al., Aging (Albany NY) 9.3 (2017): 955, doi: 10.18632 / aging.101202; Lagares, David et al., Science Translational Medicine 9.420 (2017):eaal3765, doi: 10.1126 / scitranslmed.aal3765; Pan, Jin et al. International Journal of Radiation Oncology Biology Physics 99.2 (2017): 353-361, doi: 10.1016 / j.ijrobp.2017.02.216; Bussian, Tyler J. et al. Nature 562.7728 (2018): 578-582, doi: 10.1038 / s41586-018-0543-y; Moncsek, Anja et al. Hepatology 67.1 (2018): 247-259, doi: 10.1002 / hep.29464; van Willigenburg, Hester, Peter LJ de Keizer, and Ron WF de Bruin. Pharmacological Research 130 (2018): 322-330, doi: 10.1016 / j.phrs.2018.02.015; Walaszczyk, Anna et al. Aging Cell 18.3 (2019): e12945, doi:10.1111 / acel.12945; Aguayo-Mazzucato, Cristina et al. Cell Metabolism 30.1 (2019):129-142, doi: 10.1016 / j.cmet.2019.05.006; Sessions, Garrett A. et al. The FASEBJournal 33.11 (2019): 12364, doi: 10.1096 / fj.201900815RR; Gerdes, Erin O. Wissler et al. International Review of Neurobiology 155 (2020): 203-234, doi:10.1016 / bs.irn.2020.03.019; Sasaki, Motoko, Yasunori Sato, and YasuniNakanuma. Journal of Autoimmunity 107 (2020): 102377, doi: 10.1016 / j.jaut.2019.102377; Yabluchanskiy, Andriy et al. Geroscience 42 (2020): 409-428, doi: 10.1007 / s11357-020-00154-8; Dookun, Emily et al. Aging Cell 19.10 (2020):e13249, doi: 10.1111 / acel.13249; Jia, Kangni et al. Journal of Cardiovascular Pharmacology 76.4 (2020): 452-460, doi: 10.1097 / FJC.0000000000000878; Sierra-Ramirez, Arantzazu et al. Aging (Albany NY) 12.12 (2020): 11337, doi: 10.18632 / aging.103607; Yang, Hao et al. Aging (Albany NY) 12.13 (2020): 12750, doi:10.18632 / aging.103177; Lawrie, Allan and Sheila E. Francis. The Journal of Clinical Investigation 131.11 (2021): e149721, doi: 10.1172 / JCI149721; Paramos-de-Carvalho, Diogo et al. Cell Reports 36.1 (2021): 109334,doi: 10.1016 / j.celrep.2021.109334;Tarantini, Stefano et al. GeroScience 43.5 (2021): 2427-2440, doi: 10.1007 / s11357-021-00440-z;Park, Ji Hee et al. The British Journal of Dermatology (2022) 186(4):740-742, doi: 10.1111 / bjd.20893;Fielder, Edward et al. ELife 11 (2022): e75492, doi: 10.7554 / eLife.75492;Suzuki, Keiji et al. MutationResearch / Genetic Toxicology and Environmental Mutagenesis 876 (2022): 503448, doi: 10.1016 / j.mrgentox.2022.503448; He, An et al. American Journal of Transplantation 22.11 (2022): 2529-2547, doi: 10.1111 / ajt.17154; Johnson, Laura A. et al. Inflammatory Bowel Diseases 28.2 (2022): 161-175, doi: 10.1093 / ibd / izab166; Miura, Yugo et al. Stem Cell Research & Therapy 13.1 (2022): 222, doi: 10.1186 / s13287-022-02901-4; Cooley, Joseph C. et al. JCI Insight 8.3 (2023):e163762, doi: 10.1172 / jci.insight.163762; Watanabe, Yusuke et al. Hepatology Research 53 (2023): 460-472, doi: 10.1111 / hepr.13879; and Takaya, Kento et al., Rejuvenation Research 26.1 (2023): 9-20, doi: 10.1089 / rej.2022.0048.

[0870] This document provides for the use of the compounds provided herein or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for the treatment of fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells (e.g., any fibrotic disease or condition and / or senescent cell-related disease or condition provided herein).

[0871] This document provides for the use of the compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as a medicament for the treatment of fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells (e.g., any fibrotic disease or condition and / or disease or condition associated with senescent cells provided herein).

[0872] This article provides for the use of the compounds provided herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells (e.g., any fibrotic disease or condition and / or senescent cell-related disease or condition provided herein).

[0873] This article also provides the compounds provided herein or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof, which are used as medicines for treating fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells (e.g., any fibrotic disease or condition and / or disease or condition associated with senescent cells provided herein).

[0874] This document provides for the use of compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment of fibrotic diseases or conditions and / or diseases or conditions associated with senescent cells (e.g., any fibrotic disease or condition and / or senescent cell-related disease or condition provided herein).

[0875] A method for regulating (e.g., reducing) BCL-X in cells is also provided. L A method for protein activity, the method comprising contacting the cell with an effective compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, wherein the method comprises administering to a subject an effective amount of the compound provided herein 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.

[0876] As used herein, the term “contact” means bringing together the indicated portions of an in vitro or in vivo system. For example, “contacting” cells with a compound provided herein includes applying the compound provided herein to cells in vitro or in vivo, including, for example, introducing the compound provided herein into a sample containing cells (e.g., cells grown in a culture or derived from a patient), organoids, or organisms (e.g., animals (e.g., tumor-bearing animals) or humans).

[0877] It also provides a way to regulate (e.g., reduce) BCL-X in cells. L A protein-level method, comprising contacting the cell with a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, BCL-X, compared to cells not contacted with a compound provided herein or a pharmaceutically acceptable salt thereof, [is mentioned]. LThe protein level is reduced by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%). In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, wherein the method includes introducing a protein containing BCL-X... L The subject of the protein-containing cell is administered an effective amount of the compound provided herein 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.

[0878] It also provides a method to induce BCL-X in cells. L A method for protein ubiquitination, comprising contacting the cell with a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, wherein the method comprises introducing a compound containing BCL-X. L The subject of the protein-containing cell is administered an effective amount of the compound provided herein 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.

[0879] It also provides a method for forming BCL-X in cells. L A method for contacting a cell with a ternary complex of a protein, a compound provided herein or a pharmaceutically acceptable salt thereof, and a CRBN protein or a fragment thereof, the method comprising contacting the cell with a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, wherein the method comprises introducing a cell containing BCL-X... L The subject of the protein-containing cell is administered an effective amount of the compound provided herein 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.

[0880] This article also provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound provided herein as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0881] This document further provides a method for increasing cell death in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound provided herein as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. This document also provides a method for increasing tumor cell death in a subject. This method comprises administering to a subject a compound provided herein or a pharmaceutically acceptable salt thereof in an amount that effectively increases tumor cell death.

[0882] When used as a medicine, the compounds provided herein or their pharmaceutically acceptable salts may be administered in the form of pharmaceutical compositions as described herein.

[0883] This article also provides a method for inducing BCL-X in mammalian cells. L A method for protein degradation, comprising contacting mammalian cells with an effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof.

[0884] This article also provides a method for treating a subject with cancer, wherein the method includes:

[0885] A therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof may be administered as a monotherapy or in combination with a first anticancer agent to a subject who has already been given one or more doses of the first anticancer agent.

[0886] This article also provides a method for treating a subject with cancer, wherein the method includes:

[0887] (a) administering one or more doses of a first anticancer agent to the subject; and

[0888] (b) Following (a), administer to the subject a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof as a monotherapy or in combination with a first anticancer agent.

[0889] This article also provides a method for treating a subject with cancer, wherein the method includes:

[0890] (a) administering one or more doses of a first anticancer agent to the subject; and

[0891] (b) Following (a), administer to the subject a therapeutically effective amount of the compound provided herein or a pharmaceutically acceptable salt thereof as a monotherapy or in combination with a second anticancer agent.

[0892] combination

[0893] In any of the indications described herein, the compounds provided herein or their pharmaceutically acceptable salts may be used as monotherapy. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts may be administered prior to the administration of additional therapeutic agents or additional therapies. For example, one or more doses of the compounds provided herein or their pharmaceutically acceptable salts may be administered to a subject in need over a period of time, followed by at least partial resection of the tumor. In some embodiments, treatment with one or more doses of the compounds provided herein or their pharmaceutically acceptable salts may reduce the size of the tumor (e.g., tumor burden) prior to at least partial resection of the tumor.

[0894] In some embodiments, one or more doses of the compound provided herein or a pharmaceutically acceptable salt thereof may be administered to a subject in need over a period of time and after one or more rounds of radiotherapy. In some embodiments, treatment with one or more doses of the compound provided herein or a pharmaceutically acceptable salt thereof to reduce tumor size (e.g., tumor burden) prior to one or more rounds of radiotherapy.

[0895] In some embodiments of any of the methods described herein, the compound provided herein or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or treatments (e.g., chemotherapy).

[0896] Other non-limiting examples of therapies and therapeutic agents include: RAS pathway targeted therapies (e.g., Ras / RAF / MEK / PI3K pathway inhibitors, (e.g., Ras inhibitors (e.g., KRas inhibitors), KRas targeted therapies, SOS1 inhibitors, SOS1 / Ras protein-protein interaction inhibitors, SHP2 inhibitors, PI3K-AKT-mTOR pathway inhibitors)), kinase targeted therapies (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). Formulations (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 with 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, farnesyltransferase 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-targeting agents (including immunomodulatory imide drugs (sometimes referred to as "IMiD" or "CELMoD")), and immunotherapies (e.g., anti-PD1 therapy or anti-PD-L1 therapy) and radiation therapy.

[0897] As used herein, a biosimilar antibody is an antibody or antigen-binding fragment that has the same primary amino acid sequence as a reference antibody and optionally may have detectable differences in post-translational modifications (e.g., glycosylation and / or phosphorylation) compared to the reference antibody (e.g., a different glycoform).

[0898] In some implementations, additional therapies or therapeutic agents include Abl inhibitors (e.g., BCR-Abl inhibitors), ALK inhibitors, AURKA inhibitors, BCL-2 inhibitors, Braf inhibitors, CDK2 inhibitors, CDK4 / 6 inhibitors, CDK7 inhibitors, CDK9 inhibitors, EGFR inhibitors, anti-EGFR antibodies or anti-EGFR antibody-drug conjugates, ERK inhibitors, EZH2 inhibitors, FGFR1 inhibitors, FGFR2 inhibitors, FGFR3 inhibitors, FGFR4 inhibitors, HER2 inhibitors, and anti-HE4 inhibitors. R2 antibodies or anti-HER2 antibody-drug conjugates, JAK inhibitors, KRas inhibitors, MEK inhibitors, MET inhibitors, Hif2α inhibitors, PARP inhibitors, VEGFR inhibitors, LSD1 inhibitors, BET inhibitors, STING agonists, telomerase inhibitors, TORC1 / 2 inhibitors, immunomodulatory imide drugs, immunotherapies (e.g., PD-1 inhibitors (e.g., anti-PD1 therapy), PD-L1 inhibitors (e.g., anti-PD-L1 therapy)), L-asparaginase, chemotherapy, radiotherapy, or combinations thereof.

[0899] In some implementations, additional therapies or therapeutic agents are Abl degraders (e.g., BCR-Abl degraders), ALK degraders, AURKA degraders, BCL-2 degraders, BRaf degraders, CDK2 degraders, CDK4 / 6 degraders, CDK7 degraders, CDK9 degraders, EGFR degraders, ERK degraders, EZH2 degraders, FGFR1 degraders, FGFR2 degraders, FGFR3 degraders, FGFR4 degraders, HER2 degraders, JAK2 degraders, KRas degraders, MEK degraders, MET degraders, Hif2α degraders, PARP degraders, VEGFR degraders, LSD1 degraders, BET degraders, telomerase degraders, TORC1 / 2 degraders, immunomodulatory imide drugs, immunotherapy (e.g., anti-PD1 therapy or anti-PD-L1 therapy), chemotherapy, radiotherapy, or combinations thereof.

[0900] In some implementations, the Abl inhibitor (e.g., a BCR-Abl inhibitor) is aciminib (e.g., aciminib hydrochloride), bafetinib, bosutinib (e.g., bosutinib monohydrate), danusertib, dasatinib (e.g., dasatinib monohydrate), flumatinib (e.g., flumatinib mesylate), or imatinib (e.g., imatinib mesylate). Nilotinib (e.g., nilotinib monochloride hydrate), olverembatinib (e.g., olverembatinib mesylate), ponatinib (e.g., ponatinib hydrochloride), radotinib (e.g., radotinib dihydrochloride), ruserontinib, vandetanib, AN-019, AT-9283, IkT-148009, NPB-001-056, or combinations thereof.

[0901] In some implementations, 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 implementations, 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.

[0902] In some implementations, the AURKA inhibitor is alisertib, danusertib, ilorasertib, tinengotinib, AT-9283, BI-811283, ENMD-2076, or a combination thereof.

[0903] In some implementations, the BCL-2 inhibitor is lisaftoclax, navitoclax, obatoclax, venetoclax, oblimersen (e.g., oblimersen sodium), beclanorsen, AZD-0466, BGB-11417, UBX-1325 (or its phosphate prodrug), UBX-1967 (or its phosphate prodrug), ZN-d5, or a combination thereof.

[0904] In some implementations, the cancer is lung cancer (e.g., SCLC), and the additional therapy or treatment agent is a BCL-2 inhibitor (e.g., lisaftoclax, navittox, obatoclax, venetumola, olimoxone (e.g., olimoxone sodium), becquerelson, AZD-0466, BGB-11417, UBX-1325 (or its phosphate prodrug), UBX-1967 (or its phosphate prodrug), or ZN-d5). In some implementations, the cancer is lung cancer (e.g., SCLC), and the additional therapy or treatment agent is venetumola.

[0905] In some implementations, the cancer is non-Hodgkin's lymphoma, and the additional therapy or treatment agent is a BCL-2 inhibitor (e.g., lisaftoclax, navittox, obatoclax, venetumola, olimoxone (e.g., olimoxone sodium), becquerelson, AZD-0466, BGB-11417, UBX-1325 (or its phosphate prodrug), UBX-1967 (or its phosphate prodrug), or ZN-d5). In some implementations, the cancer is non-Hodgkin's lymphoma, and the additional therapy or treatment agent is venetumola.

[0906] In some implementations, BRaf inhibitors are avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), and encorafenib (e.g., BRAFTOVI). ™ LGX818), naporafenib (LXH254), sorafenib (e.g., sorafenib tosylate), vemurafenib (e.g., ZELBORAF) ®RO5185426), ARQ-736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265 (RAF265), FORE-8394 (PLX-8394), GDC-0879, GDC-5573 (HM95573), HLX-208, PLX-3603, PLX-4720 or combinations thereof.

[0907] In some embodiments, the BRaf V600E mutation can be detected in samples from the subject (e.g., detecting the BRAF gene with a mutation corresponding to the V600E mutation in the BRaf protein and / or detecting the BRaf protein with the V600E mutation). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with the BRaf V600E mutation.

[0908] In some implementations, the cancer is a BRaf-mutant CRC (e.g., BRaf V600E-mutant CRC), and the additional therapy or treatment agent is a BRaf inhibitor (e.g., avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), or caninefenib (e.g., BRAFTOVI). ™ LGX818), Naborafenib (LXH254), Sorafenib (e.g., Sorafenib Tosylate), Vemurafenib (e.g., ZELBORAF) ® The following are listed as potential treatments: 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 implementations, the cancer is a BRaf-mutant CRC (e.g., BRaf V600E-mutant CRC), and the additional therapy or treatment agent is a BRaf inhibitor (e.g., avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), cannefenib (e.g., BRAFTOVI). ™ LGX818), Naborafenib (LXH254), Sorafenib (e.g., Sorafenib Tosylate), Vemurafenib (e.g., ZELBORAF) ®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 anti-EGFR antibodies or anti-EGFR antibody-drug conjugates (e.g., amivantamab) (e.g., amivantamab-vmjw or its biosimilars), cetuximab (e.g., ERBITUX) ® (Cetuximab) or its biosimilars (e.g., CMAB-009, CPGJ-602, or KL-140), sarotalocan (AKALUX) ® (Sacitoximab or its biosimilars), depatuxizumab, duligotuzumab, futuximab, imgatuzumab, modotuximab, necitumumab (e.g., PORTRAZZA) ® (Nexusutuzumab) or its biosimilars), nimotuzumab (e.g., BIOMAbEGFR) ® (nimotuzumab) or its biosimilars), panitumumab (e.g., VECTIBIX) ® (Panitumab or its biosimilar), tomuzotuximab, zalutumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SI-B-001, TAS-0313 or their biosimilars. In some implementations, the cancer is a BRaf-mutant CRC (e.g., BRaf V600E-mutant CRC), and the additional therapy or treatment agent is a BRaf inhibitor (e.g., avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), cannefenib (e.g., BRAFTOVI). ™ LGX818), Naborafenib (LXH254), Sorafenib (e.g., Sorafenib Tosylate), Vemurafenib (e.g., ZELBORAF) ®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., ERBITUX) ® (Cetuximab) or its biosimilars (e.g., CMAB-009, CPGJ-602, or KL-140)). In some implementations, the cancer is a BRaf-mutant CRC (e.g., BRaf V600E-mutant CRC), and the additional therapy or treatment agent is a BRaf inhibitor (e.g., avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), or cannefenib (e.g., BRAFTOVI). ™ LGX818), Naborafenib (LXH254), Sorafenib (e.g., Sorafenib Tosylate), Vemurafenib (e.g., ZELBORAF) ® 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., VECTIBIX) ® (Panitumab) or its biosimilars). In some implementations, the cancer is BRaf-mutant CRC (e.g., BRaf V600E-mutant CRC), and the additional therapy or treatment agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), cannefenib (e.g., BRAFTOVI). ™ LGX818) or vemurafenib (e.g., ZELBORAF) ® RO5185426) and cetuximab (e.g., ERBITUX) ® (Cetuximab) or its biosimilars (e.g., CMAB-009, CPGJ-602, or KL-140). In some implementations, the cancer is a BRaf-mutant CRC (e.g., BRaf V600E-mutant CRC), and the additional therapy or treatment agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) or cannefenib (e.g., BRAFTOVI). ™ LGX818) or vemurafenib (e.g., ZELBORAF)® RO5185426) and panitumumab (e.g., VECTIBIX) ® (Panitumab or its biosimilar). In some implementations, the cancer is BRaf-mutant CRC (e.g., BRaf V600E-mutant CRC), and the additional therapy or treatment agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and cetuximab (e.g., ERBITUX). ® (Cetuximab) or its biosimilars (e.g., CMAB-009, CPGJ-602, or KL-140)). In some implementations, the cancer is BRaf-mutant CRC (e.g., BRaf V600E-mutant CRC), and the additional therapy or treatment agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and panitumumab (e.g., VECTIBIX). ® (panitumab) or its biosimilars).

[0909] In some implementations, the cancer is BRaf-mutant NSCLC (e.g., BRaf V600E-mutant NSCLC), and the additional therapy or treatment agent is a BRaf inhibitor (e.g., avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), or caninefenib (e.g., BRAFTOVI). ™ LGX818), Naborafenib (LXH254), Sorafenib (e.g., Sorafenib Tosylate), Vemurafenib (e.g., ZELBORAF) ®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., avotometinib, binimetinib, cobimetinib) Tinib (e.g., cobimetinib fumarate), mirdametinib, pimaertib, refametinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide), zapnometinib, FCN-159, GSK-1120212, NFX-179, or TAK-733. In some implementations, the cancer is BRaf-mutant NSCLC (e.g., BRaf V600E-mutant NSCLC), and the additional therapy or treatment agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), cannefenib (e.g., BRAFTOVI). ™ LGX818) or vemurafenib (e.g., ZELBORAF) ® The treatment options include BRaflinib (e.g., BRaflinib fumarate), selumetinib (e.g., selumetinib sulfate), or trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is BRaf-mutated NSCLC (e.g., BRaf V600E-mutated NSCLC), and the additional therapy or treatment agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is BRaf-mutated NSCLC (e.g., BRaf V600E-mutated NSCLC), and the additional therapy or treatment agent is vemurafenib (e.g., ZELBORAF). ® RO5185426) and cobimetinib (e.g., cobimetinib fumarate). In some implementations, the cancer is BRaf-mutant NSCLC (e.g., BRaf V600E-mutant NSCLC), and the additional therapy or treatment agent is cannefenib (e.g., BRAFTOVI). ™ (LGX818) and Bimetinib.

[0910] In some implementations, the cancer is BRaf-mutant melanoma (e.g., BRaf V600E-mutant melanoma), and the additional therapy or treatment agent is a BRaf inhibitor (e.g., avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), or caninefenib (e.g., BRAFTOVI). ™ LGX818), Naborafenib (LXH254), Sorafenib (e.g., Sorafenib Tosylate), Vemurafenib (e.g., ZELBORAF) ® The following are listed as potential treatments: 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 implementations, the cancer is BRaf-mutant melanoma (e.g., BRaf V600E-mutant melanoma), and the additional therapy or treatment agent is a BRaf inhibitor (e.g., avotometinib (RO5126766), dabrafenib (e.g., dabrafenib mesylate, GSK2118436), cannefenib (e.g., BRAFTOVI). ™ LGX818), Naborafenib (LXH254), Sorafenib (e.g., Sorafenib Tosylate), Vemurafenib (e.g., ZELBORAF) ®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., avotometinib, binimetinib, cobimetinib) Tinib (e.g., cobimetinib fumarate), mirdametinib, pimaertib, refametinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide), zapnometinib, FCN-159, GSK-1120212, NFX-179, or TAK-733. In some implementations, the cancer is BRaf-mutant melanoma (e.g., BRaf V600E-mutant melanoma), and the additional therapy or treatment agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436), cannefenib (e.g., BRAFTOVI). ™ LGX818) or vemurafenib (e.g., ZELBORAF) ® The treatment options include BRaflinib (e.g., BRaflinib fumarate), cobimetinib (e.g., selmetinib sulfate), or trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is BRaf-mutant melanoma (e.g., BRaf V600E-mutant melanoma), and the additional therapy or treatment agent is dabrafenib (e.g., dabrafenib mesylate, GSK2118436) and trametinib (e.g., trametinib dimethyl sulfoxide). In some embodiments, the cancer is BRaf-mutant melanoma (e.g., BRaf V600E-mutant melanoma), and the additional therapy or treatment agent is vemurafenib (e.g., ZELBORAF). ® RO5185426) and cobimetinib (e.g., cobimetinib fumarate). In some implementations, the cancer is BRaf-mutant melanoma (e.g., BRaf V600E-mutant melanoma), and the additional therapy or treatment agent is cannefenib (e.g., BRAFTOVI). ™ (LGX818) and bimetinib. In some such implementations, the subject has previously been treated with immunotherapy.

[0911] In some implementations, the CDK2 inhibitor is ebvaciclib, fadraciclib, milciclib, pacritinib (e.g., pacritinib citrate), roniciclib, roscovitine, BLU-222, NUV-422, PF-07104091, TQB-3616, or a combination thereof.

[0912] In some implementations, 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 combinations thereof.

[0913] In some implementations, the CDK7 inhibitor is mircili, roscovitine, samuraciclib, or a combination thereof.

[0914] In some implementations, the CDK9 inhibitor is fadraciclib, rivicil, roniciclib, roscovitine, zotiraciclib, AZD-4573, KB-0742, or a combination thereof.

[0915] In some implementations, the EGFR inhibitors are abivertinib, afatinib (e.g., afatinib dimaleate), alflutinib (e.g., alflutinib mesylate), almonertinib (e.g., almonertinib mesylate), befotertinib, brigatinib, canertinib, dacomitinib (e.g., dacomitinib monohydrate), dovitinib, erlotinib (e.g., erlotinib hydrochloride), gefitinib, icotinib, lapatinib (e.g., lapatinib dimethylbenzenesulfonate monohydrate), larotinib, lazertinib, limertinib, and moboccinib. nertinib (e.g., mobocetinib 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, anti-EGFR antibody or anti-EGFR antibody-drug conjugate or combination thereof.

[0916] In some implementations, the anti-EGFR antibody or anti-EGFR antibody-drug conjugate is ervantamab (e.g., amivantamab-vmjw or its biosimilar), cetuximab (e.g., ERBITUX), or other similar antibodies. ® (Cetuximab) or its biosimilars (e.g., CMAB-009, CPGJ-602, or KL-140), sacetuximab (AKALUX) ®(Sacitocilizumab or its biosimilars), Depertuzumab, Dugoutuzumab, Votocilizumab, Ingatocilizumab, Zartuximab, Nexitocilizumab (e.g., Portrazza) ® (Nexusutuzumab) or its biosimilars), nimotuzumab (e.g., BIOMAb EGFR) ® (nimotuzumab) or its biosimilars), panitumumab (e.g., VECTIBIX) ® (Panitumab) or its biosimilars), toltuximab, zalumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SI-B-001, TAS-0313, their biosimilars, or combinations thereof. In some embodiments, the anti-EGFR antibody or anti-EGFR antibody-drug conjugate is emivantamab (e.g., amivantamab-vmjw or its biosimilar), cetuximab (e.g., ERBITUX), or a combination thereof. ® (Cetuximab) or its biosimilars (e.g., CMAB-009, CPGJ-602, or KL-140), sacetuximab (AKALUX) ® (Sacitocilizumab or its biosimilars), Depertuzumab, Dugoutuzumab, Votocilizumab, Ingatocilizumab, Zartuximab, Nexitocilizumab (e.g., Portrazza) ® (Nexusutuzumab) or its biosimilars), nimotuzumab (e.g., BIOMAb EGFR) ® (nimotuzumab) or its biosimilars), panitumumab (e.g., VECTIBIX) ® (panitumumab) or its biosimilars), toltuximab, zalumumab, EMD-55900, EMD-82633, GC-1118, HLX-07, ICR-62, SCT-200, SI-B-001, their biosimilars or combinations thereof.

[0917] In some embodiments, EGFR mutations (e.g., EGFR exon 19 deletion or EGFR L858R mutation (with or without EGFR T790M mutation)) can be detected in samples from the subject (e.g., detecting mutations in mutated EGFR genes (e.g., those corresponding to EGFR exon 19 deletion or EGFR L858R mutation (with or without EGFR T790M mutation) in the EGFR protein) and / or detecting mutated EGFR proteins (e.g., EGFR exon 19 deletion or EGFR L858R mutation (with or without EGFR T790M mutation))). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with an EGFR mutation (e.g., EGFR exon 19 deletion or EGFR L858R mutation (with or without EGFR T790M mutation)).

[0918] In some implementations, the cancer is EGFR-mutant NSCLC (e.g., EGFR exon 19 deletion NSCLC or EGFR L858R (with or without T790M) mutant NCLC), and the additional therapy or treatment agent is an EGFR inhibitor (e.g., avitinib, afatinib (e.g., afatinib dimaleate), aflutinib (e.g., aflutinib mesylate), amitinib (e.g., amitinib mesylate), befotinib, brigatinib, canatinib, dacomitinib (e.g., dacomitinib monohydrate), dovirtinib, erlotinib (e.g., erlotinib hydrochloride), gefitinib, icotinib, lapatinib (e.g., lapatinib dimethylbenzenesulfate monohydrate), larotrectinib, lazazetinib, ... Rimotinib, Mobocetinib (e.g., Mobocetinib succinate), Nazartinib, Lenatinib (e.g., Lenatinib maleate), Omotinib, Osimertinib (e.g., Osimertinib mesylate), Peritinib, Poziotinib, Pyrotinib (e.g., Pyrotinib maleate), Roxetinib (SKLB-1028), Saptinib, Suvortinib, Tervatinib, Vandetanib, Vanitinib, Zoritinib, BIBW-2948, BPI-7711, HA-121-28, SH-1028, or anti-EGFR antibodies or anti-EGFR antibody-drug conjugates. In some implementations, the cancer is EGFR-mutant NSCLC (e.g., EGFR exon 19 deletion NSCLC or EGFR L858R (with or without T790M) mutant NCLC), and the additional therapy or treatment agent is osimertinib (e.g., osimertinib mesylate).

[0919] In some implementations, the ERK inhibitor is rineterkib, temuterkib, unitinib, ASN-0007, ASTX-029, ATG-017, BPI-27336, HH-2710, JSI-1187, MK-8353, or a combination thereof.

[0920] In some implementations, the EZH2 inhibitor is lirametostat, tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, PF-6821497, SHR-2554, XNW-5004, or a combination thereof. In some implementations, the EZH2 inhibitor also inhibits EZH1 (also known as an EZH1 / 2 inhibitor).

[0921] In some implementations, the cancer is peripheral T-cell lymphoma, and the additional therapy or treatment agent is an EZH2 inhibitor (e.g., lirametostat, tazestat (e.g., tazestat hydrobromide), valmettostat (e.g., valmettostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, PF-6821497, SHR-2554, or XNW-5004).

[0922] In some implementations, the FGFR1 inhibitor is daruseti, dovirtinib, erdafitinib, futibatinib, infigratinib (e.g., infigratinib phosphate), lenvatinib (e.g., lenvatinib mesylate), lucitinib, nintedanib (e.g., nintedanib ethoxylate), pemigatinib, surufatinib, tasurgratinib, tinengotinib, zoligratinib, FH-2001, HMPL-453, LY-2874455, or combinations thereof.

[0923] In some implementations, the FGFR2 inhibitor is erdatinib, fabatinib, infuratinib (e.g., infuratinib phosphate), deritinib, pemitinib, tasugtinib, zoletinib, bematuzumab (or their biosimilars), FH-2001, HMPL-453, LY-2874455, or a combination thereof.

[0924] In some implementations, the FGFR3 inhibitor is dovirtinib, erdatinib, fubatinib, infuratinib (e.g., infuratinib phosphate), deritinib, masitinib, nintedanib, pemitinib, tasugtinib, zoletinib, vofatamab (or their biosimilars), EXEL-0999, FH-2001, HMPL-453, LY-2874455, or a combination thereof.

[0925] In some implementations, the FGFR4 inhibitor is axitinib, erdatinib, fubatinib, inphenigranilinib (e.g., inphenigranilinib phosphate), irpagratinib, nintedanib, pemitinib, FH-2001, H3B-6527, LY-2874455, or a combination thereof.

[0926] In some implementations, the HER2 inhibitor is afatinib (e.g., afatinib dimaleate), dacomitinib (e.g., dacomitinib monohydrate), lapatinib (e.g., lapatinib dibenzylsulfonate monohydrate), mobocetinib (e.g., mobocetinib succinate), neratinib (e.g., neratinib maleate), poziotinib, pyrotinib (e.g., pyrotinib maleate), suvortinib, tervatinib, tucatinib, vanitinib, an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate, or a combination thereof.

[0927] In some implementations, the anti-HER2 antibody or anti-HER2 antibody-drug conjugate is anbenitamab, cinrebafusp alfa, coprelotamab, disitamab vedotin, ertumaxomab, gancotamab, inetetamab, margetuximab (e.g., margetuximab-cmkb or its biosimilar), or pertuzumab (e.g., PERJETA). ® (pertuzumab) or its biosimilars (e.g., HLX-11), trastuzumab (e.g., HERCEPTIN)® (trastuzumab) or its biosimilars (e.g., Faceptor) ® (trastuzumab), HERTICAD ® (Trastuzumab), TUZNUE ® (Trastuzumab), ZERCEPAC ® Trastuzumab (trastuzumab-ANNS, trastuzumab-DKST, trastuzumab-DTTB, trastuzumab-PKRB, trastuzumab-QYYP, EG-12014 or TX-05), trastuzumab (e.g., fam-trastuzumab deruxtecan-NXKI or its biosimilars), trastuzumab duocarmazine, trastuzumab emtansine (e.g., KADCYLA) ® Trastuzumab emtansine or its biosimilars (e.g., UJVIRA) ® Trastuzumab emtansine (TEM), trastuzumab hyaluronidase (e.g., trastuzumab hyaluronidase-oysk or its biosimilars), zanidatamab, zenocutuzumab, AVX-901, IDM-1, TPIV-100, TAA-013, SHR-A1811, BAT-8001, MDX-210, Alpha-Her2-pAF1-AS-269, MRG-002, DF-1001, AC-101, MM-111, their biosimilars, or combinations thereof. In some implementations, the anti-HER2 antibody or anti-HER2 antibody-drug conjugate is anbenitamab, cinrebafusp alfa, coprelotamab, disitamab vedotin, ertumaxomab, gancotamab, inetetamab, margetuximab (e.g., margetuximab-cmkb or its biosimilar), or pertuzumab (e.g., PERJETA). ® (pertuzumab) or its biosimilars (e.g., HLX-11), trastuzumab (e.g., HERCEPTIN) ® (trastuzumab) or its biosimilars (e.g., Faceptor) ® (trastuzumab), HERTICAD® (Trastuzumab), TUZNUE ® (Trastuzumab), ZERCEPAC ® Trastuzumab (trastuzumab-ANNS, trastuzumab-DKST, trastuzumab-DTTB, trastuzumab-PKRB, trastuzumab-QYYP, EG-12014 or TX-05), trastuzumab (e.g., fam-trastuzumab deruxtecan-NXKI or its biosimilars), trastuzumab duocarmazine, trastuzumab emtansine (e.g., KADCYLA) ® Trastuzumab emtansine or its biosimilars (e.g., UJVIRA) ® Trastuzumab emtansine (TEM), trastuzumab hyaluronidase (e.g., trastuzumab hyaluronidase-oysk or its biosimilars), zanidatamab, zenocutuzumab, TAA-013, SHR-A1811, BAT-8001, MDX-210, Alpha-Her2-pAF1-AS-269, MRG-002, DF-1001, AC-101, MM-111, their biosimilars, or combinations thereof.

[0928] In some embodiments, the HER2+ status can be detected in samples from the subject (e.g., by immunohistochemistry (IHC) and / or fluorescence in situ hybridization (FISH)). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with a HER2+ status.

[0929] In some embodiments, the low HER2 status can be detected in samples from the subject (e.g., by IHC and / or FISH). In some embodiments, the subject is identified (e.g., prior to administration of the compounds provided herein) as having cancer with a low HER2 status.

[0930] In some embodiments, HER2-status can be detected in samples from the subject (e.g., by IHC and / or FISH). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with a HER2-status.

[0931] In some embodiments, ER expression status can be detected in samples from the subject (e.g., by IHC and / or FISH). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with ER expression. In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer without ER expression.

[0932] In some embodiments, PR expression status can be detected in samples from the subject (e.g., by IHC and / or FISH). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with PR expression. In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer without PR expression.

[0933] In some implementations, the cancer is HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is a HER2 inhibitor (e.g., afatinib (e.g., afatinib dimaleate), dacomitinib (e.g., dacomitinib monohydrate), lapatinib (e.g., lapatinib dimethylbenzenesulfonate monohydrate), mobocetinib (e.g., mobocetinib succinate), neratinib (e.g., neratinib maleate), poziotinib, pyrotinib (e.g., pyrotinib maleate), suvortinib, tervatinib, tucatinib, vanitinib, or an anti-HER2 antibody or anti-HER2 antibody-drug conjugate). In some implementations, the cancer is HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is tucatinib. In some implementations, the cancer is HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate (e.g., anbenitamab, cinrebafusp alfa, culotuzumab, vedicetuzumab, ertuxomab, gantuzumab, inetuzumab, magruciximab (e.g., margetuximab-cmkb or its biosimilar), pertuzumab (e.g., PERJETA) ® (pertuzumab) or its biosimilars (e.g., HLX-11), trastuzumab (e.g., HERCEPTIN) ® (trastuzumab) or its biosimilars (e.g., Faceptor) ® (trastuzumab), HERTICAD ® (Trastuzumab), TUZNUE® (Trastuzumab), ZERCEPAC ® Trastuzumab (trastuzumab-ANNS, trastuzumab-DKST, trastuzumab-DTTB, trastuzumab-PKRB, trastuzumab-QYYP, EG-12014 or TX-05), trastuzumab deruxtecan-nxki (e.g., fam-trastuzumab deruxtecan-nxki or its biosimilars), trastuzumab duocarmazine, trastuzumab emtansine (e.g., KADCYLA) ® Trastuzumab emtansine or its biosimilars (e.g., UJVIRA) ® Trastuzumab emtansine (Trastuzumab hyaluronidase) (e.g., trastuzumab hyaluronidase-oysk or its biosimilar), zineb, zanubrutinib, AVX-901, IDM-1, TPIV-100, TAA-013, SHR-A1811, BAT-8001, MDX-210, Alpha-Her2-pAF1-AS-269, MRG-002, DF-1001, AC-101, MM-111 or their biosimilars). In some implementations, the cancer is HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is trastuzumab (e.g., HERCEPTIN). ® (trastuzumab) or its biosimilars (e.g., Faceptor) ® (trastuzumab), HERTICAD ® (Trastuzumab), TUZNUE ® (Trastuzumab), ZERCEPAC ®(Trastuzumab), trastuzumab-ANNS, trastuzumab-DKST, trastuzumab-DTTTB, trastuzumab-PKRB, trastuzumab-QYYP, EG-12014, or TX-05). In some embodiments, the cancer is HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is trastuzumab deruxtecan-nxki (e.g., fam-trastuzumab deruxtecan-nxki or its biosimilar). In some embodiments, the cancer is HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy is trastuzumab emtansine or its biosimilar. In some embodiments, the cancer is HER2-low breast cancer, and the additional therapy is an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate. In some implementations, the cancer is HER2-low breast cancer, and the additional treatment is trastuzumab (e.g., fam-trastuzumab deruxtecan-nxki or its biosimilar).

[0934] In some implementations, JAK inhibitors are adelatinib, baricitinib, brepocitinib, deuruxolitinib, fedratinib (e.g., fedratinib dihydrochloride monohydrate), filgotinib (e.g., filgotinib maleate), gandotinib, gusacitinib, ilginatinib, izencitinib, and jaktinib. The JAK inhibitors are finitib, momelotinib (e.g., momelotinib dihydrochloride), nezulcitinib, pacritinib (e.g., pacritinib citrate), peficitinib (e.g., peficitinib hydrobromide), ropsacitinib, ruxolitinib (e.g., ruxolitinib phosphate), tasocitinib (e.g., tofacitinib citrate), AT-9283, TQ-05105, or combinations thereof. In some embodiments, the JAK inhibitor is finitib (e.g., finitib dihydrochloride monohydrate), momelotinib (e.g., momelotinib dihydrochloride), palitinib (e.g., palitinib citrate), ruxolitinib (e.g., ruxolitinib hydrochloride monohydrate), or combinations thereof. In some embodiments, the JAK inhibitor is finitib (e.g., finitib dihydrochloride monohydrate). In some embodiments, the JAK inhibitor is momellotinib (e.g., momellotinib dihydrochloride). In some embodiments, the JAK inhibitor is palitinib (e.g., palitinib citrate). In some embodiments, the JAK inhibitor is ruxolitinib (e.g., ruxolitinib phosphate).

[0935] In some embodiments, the JAK V617F mutation can be detected in a sample from the subject (e.g., detecting the JAK2 gene with a mutation corresponding to the V617F mutation in the JAK2 protein and / or detecting the JAK2 protein with the V617F mutation). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with the JAK2 V617F mutation. In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer lacking the JAK2 V617F mutation.

[0936] In some implementations, the cancer is post-MPN AML, M6-AML, or M7-AML, and the additional therapy or treatment agent is a JAK inhibitor (e.g., ruxolitinib (e.g., ruxolitinib phosphate), fendatinib (e.g., fendatinib dihydrochloride monohydrate), momelotinib (e.g., momelotinib dihydrochloride), or palitinib (e.g., palitinib citrate)). In some implementations, the patient has received a prior line of treatment containing a JAK inhibitor. In some implementations, the patient has not received a prior line of treatment containing a JAK inhibitor.

[0937] In some implementations, the cancer is intermediate-risk (e.g., intermediate-risk-1 and / or intermediate-risk-2) or high-risk myelofibrosis (e.g., primary myelofibrosis, post-esophagectomy myelofibrosis, or post-polycythemia vera myelofibrosis), and the additional therapy or treatment agent is a JAK inhibitor (e.g., ruxolitinib (e.g., ruxolitinib phosphate), fendatinib (e.g., fendatinib dihydrochloride monohydrate), momelotinib (e.g., momelotinib dihydrochloride), or palitinib (e.g., palitinib citrate)). In some implementations, the cancer is intermediate-risk (e.g., intermediate-risk-1 and / or intermediate-risk-2) or high-risk myelofibrosis (e.g., primary myelofibrosis, post-esophagectomy myelofibrosis, or post-polycythemia vera myelofibrosis), and the additional therapy or treatment agent is a JAK inhibitor (e.g., ruxolitinib (e.g., ruxolitinib phosphate), fendatinib (e.g., fendatinib dihydrochloride monohydrate), momerlotinib (e.g., momerlotinib dihydrochloride), or palitinib (e.g., palitinib citrate)) and a BET inhibitor (e.g., arobuxe, apatalone, mivebuxe, pelabresib, trotabresib, ABBV-744, BI-2536, BMS-986158, INCB-057643, JAB-8263, ODM-207, PLX-2853, or ZEN-003694). In some implementations, the cancer is intermediate-risk (e.g., intermediate-risk-1 and / or intermediate-risk-2) or high-risk myelofibrosis (e.g., primary myelofibrosis, post-esophagectomy myelofibrosis, or post-polycythemia vera myelofibrosis) with a JAK2 mutation (e.g., JAK2 V617F mutation), and the additional therapy or treatment agent is a JAK inhibitor (e.g., ruxolitinib (e.g., ruxolitinib phosphate), fendatinib (e.g., fendatinib dihydrochloride monohydrate), momellotinib (e.g., momellotinib dihydrochloride), or palitinib (e.g., palitinib citrate)).In some implementations, the cancer is characterized by a JAK2 mutation (e.g., JAK2). The patient is at intermediate risk (e.g., intermediate risk-1 and / or intermediate risk-2) or high risk of myelofibrosis (e.g., primary myelofibrosis, post-esophagectomy myelofibrosis, or post-polycythemia vera myelofibrosis) and the additional therapy or treatment agent is a JAK inhibitor (e.g., ruxolitinib (e.g., ruxolitinib phosphate), fendatinib (e.g., fendatinib dihydrochloride monohydrate), momerlotinib (e.g., momerlotinib dihydrochloride), or palitinib (e.g., palitinib citrate)) and a BET inhibitor (e.g., arobuxe, apatalone, mivebuxe, pelabresib, trotabresib, ABBV-744, BI-2536, BMS-986158, INCB-057643, JAB-8263, ODM-207, PLX-2853, or ZEN-003694). In some embodiments, the JAK inhibitor is fadatinib (e.g., fadatinib dihydrochloride monohydrate). In some embodiments, the JAK inhibitor is momellotinib (e.g., momellotinib dihydrochloride). In some embodiments, the JAK inhibitor is palitinib (e.g., palitinib citrate). In some embodiments, the JAK inhibitor is ruxolitinib (e.g., ruxolitinib phosphate). In some embodiments, the patient has received a prior line of treatment containing a JAK inhibitor. In some embodiments, the patient has not received a prior line of treatment containing a JAK inhibitor. In some embodiments, treatment efficacy can be measured by a reduction in spleen volume (e.g., a spleen volume reduction greater than or equal to 35% (SVR)). 35 (e.g., measured by MRI or CT), total symptom score (e.g., a reduction in total symptom score greater than or equal to 50% (TSS) 50 (e.g., measured using the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0) or both, for example, measured 24 weeks after the start of treatment; see, for example, Harrison, Claire et al., New England Journal of Medicine 366.9 (2012): 787-798, doi: 10.1056 / NEJMoa1110556; and Verstovsek, Srdan et al., New England Journal of Medicine 366.9 (2012): 799-807, doi: 10.1056 / NEJMoa1110557. In some implementations, treatment efficacy can be measured by indicators such as SVR. 35 and / or TSS 50Supplements or alternatives to: anemia response (e.g., measured by the current International Working Group-Myeloproliferative Biota Study and European LeukemiaNet (IWG-MRT / ELN) criteria), myelofibrosis (e.g., measured by bone marrow biopsy according to the European Consensus Grading System, e.g., measured at 24 or 96 weeks after the start of treatment), variant allele score (e.g., JAK2 V617F variant allele score), transfusion independence, overall survival, leukemia-free survival, changes in physical function (e.g., measured by the European Organisation for Research and Treatment of Cancer (EORTC) Physical Function Domain Quality of Life Questionnaire (QLQ)-C30 or death), changes in fatigue (e.g., assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue SF 7a), or a combination thereof.

[0938] In some implementations, the KRas inhibitor is adagrasib, divarasib (GDC-6036), sotorarasib, ARS-1620, ARS-3248, ARS-853, ASP-3082, ATG-012, BI-1701963, BI-1823911, BPI-421286, D-1553, ERAS-3490, GFH-925, JAB-21822, JDQ-443, LY-3537982, MRTX-1133, MRTX-1257, RMC-6236, RMC-6291, RSC-1255, or combinations thereof. Other KRas inhibitors are disclosed, for example, in International Publication Nos. WO 2024 / 040131 and WO 2024 / 112654.

[0939] In some embodiments, KRas mutations (e.g., KRas G12C mutations or KRas G12D mutations) can be detected in samples from the subject (e.g., detecting the KRAS gene with mutations corresponding to G12C or G12D mutations in the KRas protein and / or detecting the KRas protein with G12C or G12D mutations). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with a KRas G12C mutation. In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with a KRas G12D mutation.

[0940] In some implementations, the cancer is KRas-mutant lung cancer (e.g., KRas-mutant NSCLC), KRas-mutant CRC, or KRas-mutant pancreatic cancer, and the additional therapy or treatment agent is a KRas inhibitor (e.g., adagrasib, divarasib (GDC-6036), sotorasib, ARS-1620, ARS-3248, ARS-853, ASP-3082, ATG-012, BI-1701963, BI-1823911, BPI-421286, D-1553, ERAS-3490, GFH-925, JAB-21822, JDQ-443, LY-3537982, MRTX-1133, MRTX-1257, RMC-6236, RMC-6291, or RSC-1255). In some embodiments, the cancer is KRas-mutant lung cancer (e.g., KRas-mutant NSCLC (e.g., KRasG12C-mutant NSCLC)), KRas-mutant CRC (e.g., KRas G12C-mutant CRC), or KRas-mutant pancreatic cancer (e.g., KRas G12C-mutant pancreatic cancer), and the additional therapy or therapeutic agent is adagrasib. In some embodiments, the cancer is KRas-mutant lung cancer (e.g., KRas-mutant NSCLC (e.g., KRas G12C-mutant NSCLC)), KRas-mutant CRC (e.g., KRas G12C-mutant CRC), or KRas-mutant pancreatic cancer (e.g., KRas G12C-mutant pancreatic cancer), and the additional therapy or therapeutic agent is divarasib. In some embodiments, the cancer is KRas-mutant lung cancer (e.g., KRas-mutant NSCLC (e.g., KRas G12C-mutant NSCLC)), KRas-mutant CRC (e.g., KRas G12C-mutant CRC), or KRas-mutant pancreatic cancer (e.g., KRas G12C-mutant pancreatic cancer), and the additional therapy or therapeutic agent is sotorazib. In some embodiments, the cancer is KRas-mutant lung cancer (e.g., KRas-mutant NSCLC (e.g., KRas G12D-mutant NSCLC)), KRas-mutant CRC (e.g., KRas G12D-mutant CRC), or KRas-mutant pancreatic cancer (e.g., KRas G12D-mutant pancreatic cancer), and the additional therapy or therapeutic agent is MRTX1133.

[0941] In some implementations, the MEK inhibitor is avotometinib, bimetinib, cobimetinib (e.g., cobimetinib fumarate), midametinib, pimasateti, refatinib, selmetinib (e.g., selmetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide), zapnometinib, FCN-159, GSK-1120212, NFX-179, TAK-733, or combinations thereof.

[0942] In some embodiments, BRCA1 mutations can be detected in samples from the subject (e.g., detecting the mutated BRCA1 gene and / or detecting the mutated BRCA1 protein). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with a BRCA1 mutation.

[0943] In some embodiments, BRCA2 mutations can be detected in samples from the subject (e.g., detecting the mutated BRCA2 gene and / or detecting the mutated BRCA2 protein). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with a BRCA2 mutation.

[0944] In some implementations, the cancer is ovarian cancer (e.g., BRCA1-mutated or BRCA2-mutated ovarian cancer, HGSOC (e.g., BRCA1-mutated or BRCA2-mutated HGSOC), or LGSOC), and the additional therapy or treatment agent is a MEK inhibitor (e.g., bimetinib, cobimetinib, selumetinib, or trametinib). In some implementations, the cancer is BRCA1-mutated ovarian cancer, and the additional therapy or treatment agent is a MEK inhibitor (e.g., bimetinib, cobimetinib, selumetinib, or trametinib). In some implementations, the cancer is BRCA2-mutated ovarian cancer, and the additional therapy or treatment agent is a MEK inhibitor (e.g., bimetinib, cobimetinib, selumetinib, or trametinib). In some implementations, the cancer is HGSOC (e.g., BRCA1-mutated HGSOC or BRCA2-mutated HGSOC), and the additional therapy or treatment agent is a MEK inhibitor (e.g., bimetinib, cobimetinib, selumetinib, or trametinib). In some implementations, the cancer is LGSOC (e.g., BRCA1-mutated HGSOC or BRCA2-mutated HGSOC), and the additional therapy or treatment agent is a MEK inhibitor (e.g., bimetinib, cobimetinib, selumetinib, or trametinib).

[0945] In some implementations, the cancer is a KRas-mutant CRC (e.g., KRas G12C-mutant NSCLC), and the additional therapy or treatment agent is a MEK inhibitor (e.g., bimetinib, cobimetinib, selmetinib, or trametinib).

[0946] In some implementations, the MET inhibitor is cabozantinib (e.g., cabozantinib S-malate), capmatinib (e.g., capmatinib hydrochloride), crizotinib, foritinib, glesatinib, gumarontinib, merestinib, pamufetinib, savolitinib, sitravatinib, tepotinib (e.g., tepotinib hydrochloride hydrate), vebreltinib, zanzalintinib (XL-092), emivantamab (e.g., amivantamab-vmjw or its biosimilar), imatozumab (or its biosimilar), RC-108, telisotuzumab. Vedotin (or its biosimilar), ABBV-400, ABN-401, AL-2846, AMG-337, SAR-125844, TQ-B-3139, or combinations thereof.

[0947] In some embodiments, MET alterations can be detected in samples from the subject (e.g., detecting an altered MET gene (e.g., gene amplification or exon 14 skipping) and / or detecting a mutated MET protein (e.g., exon 14 skipping)). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has cancer with MET alterations.

[0948] In some implementations, the cancer is MET-altered NCLC (e.g., MET-amplified NSCLC or MET exon 14 skipping NSCLC), and the additional therapy or treatment agent is a MET inhibitor (e.g., cabozantinib (e.g., cabozantinib S-malate), cabmatinib (e.g., cabmatinib hydrochloride), crizotinib, fulexinib, glibenclamide, gumetinib, mesatinib, pefitinib, cevotinib, terpoxtinib (e.g., terpoxtinib hydrochloride hydrate), veripitinib, zazalintinib (XL-092), ervantomab (e.g., amivantamab-vmjw or its biosimilar), imatozumab (or its biosimilar), RC-108, telisotuzumab). Vedotin (or its biosimilar), ABBV-400, ABN-401, AL-2846, AMG-337, SAR-125844, or TQ-B-3139. In some embodiments, the cancer is MET-altered NCLC (e.g., MET-amplified NSCLC or MET exon 14 skipping NSCLC), and the additional therapy or therapeutic agent is cabmatinib (e.g., cabmatinib hydrochloride) or terpoxtinib (e.g., terpoxtinib hydrochloride hydrate). In some embodiments, the cancer is MET-altered NCLC (e.g., MET-amplified NSCLC or MET exon 14 skipping NSCLC), and the additional therapy or therapeutic agent is telisotuzumab vedotin (or its biosimilar).

[0949] In some implementations, the Hif2α inhibitor is belzutifan, AB-521, DFF-332, NKT-2152, PT-2399, or a combination thereof.

[0950] In some embodiments, the PARP inhibitor is fuzuloparib, niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camphorsulfonate), saraparib (AZD5305), senaparib, stenoparib, talazoparib (e.g., talazoparib tosylate), veliparib, CEP-9722, JPI-289, NMS-03305293, or a combination thereof. In some embodiments, the PARP inhibitor is a PARP1 inhibitor. In some embodiments, the PARP1 inhibitor is saraparib (AZD5305), NMS-03305293, or a combination thereof.

[0951] In some implementations, the cancer is BRCA1-mutated breast cancer or BRCA2-mutated breast cancer, and the additional therapy or treatment agent is a PARP inhibitor (e.g., fuzuloparib, niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camphorsulfonate), saraparib (AZD5305), senaparib, stenoparib, taprazolepanib (e.g., taprazolepanib tosylate), veliparib, CEP-9722, JPI-289, or NMS-03305293). In some implementations, the cancer is BRCA1-mutated breast cancer or BRCA2-mutated breast cancer, and the additional therapy or treatment agent is saraparib.

[0952] In some implementations, the cancer is triple-negative breast cancer, and the additional therapy or treatment agent is a PARP inhibitor (e.g., fuzuloparib, niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camphorsulfonate), saraparib (AZD5305), senaparib, stenoparib, tapazoparib (e.g., tapazoparib tosylate), veliparib, CEP-9722, JPI-289, or NMS-03305293). In some implementations, the cancer is triple-negative breast cancer, and the additional therapy or treatment agent is saraparib.

[0953] In some implementations, the cancer is HGSOC (e.g., BRCA1-mutated HGSOC or BRCA2-mutated HGSOC), and the additional therapy or therapeutic agent is a PARP inhibitor (e.g., fuzuloparib, niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camphorsulfonate), saraparib (AZD5305), senaparib, stenoparib, tapazoparib (e.g., tapazoparib tosylate), veliparib, CEP-9722, JPI-289, or NMS-03305293). In some implementations, the cancer is HGSOC (e.g., BRCA1-mutated HGSOC or BRCA2-mutated HGSOC), and the additional therapy or therapeutic agent is saraparib.

[0954] In some implementations, the LSD1 inhibitor is bomedemstat, iadademstat, pulrodemstat, seclidemstat (HCI-2577), vafidemstat, GSK-2879552, INCB-059872, JBI-802, or a combination thereof.

[0955] In some implementations, the BET inhibitor is arobuxe, apatalone, mivebuxe, pelabresib, trotabresib, ABBV-744, BI-2536, BMS-986158, INCB-057643, JAB-8263, ODM-207, PLX-2853, ZEN-003694, or a combination thereof.

[0956] In some implementations, the cancer is myelofibrosis (e.g., primary myelofibrosis, post-esophagectomy myelofibrosis, or post-polycythemia vera myelofibrosis), and the additional therapy or treatment agent is a BET inhibitor (e.g., arobuxe, apatalone, mivebuxe, pelabresib, trotabresib, ABBV-744, BI-2536, BMS-986158, INCB-057643, JAB-8263, ODM-207, PLX-2853, or ZEN-003694).

[0957] In some implementations, the STING agonist is ulevostinag, ADU-S100, or a combination thereof.

[0958] In some implementations, the telomerase inhibitor is imetelstat (e.g., imetelstat sodium).

[0959] In some implementations, the TORC1 / 2 inhibitor is apitolisib, bimiralisib, dactolisib, deforolimus, everolimus, fosciclopirox (e.g., fosciclopirox sodium), gedatolisib, onatasertib, paxalisib, sapanisertib, sirolimus, sodium 2-hydroxylinoleate, temsirolimus, umirolimus, vistusertib, zandelisib, zotarolimus, BI-860585, CC-115, CLL-442, PF-04691502, or a combination thereof.

[0960] In some implementations, the VEGFR inhibitors are apatinib, axitinib, cabozantinib (e.g., cabozantinib S-malate), carquetinib, sidinib, dovirtinib, famitinib, fruquintinib, gliclazinib, icarseti, iloxeti, lenvatinib (e.g., lenvatinib mesylate), deritinib, nintedanib (e.g., nintedanib ethsulfate), pefitinib, pazopanib (e.g., pazopanib hydrochloride), and regorafenib (e.g., regorafenib monohydrate). (e.g., sorafenib tosylate), sutrinib (e.g., sunitinib malate), sulfatinib, tillatinib, tenengatinib, tevazanib (e.g., tevazanib hydrochloride monohydrate), vandetanib, voronib, zanzalintinib, ovavasimarab (or its biosimilar), ramucirumab (or its biosimilar), CEP-11981, ENMD-2076, ODM-203, or combinations thereof.

[0961] In some embodiments, the chemotherapy is a platinum complex, a microtubule inhibitor (e.g., a microtubule destabilizer or microtubule stabilizer), a topoisomerase inhibitor, a hypomethylating agent, or an antibody-drug conjugate, including any of them. In some embodiments, the platinum complex is carboplatin, cisplatin, lobaplatin, miriplatin, oxaliplatin, or a combination thereof. In some embodiments, the microtubule inhibitor is cabazitaxel, colchicine, deoxyepotassium B, docetaxel, eribulin, ixabepilone, nab-paclitaxel, paclitaxel, plinabulin, sabizabulin, tirbanibulin, vinblastine, vinflunine, vinorelbine, or a combination thereof. In some implementations, the microtubule inhibitor is cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, or a combination thereof. In some implementations, the topoisomerase inhibitor is aclarubicin, amsacrine, belotecan, camptothecin, daunorubicin, dexrazoxane, elliptinium, epirubicin, etoposide, geopotidacin, idarubicin, mitoxantrone, nemonoxacin, pirarubicin, pixantrone, razoxane, rubitecan, sobuzoxane, temozolomide, teniposide, topotecan, SN-38, or combinations thereof. In some embodiments, the hypomethylating agent is azacitidine, decitabine, or a combination thereof. In some embodiments, the chemotherapy is a platinum complex and a topoisomerase inhibitor (e.g., cisplatin and etoposide).In some implementations, the antibody-drug conjugate containing a microtubule inhibitor is belantamab mafodotin, brentuximab vedotin, cofetuzumab pelidotin, disitamab vedotin, enfortumab vedotin (e.g., enfortumab vedotin-ejfv or its biosimilar), mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx or its biosimilar), polatuzumab vedotin, telisotuzumab vedotin, tisotumab vedotin, trastuzumabemtansine (e.g., ado-trastuzumab emtansine or its biosimilar), tusamitamabravtansine, or upifitamab. The antibody-drug conjugates containing microtubule inhibitors include zilovertamab vedotin, Alpha-Her2-pAF1-AS-269, BAT-8001, TAA-013, their biosimilars, or combinations thereof. In some embodiments, the antibody-drug conjugate containing a microtubule inhibitor is vedotin (e.g., enfortumab vedotin-ejfv or its biosimilar). In some embodiments, the antibody-drug conjugate containing a microtubule inhibitor is somituximab (e.g., mirvetuximab soravtansine-gynx or its biosimilar). In some embodiments, the antibody-drug conjugate containing a microtubule inhibitor is trastuzumab emtansine (e.g., ado-trastuzumab emtansine or its biosimilar). In some embodiments, the antibody-drug conjugate containing a topoisomerase inhibitor is datopotamab deruxtecan, patritumab deruxtecan, sacituzumab govitecan (e.g., sacituzumab govitecan-hziy or a biosimilar thereof), trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki or a biosimilar thereof), or a combination thereof.In some embodiments, the antibody-drug conjugate containing a topoisomerase inhibitor is sacituzumab (e.g., sacituzumab govitecan-hziy or a biosimilar thereof). In some embodiments, the antibody-drug conjugate containing a topoisomerase inhibitor is trastuzumab (e.g., fam-trastuzumab deruxtecan-nxki or a biosimilar thereof).

[0962] In some implementations, the cancer is lung cancer (e.g., NSCLC (e.g., squamous cell carcinoma)), and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel).

[0963] In some implementations, the cancer is NSCLC (e.g., NSCLC with MET amplification), and the additional therapy or treatment agent is telisotuzumab vedotin.

[0964] In some implementations, the cancer is lung cancer (e.g., NSCLC), and the additional therapy or treatment agent is a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miplatin, or oxaliplatin) and anti-PD1 therapy.

[0965] In some implementations, the cancer is lung cancer (e.g., NSCLC), and the additional therapy or treatment agent is a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miplatin, or oxaliplatin) and anti-PD-L1 therapy.

[0966] In some implementations, the cancer is lung cancer (e.g., NSCLC), and the additional treatment or therapeutic agent is pemetrexed and anti-PD1 therapy.

[0967] In some implementations, the cancer is lung cancer (e.g., NSCLC), and the additional treatment or therapeutic agent is pemetrexed and anti-PD-L1 therapy.

[0968] In some embodiments, the cancer is lung cancer (e.g., SCLC), and the additional therapy or treatment agent is a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miplatin, or oxaliplatin) and a topoisomerase inhibitor (e.g., arubicin, acridine, belotecone, camptothecin, daunorubicin, dexrazoxen, eletazidine, epirubicin, etoposide, gepotidacin, idarubicin, mitoxantrone, nemonoxacin, pirarubicin, pifuran, razoxen, rubitecan, sobuzoxen, temozolomide, teniposide, topotecan, or SN-38). In some embodiments, the cancer is lung cancer (e.g., SCLC), and the additional therapy or treatment agent is carboplatin and etoposide. In some embodiments, the cancer is lung cancer (e.g., SCLC), and the additional therapy or treatment agent is cisplatin and etoposide.

[0969] In some implementations, 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), triple-negative breast cancer, or HER2-low breast cancer), and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel). In some implementations, the cancer is triple-negative breast cancer, and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel). In some implementations, the cancer is triple-negative breast cancer, and the additional therapy or treatment agent is nab-paclitaxel or paclitaxel.

[0970] In some implementations, 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), triple-negative breast cancer, or HER2-low breast cancer), and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and anti-PD1 therapy.

[0971] In some implementations, 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), triple-negative breast cancer, or HER2-low breast cancer), and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and anti-PD-L1 therapy.

[0972] In some implementations, 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), triple-negative breast cancer, or HER2-low breast cancer), and the additional therapy or treatment agent is capecitabine.

[0973] In some implementations, 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), triple-negative breast cancer, or HER2-low breast cancer), and the additional therapy or treatment agent is sacituzumab (e.g., sacituzumab govitecan-hziy or its biosimilar).

[0974] In some implementations, 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), triple-negative breast cancer, or HER2-low breast cancer), and the additional therapy or treatment agent is trastuzumab (e.g., fam-trastuzumab deruxtecan-nxki or its biosimilar).

[0975] In some implementations, 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), triple-negative breast cancer, or HER2-low breast cancer), and the additional therapy or treatment agent is trastuzumab (e.g., HERCEPTIN). ®(trastuzumab) or its biosimilars (e.g., Faceptor) ® (trastuzumab), HERTICAD ® (Trastuzumab), TUZNUE ® (Trastuzumab), ZERCEPAC ® (Trastuzumab, trastuzumab-ANNS, trastuzumab-DKST, trastuzumab-DTTB, trastuzumab-PKRB, trastuzumab-QYYP, EG-12014 or TX-05)).

[0976] In some implementations, the cancer is hormone receptor-positive breast cancer, and the additional treatment or therapeutic agent is hormone therapy (e.g., tamoxifen, toremifene, or a combination thereof).

[0977] In some implementations, the cancer is hormone receptor-positive breast cancer, and the additional therapy or treatment agent is a selective estrogen receptor degrader (SERD) (e.g., fulvestrant, elacestrant, or a combination thereof).

[0978] In some implementations, the cancer is HER2+ breast cancer (e.g., HER2+ breast cancer with ER expression, HER2+ breast cancer without ER expression), and the additional therapy or treatment agent is trastuzumab (e.g., fam-trastuzumab deruxtecan-nxki or its biosimilar) or trastuzumab emtansine (e.g., KADCYLA). ® Trastuzumab emtansine or its biosimilars (e.g., UJVIRA) ® (Trastuzumab emtansine)

[0979] In some implementations, the cancer is HER2-low breast cancer, and the additional therapy or treatment agent is trastuzumab (e.g., fam-trastuzumab deruxtecan-nxki or its biosimilar).

[0980] In some implementations, the cancer is head and neck cancer, and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel). In some implementations, the cancer is head and neck cancer, and the additional therapy or treatment agent is docetaxel.

[0981] In some implementations, the cancer is cervical cancer, and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel).

[0982] In some implementations, the cancer is endometrial cancer, and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel).

[0983] In some implementations, the cancer is prostate cancer, and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel).

[0984] In some embodiments, the cancer is ovarian cancer (e.g., HGSOC), and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel). In some embodiments, the cancer is ovarian cancer (e.g., HGSOC), and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and a platinum complex (e.g., carboplatin, cisplatin, lobaplatin, miplatin, or oxaliplatin). In some embodiments, the cancer is ovarian cancer (e.g., HGSOC), and the additional therapy or treatment agent is nab-paclitaxel or paclitaxel and carboplatin.

[0985] In some implementations, the cancer is pancreatic cancer, and the additional therapy or treatment agent is a microtubule inhibitor (e.g., cabazitaxel, docetaxel, nab-paclitaxel, or paclitaxel) and gemcitabine.

[0986] In some implementations, the cancer is bladder cancer (e.g., bladder urothelial carcinoma), and the additional therapy or treatment agent is vedotin (e.g., enfortumab vedotin-ejfv or its biosimilar).

[0987] In some implementations, the cancer is bladder cancer (e.g., bladder urothelial carcinoma), and the additional therapy or treatment agent is sacituzumab (e.g., sacituzumab govitecan-hziy or its biosimilar).

[0988] In some implementations, the cancer is triple-negative breast cancer, and the additional therapy or treatment agent is sacituzumab (e.g., sacituzumab govitecan-hziy or its biosimilar).

[0989] In some embodiments, the folate receptor-positive status can be detected in samples from the subject (e.g., by immunohistochemistry (IHC) and / or fluorescence in situ hybridization (FISH)). In some embodiments, it is determined (e.g., prior to administration of the compounds provided herein) that the subject has a folate receptor-positive cancer.

[0990] In some implementations, the cancer is folate receptor-positive ovarian cancer (e.g., folate receptor-positive HGSOC), and the additional therapy or treatment agent is somituximab (e.g., mirvetuximab soravtansine-gynx or its biosimilar).

[0991] In some implementations, the immunomodulatory imide is thalidomide, lenalidomide, pomalidomide, iberdomide, avadomide, CC-99282, or a combination thereof.

[0992] In some implementations, the anti-PD1 therapy is balstilimab, budigalimab, cadonilimab, camrelizumab, cemiplimab (e.g., cemiplimab-rwlc or its biosimilar), cetrelimab, dostarlimab (e.g., dostarlimab-gxly or its biosimilar), ezabenlimab, geptanolimab, ivonescimab, or nivolumab (e.g., OPDIVO). ® (nivolumab or its biosimilar), nofazinlimab, pembrolizumab (e.g., KEYTRUDA) ® (pembrolizumab or its biosimilars), penpulimab, pidilizumab, pimivalimab, prolgolimab, puctenlimab, retifanlimab (e.g., retifanlimab-dlwr or its biosimilars), rilvegostomig, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab (e.g., TYVYT) ®(sintilimab or its biosimilars), spartalizumab, tebotelimab, tislelizumab, toripalimab, volrustomig, vudalimab, zimberelimab, QL-1604, HX-009, INCB-086550, RG-6139, BAT-1306, SG-001, their biosimilars, or combinations thereof.

[0993] In some implementations, the PD-L1 inhibitor is INCB-086550.

[0994] In some implementations, anti-PD-L1 therapy includes adebrelimab and atezolizumab (e.g., TECENTRIQ). ® (Atezolizumab) or its biosimilars), avelumab (e.g., BAVENCIO) ® (Averrucumab or its biosimilar), bintrafusp alfa, cosibelimab, danburstotug, devalumab (e.g., IMFINZI) ® (dvalumab) or its biosimilars), envafolimab (e.g., ENWEIDA) ® (Envorimab or its biosimilars), erfonrilimab, pacmilimab, socazolimab, sugemalimab (e.g., CEJEMLY) ® Sugemalimab (or its biosimilars), A-167, APL-502, AUPM-170, BNT-311, SHR-1701, their biosimilars, or combinations thereof.

[0995] In some implementations, the additional treatment is radiation therapy.

[0996] In some implementations, the cancer is head and neck cancer (e.g., squamous cell carcinoma of the head and neck), and another treatment is radiation therapy.

[0997] In some implementations, additional therapies include BRaf inhibitors and MEK inhibitors. For example, additional therapies may include dabrafenib and trametinib, vemurafenib and cobimetinib, or cannefenib and bimetinib.

[0998] Exemplary descriptions of agents in combination with BCL-2 family inhibitors can be found in: Hikita, Hayato et al. Hepatology 52.4 (2010): 1310-1321, doi: 10.1002 / hep.23836; Chen, Jun et al. Molecular Cancer Therapeutics 10.12 (2011): 2340-2349, doi: 10.1158 / 1535-7163.MCT-11-0415; Inuzuka, Hiroyuki et al. Nature 471.7336 (2011): 104-109, doi:10.1038 / nature09732; Wertz, Ingrid E. et al. Nature 471.7336 (2011): 110-114, doi:10.1038 / nature09779; Tan, Nguyen et al. Clinical Cancer Research 17.6 (2011):1394-1404, doi: 10.1158 / 1078-0432.CCR-10-2353; Wong, Maureen et al. Molecular Cancer Therapeutics 11.4 (2012): 1026-1035, doi: 10.1158 / 1535-7163.MCT-11-0693; Corcoran, Ryan B. et al. Cancer Cell 23.1 (2013): 121-128, doi: 10.1016 / j.ccr.2012.11.007; Waibel, Michaela et al. Cell Reports 5.4 (2013): 1047-1059, doi: 10.1016 / j.celrep.2013.10.038; Frederick, Dennie T. et al. PLoS One 9.7 (2014): e101286, doi: 10.1371 / journal.pone.0101286; Vlahovic, Gordana et al. Investigational New Drugs 32.5 (2014): 976-984, doi: 10.1007 / s10637-014-0116-3; Faber, Anthony C. et al. Cancer Discovery 4.1 (2014): 42-52, doi: 10.1158 / 2159-8290.CD-13-0315; Leverson, Joel D. et al. Science Translational Medicine 7.279(2015): 279ra40-279ra40, doi: 10.1126 / scitranslmed.aaa4642; Guo, Jun et al. PLoSOne 10.3 (2015): e0114363, doi: 10.1371 / journal.pone.0114363; Lheureux, Stéphanie et al. International Journal of Cancer 136.5 (2015): E340-E350, doi:10.1002 / ijc.29104; Zoeller, Jason J. et al. Cancer Research 76.14_Supplement(2016): 4358-4358, doi: 10.1158 / 1538-7445.AM2016-4358; Weeden, Clare E. et al. Oncogene 37.32 (2018): 4475-4488, doi: 10.1038 / s41388-018-0268-2; Lucantoni, Federico et al. Cell Death & Disease 9.2 (2018): 1-13, doi: 10.1038 / s41419-017-0039-y; Iavarone, Claudia et al. Molecular Cancer Therapeutics 18.3 (2019): 642-655, doi: 10.1158 / 1535-7163.MCT-18-0413; Fleury, Hubert et al. Nature Communications 10.1 (2019): 2556, doi: 10.1038 / s41467-019-10460-1; Lohard, Steven et al. Nature Communications 11.1 (2020): 259, doi: 10.1038 / s41467-019-13689-y; Bertino, Erin M. et al. Clinical Cancer Research 27.6 (2021): 1604-1611, doi: 10.1158 / 1078-0432.CCR-20-4084; Guo, Ting et al. Aging 13.15 (2021): 19750, doi: 10.18632 / aging.203386; Puglisi, Martina et al. Future Oncology 17.21 (2021):2747-2758, doi: 10.2217 / fon-2021-0140; Harrison, Claire N. et al. Journal of Clinical Oncology 40.15 (2022): 1671, doi: 10.1200 / JCO.21.02188; Köhler, Jens et al. Molecular Cancer Therapeutics 20.4 (2021): 641-654, doi: 10.1158 / 1535-7163.MCT-20-0531; Jaaks, Patricia et al. Nature 603.7899 (2022): 166-173, doi:10.1038 / s41586-022-04437-2; Sobol, Benjamin et al. International Journal of Molecular Sciences 23.14 (2022): 7850, doi: 10.3390 / ijms23147850; Passamonti,J Clin Oncol 40, (2022) (suppl 16; abstr 7015), doi: 10.1200 / JCO.2022.40.16_suppl.7015; Qin, J Clin Oncol 40, (2022) (suppl 16; abstr e20612), doi:10.1200 / JCO.2022.40.16_suppl.e20612; Potter, Danielle S. et al. Cancer Research 82.12_Supplement (2022): 3691-3691, doi: 10.1158 / 1538-7445.AM2022-3691; and Shebl, Bassem et al. Cancer Research 82.12_Supplement (2022): 3888-3888, doi:10.1158 / 1538-7445.AM2022-3888.

[0999] This article also provides a method for treating cancer, comprising administering (a) a compound provided herein or a pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent to a subject in need, for simultaneous, separate, or sequential treatment of cancer, wherein the amounts of the compound provided herein or a pharmaceutically acceptable salt thereof and the additional therapeutic agent together are effective in treating cancer. In some embodiments, the method includes administering (c) at least one pharmaceutically acceptable carrier.

[1000] These additional therapeutic agents may be administered, together with one or more doses of the compounds provided herein or their pharmaceutically acceptable salts or pharmaceutical compositions thereof, as part of the same or different dosage forms, via the same or different routes of administration, and / or according to the same or different administration regimens in accordance with standard pharmaceutical practices known to those skilled in the art. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts, along with additional therapeutic agents, are administered simultaneously in separate doses. In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts, along with additional therapeutic agents, are administered as separate doses in any order in combination at a therapeutically effective amount (e.g., in daily or intermittent doses). In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts, along with additional therapeutic agents, are administered simultaneously in combination doses.

[1001] This document also provides (i) a pharmaceutical combination for treating cancer in a subject of need, the pharmaceutical combination comprising (a) a compound provided herein or a pharmaceutically acceptable salt thereof, and (b) at least one additional therapeutic agent (e.g., any of the other exemplary therapeutic agents described herein or known in the art), for simultaneous, separate, or sequential treatment of the cancer, wherein the amounts of the compound provided herein or a pharmaceutically acceptable salt thereof and the additional therapeutic agent together are effective in treating the cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) use of such a combination in the preparation of a medicament for treating cancer; and (iv) a commercial package or product comprising such a combination as a preparation for simultaneous, separate, or sequential use; and a method of treating cancer in a subject of need. In some embodiments, the pharmaceutical combination comprises (c) at least one pharmaceutically acceptable carrier.

[1002] As used herein, the term “treatment” refers to therapeutic or mitigating measures. Beneficial or desired clinical outcomes include, but are not limited to, complete or partial relief of symptoms associated with the disease or symptom or condition, reduction of the severity of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or reduction of the disease state (e.g., one or more disease symptoms), and remission (whether partial or complete), whether detectable or undetectable. “Treatment” may also mean extended survival compared to expected survival without treatment.

[1003] As used herein, the terms “subject,” “individual,” or “patient” are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of a disease, condition, or ailment to be treated and / or prevented.

[1004] In some implementation schemes, the subjects are pediatric subjects.

[1005] As used herein, the term “pediatric subject” refers to a subject under the age of 21 at the time of diagnosis or treatment. The term “pediatric” can be further subdivided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to two years); children (two years to 12 years); and adolescents (12 to 21 years (maximum age, excluding the 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th edition Philadelphia: WBSaunders Company, 1996; Rudolph AM et al. Rudolph's Pediatrics, 21st edition New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd edition Baltimore: Williams & Wilkins; 1994. In some implementations, the age of pediatric subjects is defined as follows: from birth to the first 28 days of life; from 29 days to under two years of age; from two years to under 12 years of age; or from 12 years to 21 years of age (maximum age, excluding the 22nd birthday). In other implementations, the age of pediatric subjects is defined as follows: from birth to the first 28 days of life; from 29 days to under one year of age; from one month to under four months of age; from three months to under seven months of age; from six months to under one year of age; from one year to under two years of age; from two years to under three years of age; from two years to under seven years of age; from three years to under five years of age; from five years to under ten years of age; from six years to under 13 years of age; from ten years to under 15 years of age; or from 15 years to under 22 years of age.

[1006] As...

Claims

1. A compound of formula (I-i1), formula (I-i2), or formula (I-i3): Equation (I-i1) Equation (I-i2) Formula (I-i3) Or its pharmaceutically acceptable salt, wherein: Z 1 Choose from the following groups: N and CH; R 1 Choose from the following groups: (a)-C(O)OH; (b)-C(O)OC 1-6 Alkyl, wherein C 1-6 Alkyl groups are optionally surrounded by 1 to 3 R groups. c Replace; and (c) -C(O)-(C 0-3 (alkylene)-phenyl, wherein the phenyl group is optionally surrounded by 1 to 3 R groups. a replace; R 2 It is CH3 or CF3; m2 is 0 or 1; Each L A1 Independently select from the following groups: -CH2-, -CHR L -and-C(R) L )2-, where: Each R L Independently select from the following groups: halogenated group, -CN, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -(C 0-3 alkylene)-(C 3-5 cycloalkyl), -(C 0-3 (alkylene)-(4- to 6-membered heterocyclic group) and optionally surrounded by 1 to 6 R c Replacement C 1-6 alkyl; a1a is an integer from 0 to 4; L A4 yes , where cc represents -(L A1a ) a1a - Attachment point; R Ya Choose from the following groups: H, R b and optionally by 1 to 3 R c Replacement C 1-6 alkyl; Each R Yb Independently select free R a and R b The group formed; c1 is 0, 1, or 2; Each R a Choose independently from the following groups: (a) Halogenated group; (b)CN; (c)-OH; (d) Oxide group; (e) optionally by 1 to 6 R c Replacement C 1-6 Alkoxy; (f)-NR d R e ; (g)C(=O)C 1-6 alkyl; (h)C(=O)OC 1-6 alkyl; (i)C(=O)N(R f )2; (j)S(O) 0-2 (C 1-6 alkyl); (k)S(O) 0-2 (C 1-6 (halogenated alkyl); and (l)C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne groups, each optionally surrounded by 1 to 6 R groups c replace; Each R b Selected independently from: -(L b ) b -R b1 and -R b1 ,in: Each b is independently 1 or 2; Each L b Choose independently from the following groups: -O-, -N(H)-, -N(C)-. 1-3 Alkyl)-, -S(O) 0-2 - C (=O) and C 1-3 Alkylene; and Each R b1 Choose independently from the following groups: C 3-6 Cycloalkyl and 4 to 8-membered heterocyclic groups, each of which is optionally surrounded by 1 to 3 R groups. g replace; Each R c Independently select from the following groups: halogenated group, CN, -OH, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -NR d R e C(=O)C 1-6 Alkyl, C(=O)OC 1-6 Alkyl, C(=O)N(R) f 2. S(O) 0-2 (C 1-6 Alkyl groups and S(O) 0-2 (C- 1-6 (halogenated alkyl); Each R d and R e Independently 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 groups), S(O) 1-2 (C- 1-6 Halogenated alkyl groups), S(O) 1-2 N(R f )2 and optionally by 1 to 3 R h Replacement C 1-6 alkyl; Each R f Independently select from the following groups: H and optionally selected by 1 to 3 Rs. h Replacement C 1-6 alkyl; Each R g Independently select from the following groups: R h , Oxide group, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups; and Each R h Independently select from the following groups: halogenated group, CN, -OH, -(C 0-3 (alkylene)-C 1-6 Alkoxy, -(C 0-3 (alkylene)-C 1-6 Haloalkoxy, -(C 0-3 alkylene)-NH2, -(C 0-3 alkylene)-N(H)(C 1-3 alkyl) and -(C 0-3 alkylene)-N(C 1-3 Alkyl)2.

2. The compound of claim 1, wherein the compound is different from the compound numbered R156 or R226 as depicted in Table R1, or their pharmaceutically acceptable salts.

3. The compound according to claim 1, wherein the compound is a compound of formula (I-i1) or a pharmaceutically acceptable salt thereof; and one or more of (1)-(5) are applicable: (1) m2 is 1, and R 2 It's CF3; (2) a1a is 0; (3) a1a is 2 or 3; (4) c1 is 1 or 2; and (5) At least one L A1a Choose from the following groups: CHR L and C(R) L )2.

4. The compound according to any one of claims 1 to 3, wherein the compound is a compound of formula (I-i1) or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 or 2, wherein the compound is a compound of formula (I-i2) or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 or 2, wherein the compound is a compound of formula (I-I3) or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1 to 6, wherein a1a is 0 or 1.

8. The compound according to any one of claims 1 to 6, wherein a1a is 2, 3 or 4 (e.g., 2 or 3).

9. The compound according to any one of claims 1 to 8, wherein each L A1a It is -CH2.

10. The compound according to any one of claims 1 to 8, wherein one of the L... A1a Yes - CHR L , where R L It is -F or C, which may be replaced by one to three -F. 1-3 Alkyl groups; and each remaining L A1a It is -CH2.

11. The compound according to any one of claims 1 to 10, wherein m2 is 1; and R 2 It is -CF3.

12. The compound according to any one of claims 1 to 11, wherein... Part of it is ;and The Part of it is .

13. The compound according to any one of claims 1 to 10, wherein m2 is 1; and R 2 It is -CH3.

14. The compound according to any one of claims 1 to 10 or 13, wherein... Part of it is ;and The Part of it is .

15. The compound according to any one of claims 1 to 14, wherein Z 1 It is CH.

16. The compound according to any one of claims 1 to 14, wherein Z 1 It is N.

17. The compound according to any one of claims 1 to 16, wherein each R Yb Choose independently from the following groups: -F, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 -F groups 1-3 Alkyl; or R Yb Choose independently from the following groups: -F, -OMe, -CH3, -CHF2, -CH2F, and -CF3.

18. The compound according to any one of claims 1 to 17, wherein... Part of it is , where R Ya It can be arbitrarily divided by 1 to 3 Rs c Replacement C 1-3 Alkyl (e.g., R) Ya (It is methyl).

19. The compound according to any one of claims 1 to 17, wherein... Part of it is , where R Ya It can be arbitrarily divided by 1 to 3 Rs c Replacement C 1-3 Alkyl; and R Yb Choose from the following groups: -F, C 1-3 Alkoxy groups and C groups optionally substituted with 1 to 3 -F groups 1-3 alkyl.

20. The compound according to claim 18 or 19, wherein R Ya It is a methyl group.

21. The compound according to any one of claims 18 to 20, wherein R Yb It is C 1-3 Alkyl group.

22. The compound according to any one of claims 18 to 20, wherein R Yb Choose from the following groups: -F, -CH3, and -OMe.

23. The compound according to any one of claims 18 to 22, wherein R Yb It's OMe.

24. The compound according to any one of claims 1 to 23, wherein R 1 It is C(O)OH.

25. The compound according to any one of claims 1 to 24, wherein the compound is selected from the group consisting of compounds numbered 112, 113, 114, 115, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 131, 132, 134, 135, 136, 137, 139, 143, 144, 147, 148 as depicted in Table C1. 154, 155, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 181, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 202, 203, 204, 205, 206, 207, 213 and 214, or their pharmaceutically acceptable salts.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. A method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

28. The method of claim 27, further comprising administering additional therapy or treatment agent.

29. The method of claim 28, wherein the additional therapy or therapeutic agent is an ALK inhibitor, BCL-2 inhibitor, BCR-Abl inhibitor, BRaf inhibitor, CDK2 inhibitor, CDK4 / 6 inhibitor, CDK7 inhibitor, CDK9 inhibitor, EGFR inhibitor, anti-EGFR antibody, ERK inhibitor, FGFR1 inhibitor, FGFR2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor, HER2 inhibitor, JAK2 inhibitor, KRas inhibitor, MEK inhibitor, MET inhibitor, PARP inhibitor, LSD1 inhibitor, BET inhibitor, telomerase inhibitor, TORC1 / 2 inhibitor, L-asparaginase, chemotherapy, radiotherapy, or combinations thereof.

30. The method according to any one of claims 27 to 29, wherein the cancer is breast cancer, colorectal cancer, bile duct cancer, colorectal cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, kidney cancer, cervical cancer, ovarian cancer, uterine cancer, head and neck cancer, hematologic cancer, lung cancer, skin cancer, or a combination thereof.

31. The method of claim 30, wherein the hematologic cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), essential thrombocytosis, polycythemia vera, myelofibrosis, or a combination thereof.

32. The method of claim 30, wherein the cancer is lung cancer.

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