Compound, complex and preparation method and application thereof

Abstract

Compounds containing aziridine moieties and methods for their synthesis are provided. The compounds can bind to monovalent organic moieties and can be used to bind targets (e.g., target proteins), such as by crosslinking the targets. In some embodiments, the monovalent organic moiety is capable of binding to a presenting protein. Also disclosed are complexes (e.g., presenting protein / compound complexes, compound / target protein complexes, or triple complexes) containing the compounds. Methods of forming the complexes and methods of modulating biological processes using the compounds and complexes are also disclosed.

Description

Background Art

[0001] The vast majority of small molecule drugs work by binding to functionally important pockets on the target protein, thereby regulating the activity of the protein. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. The fact that many such drug / target interaction pairs are known may have misled some people into believing that, given reasonable time, effort, and resources, small molecule modulators for most (if not all) proteins can be found. This is far from the case. According to current estimates, only about 10% of all human proteins can be targeted by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019). The other 90% are currently considered to be refractory or intractable to the discovery of the above-mentioned small molecule drugs. Such targets are often referred to as "undruggable". These undruggable targets include a large number of human proteins of important medical significance that have not yet been developed. Therefore, there is great interest in discovering new molecular patterns that can regulate the functions of such undruggable targets. In particular, there is a need for new compounds that are able to form a complex with a target of interest (eg, a target protein). Summary of the Invention

[0002] In general, the present disclosure provides compounds that can form complexes and / or cross-link with a target (e.g., a target protein). Also disclosed are synthetic intermediates for preparing such compounds, complexes formed by reacting the compounds, methods for synthesizing the compounds and complexes, and methods for using the compounds and complexes.

[0003] In a first aspect, the present disclosure provides a compound having the structure of Formula I:

[0004]

[0005] or a pharmaceutically acceptable salt thereof; wherein

[0006]

[0007] M + It is a cation;

[0008] R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0009] R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0010] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0011] R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0012] or

[0013] R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0014] or

[0015] R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a );

[0016] or

[0017] R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0018] or

[0019] R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d)2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0020] or

[0021] R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4 are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0022] or

[0023] R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0024] Where R and R 4 At least one of is not hydrogen;

[0025] R 3 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0026] R 1a 、R 2a 、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0027] R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0028] R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0029] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0030] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ia:

[0031]

[0032] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ib:

[0033]

[0034] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ic:

[0035]

[0036] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Id:

[0037]

[0038] In some embodiments, R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted C6-C 10 In some embodiments, R 3 is an optionally substituted C1-C6 alkyl. 3 is methyl, ethyl or benzyl.

[0039] In some embodiments, M + For Li + .

[0040] In some embodiments, R 3 for:

[0041]

[0042] In some embodiments, Z is

[0043] In another aspect, the present disclosure provides a compound having the structure of Formula II:

[0044]

[0045] or a pharmaceutically acceptable salt thereof,

[0046] Among them A 1 For the unit price organic part;

[0047] Q is

[0048] R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0049] R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0050] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0051] R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5- to 10-membered heteroaryl or -Si(R 1a )3;

[0052] R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0053] or

[0054] R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a );

[0055] or

[0056] R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0057] or

[0058] R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0059] or

[0060] R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4 are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0061] or

[0062] R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0063] Where R and R 4 At least one of is not hydrogen;

[0064] R 1a 、R 2a、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0065] R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0066] R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0067] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0068] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIa:

[0069]

[0070] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIb:

[0071]

[0072] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIc:

[0073]

[0074] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IId:

[0075]

[0076] In some embodiments, Q is

[0077] In another aspect, the present disclosure provides a compound / target protein complex having a structure of Formula III or a pharmaceutically acceptable salt thereof:

[0078]

[0079] Among them A 1 For the unit price organic part;

[0080] Q is

[0081] P 1 A 2 , and P 2 is hydrogen; or P 1 is a hydroxyl group, and P 2 A 2 ;

[0082] A 2 is the target protein;

[0083] R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0084] R 1is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0085] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0086] R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5- to 10-membered heteroaryl or -Si(R 1a )3;

[0087] or R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0088] or

[0089] R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a );

[0090] or

[0091] R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0092] or

[0093] R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0094] or

[0095] R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4 are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0096] or

[0097] R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0098] Where R and R 4 At least one of is not hydrogen;

[0099] R 1a 、R 2a 、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0100] R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0101] R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0102] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0103] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-1:

[0104]

[0105] Among them A 3 is the remaining portion of the target protein.

[0106] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-2:

[0107]

[0108] Among them A 3 is the remaining portion of the target protein.

[0109] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-3:

[0110]

[0111] Among them A 3 is the remaining portion of the target protein.

[0112] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-4:

[0113]

[0114] Among them A 3 is the remaining portion of the target protein.

[0115] In some embodiments, the compound / target protein complex has the structure of the compound / target protein complex as described in Technical Solution 16, wherein the compound / target protein complex has the structure of Formula IIIb-1:

[0116]

[0117] Among them A 3 is the remaining portion of the target protein.

[0118] In some embodiments, the compound / target protein complex has the structure of Formula IIIb-2:

[0119]

[0120] Among them A 3 is the remaining portion of the target protein.

[0121] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-1:

[0122]

[0123] Among them A 3 is the remaining portion of the target protein.

[0124] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-2:

[0125]

[0126] Among them A 3 is the remaining portion of the target protein.

[0127] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-3:

[0128]

[0129] Among them A 3 is the remaining portion of the target protein.

[0130] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-4:

[0131]

[0132] Among them A 3 is the remaining portion of the target protein.

[0133] In some embodiments, the compound / target protein complex has the structure of Formula IIId-1:

[0134]

[0135] Among them A 3 is the remaining portion of the target protein.

[0136] In some embodiments, the compound / target protein complex has the structure of Formula IIId-2:

[0137]

[0138] Among them A 3 is the remaining portion of the target protein.

[0139] In some embodiments, the compound / target protein complex has the structure of Formula IIIe-1:

[0140]

[0141] Among them A 3 is the remaining portion of the target protein.

[0142] In some embodiments, the compound / target protein complex has the structure of Formula IIIe-2:

[0143]

[0144] Among them A 3 is the remaining portion of the target protein.

[0145] In some embodiments of any of the compounds or compound / target protein complexes described herein, R is an optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 In some embodiments, R is an optionally substituted C2-C6 alkylene group, an optionally substituted C2-C6 alkylene group, or an optionally substituted C2-C6 alkylene group. 10 In some embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, R is In some embodiments, R is In some embodiments, R is an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl. In some embodiments, R is a carbocationically stabilized electron-donating group, that is, R is a substituent that stabilizes the positive charge or partial positive charge on the carbon to which it is attached.

[0146] In some embodiments of any of the compounds or compound / target protein complexes described herein, R 1 For hydrogen.

[0147] In some embodiments of any of the compounds or compound / target protein complexes described herein, R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 In some embodiments, R 2 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C3-C 10 In some embodiments, R 2 is an optionally substituted C1-C6 alkyl. 2 is optionally substituted C3-C 10 In some embodiments, R 2 is an optionally substituted 3- to 10-membered heterocycloalkyl. 2 for:

[0148]

[0149] In some embodiments, R 2 for:

[0150]

[0151] In some embodiments, R 2 It is a methyl group.

[0152] In some embodiments of any of the compounds or compound / target protein complexes described herein, R 4 For hydrogen.

[0153] In some embodiments of the compounds or compound / target protein complexes described herein, A 1 is or comprises a protein. In some embodiments, A 1 is or comprises a nucleic acid. In some embodiments, A 1 is or comprises a small molecule. In some embodiments, A 1 is or comprises a macrocyclic small molecule. In some embodiments, A 1 is or contains a degrading agent.

[0154] In some embodiments, A 1 Has the structure of Formula IV:

[0155]

[0156] where the dashed lines represent zero, one, two, three, or four non-adjacent double bonds;

[0157] A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is connected to -CH(R 10 )-, an optionally substituted C2-C4 alkylene, an optionally substituted C1-C4 heteroalkylene or an optionally substituted C2-C4 alkenylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene or an optionally substituted 5- to 10-membered heteroarylene;

[0158] X 1 is an optionally substituted C1-C2 alkylene, NR, O or S(O) n ;

[0159] X 2 is O or NH;

[0160] X 3 N or CH;

[0161] n is 0, 1, or 2;

[0162] R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2;

[0163] Each R ’ are independently H or optionally substituted C1-C4 alkyl;

[0164] Y 1 is C, CH or N;

[0165] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0166] Y 5 is CH, CH2 or N;

[0167] Y 6 is C(O), CH, CH2 or N;

[0168] R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or

[0169] R 1 and R 2 and, taken together with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0170] R 2 R is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; 3 does not exist, or

[0171] R 2 and R 3 and the atoms to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0172] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0173] R5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl;

[0174] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or

[0175] R 6 and R 7 and, in combination with the carbon atoms to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0176] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0177] R 7 and R 8 Combined with the carbon atom to which it is connected to form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;

[0178] R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or, in combination with the carbon to which they are attached, form a carbonyl;

[0179] R 7’ is hydrogen, halogen or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0180] R 7’ and R 8’ and, in combination with the carbon atoms to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0181] R 9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or

[0182] R 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0183] R 9’ is hydrogen or an optionally substituted C1-C6 alkyl group;

[0184] R 10 is hydrogen, halogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl;

[0185] R 10a is hydrogen or halogen;

[0186] R 11 is hydrogen or C1-C3 alkyl; and

[0187] R 34 is hydrogen or C1-C3 alkyl,

[0188] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0189] In some embodiments, A 1 Having the structure of formula V:

[0190]

[0191] wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene;

[0192] X 1 is CH2 or O;

[0193] m is 1 or 2;

[0194] n is 0 or 1;

[0195] R 1 is hydrogen or an optionally substituted 3- to 10-membered heterocycloalkyl;

[0196] R 2 is an optionally substituted C1-C6 alkyl group; and

[0197] R 3 is optionally substituted C1-C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl, wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0198] In some embodiments, A 1Has the structure of formula VI:

[0199]

[0200] wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene;

[0201] X 1 、X 2 and X 3 Each independently selected from CH2, CHF, CF2, C=O or O;

[0202] m is 1 or 2;

[0203] n is 0 or 1;

[0204] R 1 is hydrogen, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl;

[0205] R 2 is an optionally substituted C1-C6 alkyl group; and

[0206] R 3 is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted heterocycloalkyl group,

[0207] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0208] In some embodiments, A 1 Having the structure of any one of Formulas VII, VIII and IX:

[0209]

[0210] wherein o and p are independently 0, 1 or 2;

[0211] q is an integer between 0 and 7;

[0212] r is an integer between 0 and 4;

[0213] X 4 and X 5 Each independently absent, CH2, O, S, SO, SO2 or NR 11 ;

[0214] R 6 and R 7and each is independently hydrogen, hydroxy, optionally substituted amino, halogen, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10 arylC1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroarylC1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C9 heterocyclylC1-C6 alkyl, or R 6 and R 7 Combines with the carbon atom to which it is bound to form C=O;

[0215] Each R 8 are independently hydroxy, optionally substituted amino, halogen, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10 Aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocyclyl or optionally substituted C2-C9 heterocyclyl C1-C6 alkyl, or two R 8 Combining to form optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl;

[0216] R 9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10ArylC1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroarylC1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclylC1-C6 alkyl;

[0217] R 10 is an optionally substituted C1-C6 alkyl group;

[0218] Each R 11 are independently hydroxy, cyano, optionally substituted amino, halogen, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10 ArylC1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroarylC1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclylC1-C6 alkyl; and

[0219] R 12 and R 13 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, C3-C7 carbocyclyl, optionally substituted C6-C 10 aryl C1-C6 alkyl and optionally substituted C3-C7 carbocyclyl C1-C6 alkyl.

[0220] In yet another aspect, the present disclosure provides a ternary complex comprising a presenting protein, a compound described herein, and a target protein.

[0221] In some embodiments of the compound / target protein complexes or ternary complexes described herein, the target protein is a GTPase, a GTPase-activating protein, a guanine nucleotide exchange factor, a heat shock protein, an ion channel, a coiled-coil protein, a kinase, a phosphatase, a ubiquitin ligase, a transcription factor, a chromatin modifier / remodeler, a protease, or a protein with canonical protein-protein interaction domains and motifs.

[0222] In some embodiments, the target protein is a GTPase selected from the group consisting of DIRAS1, DIRAS2, DIRAS3, ERAS, GEM, HRAS, KRAS, MRAS, NKIRAS1, NKIRAS2, NRAS, RALA, RALB, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, RASD1, RASD2, RASL10A, RASL10B, RASL11A, RASL11B, RASL12, REM1, REM2, RERG, RERGL, RRAD, RRAS, RRAS2, RHOA, RHOB, RHOBTB1, RHOBTB2, RHOB TB3, RHOC, RHOD, RHOF, RHOG, RHOH, RHOJ, RHOQ, RHOU, RHOV, RND1, RND2, RND3, RAC1, RAC2, RAC3, CDC42, RAB1A, RAB1B, RAB2, RAB3A, RAB3B, RAB3C, RAB3 D. RAB4A, RAB4B, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B, RAB6C, RAB7A, RAB7B, RAB7L1, RAB8A, RAB8B, RAB9, RAB9B, RABL2A, RABL2B, RABL4, RAB10, RAB11A , RAB11B, RAB12, RAB13, RAB14, RAB15, RAB17, RAB18, RAB19, RAB20, RAB21, RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28, RAB2B, RAB3 0. RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37, RAB38, RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, RAB41, RAB42, RAB43, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, ARF1, ARF3, ARF4, ARF5, ARF6, ARL1, ARL2, ARL3, ARL4, ARL5, ARL5C, ARL6, ARL7, ARL8, ARL9, ARL10A, ARL10B, ARL10C, ARL 11. ARL13A, ARL13B, ARL14, ARL15, ARL16, ARL17, TRIM23, ARL4D, ARFRP1, ARL13B, RAN, RHEB, RHEBL1, RRAD, GEM, REM, REM2, RIT1, RIT2, RHOT1 and RHOT2.In some embodiments, the target protein is a member of the RAS family. In some embodiments, the target protein is HRAS, KRAS or NRAS. In some embodiments, the target protein is a mutated HRAS, a mutated KRAS or a mutated NRAS. In some embodiments, the target protein is not RAS (e.g., not HRAS, not KRAS or not NRAS, for example, not a mutated HRAS, not a mutated KRAS or not a mutated NRAS). In some embodiments, the target protein is KRAS. In some embodiments, the target protein is a GTPase activating factor selected from the following: NF1, IQGAP1, PLEXIN-B1, RASAL1, RASAL2, ARHGAP5, ARHGAP8, ARHGAP12, ARHGAP22, ARHGAP25, BCR, DLC1, DLC2, DLC3, GRAF, RALBP1, RAP1GAP, SIPA1, TSC2, AGAP2, ASAP1 and ASAP3.

[0223] In some embodiments, the target protein is a guanine nucleotide exchange factor selected from the group consisting of CNRASGEF, RASGEF1A, RASGRF2, RASGRP1, RASGRP4, SOS1, RALGDS, RGL1, RGL2, RGR, ARHGEF10, ASEF / ARHGEF4, ASEF2, DBS, ECT2, GEF-H1, LARG, NET1, OBSCURIN, P-REX1, P-REX2, PDZ-RHOGEF, TEM4, TIAM1, TRIO, VAV1, VAV2, VAV3, DOCK1, DOCK2, DOCK3, DOCK4, DOCK8, DOCK10, C3G, BIG2 / ARFGEF2, EFA6, FBX8, and GEP100.

[0224] In some embodiments, the target protein is a protein having a protein-protein interaction domain selected from the group consisting of: ARM, BAR, BEACH, BH, BIR, BRCT, BROMO, BTB, C1, C2, CARD, CC, CALM, CH, CHROMO, CUE, DEATH, DED, DEP, DH, EF-hand, EH, ENTH, EVH1, F-box, FERM, FF, FH2, FHA, FYVE, GAT, GEL, GLUE, GRAM, GRIP, GYF, HEA T, HECT, IQ, LRR, MBT, MH1, MH2, MIU, NZF, PAS, PB1, PDZ, PH, POLO-Box, PTB, PUF, PWWP, PX, RGS, RING, SAM, SC, SH2, SH3, S OCS, SPRY, START, SWIRM, TIR, TPR, TRAF, SNARE, TUBBY, TUDOR, UBA, UEV, UIM, VHL, VHS, WD40, WW, SH2, SH3, TRAF, bromodomain and TPR.

[0225] In some embodiments, the target protein is a heat shock protein selected from the group consisting of: Hsp20, Hsp27, Hsp70, Hsp84, αB crystallin, TRAP-1, hsf1, and Hsp90.

[0226] In some embodiments, the target protein is an ion channel selected from the group consisting of: Cav2.2, Cav3.2, IKACh, Kv1.5, TRPA1, NAv1.7, Nav1.8, Nav1.9, P2X3, or P2X4.

[0227] In some embodiments, the target protein is a coiled-coil protein selected from the group consisting of Synaptonemal, SPAG4, VAV1, MAD1, ROCK1, RNF31, NEDP1, HCCM, EEA1, Vimentin, ATF4, Nemo, SNAP25, Syntaxin 1a, FYCO1, and CEP250.

[0228] In some embodiments, the target protein is a kinase selected from the group consisting of ABL, ALK, AXL, BTK, EGFR, FMS, FAK, FGFR1, 2, 3, 4, FLT3, HER2 / ErbB2, HER3 / ErbB3, HER4 / ErbB4, IGF1R, INSR, JAK1, JAK2, JAK3, KIT, MET, PDGFRA, PDGFRB, RETRON, ROR1, ROR2, ROS, SRC, SYK, TIE1, TIE2, TRKA, TRKB, KDR, AKT1, AKT2, A KT3, PDK1, PKC, RHO, ROCK1, RSK1, RKS2, RKS3, ATM, ATR, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, ERK1, ERK2 , ERK3, ERK4, GSK3A, GSK3B, JNK1, JNK2, JNK3, AurA, ARuB, PLK1, PLK2, PLK3, PLK4, IKK, KIN1, cRaf, PKN3, c-Src, Fak, PyK2, and AMPK.

[0229] In some embodiments, the target protein is a phosphatase selected from the group consisting of: WIP1, SHP2, SHP1, PRL-3, PTP1B, and STEP.

[0230] In some embodiments, the target protein is a ubiquitin ligase selected from the group consisting of: BMI-1, MDM2, NEDD4-1, β-TRCP, SKP2, E6AP, and APC / C.

[0231] In some embodiments, the target protein is a chromatin modifier / remodeler encoded by a gene selected from the group consisting of: BRG1, BRM, ATRX, PRDM3, ASH1L, CBP, KAT6A, KAT6B, MLL, NSD1, SETD2, EP300, KAT2A, and CREBBP.

[0232] In some embodiments, the target protein is a transcription factor encoded by a gene selected from the group consisting of: EHF, ELF1, ELF3, ELF4, ELF5, ELK1, ELK3, ELK4, ERF, ERG, ETS1, ETV1, ETV2, ETV3, ETV4, ETV5, ETV6, FEV, FLI1, GAVPA, SPDEF, SPI1, SPIC, SPIB, E2F1, E2F2, E2F3, E2F4, E2F7, E2F8, ARNTL, BHLHA15, BHLHB2, BHLBHB3, BHLHE22, BHLHE23, BHLHE41, CLOCK, FIGLA, HAS5, HES 7. HEY1, HEY2, ID4, MAX, MESP1, MLX, MLXIPL, MNT, MSC, MYF6, NEUROD2, NEUROG2, NHLH1, OLIG1, OLIG2, OLIG3, SREBF2, TCF3, TCF4, TFAP4, TFE3, TFEB, TF EC, USF1, ARF4, ATF7, BATF3, CEBPB, CEBPD, CEBPG, CREB3, CREB3L1, DBP, HLF, JDP2, MAFF, MAFG, MAFK, NRL, NFE2, NFIL3, TEF, XBP1, PROX1, TEAD1, TEAD3 ,TEAD4,ONECUT3,ALX3,ALX4,ARX,BARHL2,BARX,BSX,CART1,CDX1,CDX2,DLX1,DLX2,DLX3,DLX4,DLX5,DLX6,DMBX1,DPRX,DRGX,DUXA,EMX1,EMX2,EN1 , EN2, ESX1, EVX1, EVX2, GBX1, GBX2, GSC, GSC2, GSX1, GSX2, HESX1, HMX1, HMX2, HMX3, HNF1A, HNF1B, HOMEZ, HOXA1, HOXA10, HOXA13, HOXA2, HOXAB13, HOX B2, HOXB3, HOXB5, HOXC10, HOXC11, HOXC12, HOXC13, HOXD11, HOXD12, HOXD13, HOXD8, IRX2, IRX5, ISL2, ISX, LBX2, LHX2, LHX6, LHX9, LMX1A, LMX1B, MEIS 1. MEIS2, MEIS3, MEOX1, MEOX2, MIXL1, MNX1, MSX1, MSX2, NKX2-3, NKX2-8, NKX3-1, NKX3-2, NKX6-1, NKX6-2, NOTO, ONECUT1, ONECUT2, OTX1, OTX2, PDX1,PHOX2A、PHOX2B、PITX1、PITX3、PKNOX1、PROP1、PRRX1、PRRX2、RAX、RAXL1、RHOXF1、SHOX、SHOX2、TGIF1、TGIF2、TGIF2LX、UNCX、VAX1、VAX2、VENTX、VSX1、VSX2、CUX1、CUX2、POU1F1、POU2F1、POU2F2、POU2F3、POU3F1、POU3F2、POU3F3、POU3F4、POU4F1、POU4F2、POU4F3、POU5F1P1、POU6F2、RFX2、RFX3、RFX4、RFX5、TFAP2A、TFAP2B、TFAP2C、GRHL1、TFCP2、NFIA、NFIB、NFIX、GCM1、GCM2、HSF1、HSF2、HSF4、HSFY2、EBF1、IRF3、IRF4、IRF5、IRF7、IRF8、IRF9、MEF2A、MEF2B、MEF2D、SRF、NRF1、CPEB1、GMEB2、MYBL1、MYBL2、SMAD3、CENPB、PAX1、PAX2、PAX9、PAX3、PAX4、PAX5、PAX6、PAX7、BCL6B、EGR1、EGR2、EGR3、EGR4、GLIS1、GLIS2、GLI2、GLIS3、HIC2、HINFP1、KLF13、KLF14、KLF16、MTF1、PRDM1、PRDM4、SCRT1、SCRT2、SNAI2、SP1、SP3、SP4、SP8、YY1、YY2、ZBED1、ZBTB7A、ZBTB7B、ZBTB7C、ZIC1、ZIC3、ZIC4、ZNF143、ZNF232、ZNF238、ZNF282、ZNF306、ZNF410、ZNF435、ZBTB49、ZNF524、ZNF713、ZNF740、ZNF75A、ZNF784、ZSCAN4、CTCF、LEF1、SOX10、SOX14、SOX15、SOX18、SOX2、SOX21、SOX4、SOX7、SOX8、SOX9、SRY、TCF7L1、FOXO3、FOXB1、FOXC1、FOXC2、FOXD2、FOXD3、FOXG1、FOXI1、FOXJ2、FOXJ3、FOXK1、FOXL1、FOXO1、FOXO4、FOXO6、FOXP3、EOMES、MGA、NFAT5、NFATC1、NFKB1、NFKB2、TP63、RUNX2、RUNX3、T、TBR1、TBX1、TBX15、TBX19、TBX2、TBX20, TBX21, TBX4, TBX5, AR, ESR1, ESRRA, ESRRB, ESRRG, HNF4A, NR2C2, NR2E1, NR2F1, NR2F6, NR3C1, NR3C2, NR4A2, RARA, RARB, RARG, RORA, RXRA, RXRB, RXRG, THRA, THRB, VDR, GATA3, GATA4, GATA5, C-myc, Max, Stat3, androgen receptor, C-Jun, C-Fox, N-Myc, L-Myc, MITF, Hif-1α, Hif-2α, Bcl6, E2F1, NF-κB, Stat5, and ER (coact).

[0233] In some embodiments, the target protein is selected from the group consisting of: TrkA, P2Y14, mPEGS, ASK1, ALK, Bcl-2, BCL-XL, mSIN1, RORγt, IL17RA, eIF4E, TLR7 R, PCSK9, IgE R, CD40, CD40L, Shn-3, TNFR1, TNFR2, IL31RA, OSMR, IL12β1,2, Tau, FASN, KCTD 6, KCTD 9, Raptor, Rictor, RALGAPA, RALGAPB, annexin family members, BCOR, NCOR, beta catenin, AAC 11, PLD1, PLD2, Frizzled7, RaLP, MLL-1, Myb, Ezh2, RhoGD12, EGFR, CTLA4R, GCGC (coact), adiponectin R2, GPR81, IMPDH2, IL-4R, IL-13R, IL-1R, IL2-R, IL-6R, IL-22R, TNF-R, TLR4, Nrlp3, and OTR.

[0234] In another aspect, the present disclosure provides a presenting protein / compound complex comprising a presenting protein and a compound described herein.

[0235] In some embodiments of the ternary complex or presenting protein / compound complex described herein, the presenting protein is a prolyl isomerase. In some embodiments, the presenting protein is a member of the FKBP family, a member of the cycloserine protease family, or PIN1. In some embodiments, the presenting protein is a member of the following FKBP family selected from: FKBP12, FKBP12.6, FKBP13, FKBP19, FKBP22, FKBP23, FKBP25, FKBP36, FKBP38, FKBP51, FKBP52, FKBP60, FKBP65, and FKBP133. In some embodiments, the member of the FKBP family is FKBP12, FKBP12.6, FKBP25, or FKBP52. In some embodiments, the presenting protein is a member of the cycloserine protease family selected from the group consisting of PP1A, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, PPWD1, PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, and PPIAL4G. In some embodiments, the member of the cycloserine protease family is PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, or PPIAL4G.

[0236] In another aspect, the present disclosure provides methods of modulating a target protein by contacting the target protein with a compound or presenting protein / compound complex described herein.

[0237] In another aspect, the present disclosure provides methods of inhibiting a target protein by contacting the target protein with a compound or presenting protein / compound complex described herein.

[0238] In another aspect, the present disclosure provides methods of activating a target protein by contacting the target protein with a compound or presenting protein / compound complex described herein.

[0239] In another aspect, the present disclosure provides methods of forming the ternary complex described herein by contacting a target protein with a presenting protein / compound complex described herein.

[0240] In some embodiments of the aforementioned methods, upon contact with the target protein, the target protein forms a covalent bond with the compound or presenting protein / compound complex. In some embodiments, upon contact with the target protein, an aspartic acid, glutamic acid, cysteine, glutamine, asparagine, lysine, or histidine residue of the target protein forms a covalent bond with the compound or complex. In some embodiments, upon contact with the target protein, an aspartic acid, glutamic acid, cysteine, glutamine, or asparagine residue of the target protein forms a covalent bond with the compound or complex.

[0241] In another aspect, the present disclosure provides a method for cross-linking a compound as described herein to a second moiety by contacting the second moiety with the compound under conditions sufficient to form a covalent bond between the compound and the second moiety. Such conditions include an orientation and a residence time sufficient for the compound and the second moiety to form a covalent bond. Methods for determining whether a covalent bond has formed are known in the art, for example, using FRET, mass spectrometry, or gel shift analysis. In some embodiments, the second moiety is a target protein.

[0242] In another aspect, the present disclosure provides methods for forming a presenting protein / compound complex as described herein, by contacting a presenting protein with a compound as described herein under conditions sufficient to allow complex formation. In some embodiments, the complex is formed by non-covalent interactions. Methods for measuring such interactions are known in the art, for example, using FRET.

[0243] In another aspect, the present disclosure provides a method of forming the ternary complex described herein, comprising the steps of:

[0244] a) contacting a presenting protein with a compound described herein under conditions sufficient to allow formation of a presenting protein / compound complex; and

[0245] b) contacting the presenting protein / compound complex with the target protein under conditions that allow formation of a ternary complex.

[0246] In some embodiments, the binding affinity of the presenting protein / compound complex to the target protein is at least 5-fold higher than that of the presenting protein or compound alone. In some embodiments, the presenting protein or compound does not substantially bind to the target protein without forming a presenting protein / compound complex.

[0247] On the other hand, the present disclosure provides a method for treating a disease or condition in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound as described herein. In some embodiments, the subject has previously received a prior therapy, such as a cancer therapy. In some embodiments, the subject has developed resistance to a prior therapy (e.g., a cancer therapy).

[0248] In particular, it is contemplated that any limitation discussed with respect to one embodiment of the present disclosure may apply to any other embodiment of the present disclosure. In addition, any compound or composition of the present disclosure may be used in any method of the present disclosure, and any method of the present disclosure may be used to produce or utilize any compound or composition of the present disclosure.

[0249] Definitions and Chemical Terms

[0250] In this application, unless the context indicates otherwise, (i) the term "a / a" means "one or more"; (ii) the term "or" is used to mean "and / or" (unless explicitly indicated to refer to only alternatives or the alternatives are mutually exclusive), although this disclosure supports definitions referring only to alternatives and "and / or"; (iii) the terms "comprising" and "including" are understood to cover the listed components or steps alone or together with one or more other components or steps; and (iv) where a range is provided, the endpoints are included.

[0251] As used herein, the term "about" is used to indicate that a value includes the standard deviation of the error of the device or method for determining the value. In certain embodiments, the term "about" refers to a range of values ​​in the range of (greater than or less than) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction of the stated value, unless otherwise stated or otherwise apparent from the context (e.g., where such numerals will exceed 100% of possible values).

[0252] As used herein, the term "adjacent," in the context of describing adjacent atoms, refers to divalent atoms that are directly connected by a covalent bond.

[0253] As used herein, "compounds of the present invention," "compounds disclosed herein," or "compounds described herein," and similar terms, whether explicitly mentioned or not, refer to compounds of Formula I or Formula II, and subformulae thereof, and compounds of Table 3, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof.

[0254] The term "wild-type" refers to an entity having structure or activity as found in nature in a "normal" (as opposed to mutant, diseased, altered, etc.) state or background. Those skilled in the art will appreciate that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0255] Those skilled in the art will appreciate that certain compounds described herein may exist in one or more different isomers (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., wherein one or more atoms have been substituted with a different isotope of an atom, such as hydrogen for deuterium). Unless otherwise indicated or clear from the context, the structures shown are understood to represent any such isomers or isotopic forms, either individually or in combination.

[0256] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be separated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are encompassed in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be separated as mixtures of isomers or as separated isomeric forms.

[0257] In some embodiments, one or more compounds presented herein can exist in different tautomeric forms. As will be clear from the context, reference to such compounds encompasses all such tautomeric forms unless expressly excluded. In some embodiments, tautomeric forms result from the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, tautomeric forms may be prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge as the reference form. Examples of moieties with prototropic tautomeric forms are keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions in a heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. In some embodiments, the tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, the tautomeric forms are caused by acetal interconversion.

[0258] Unless otherwise stated, structures shown herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P. 33 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled) can be used in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful due to their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e., 2 H) substitution may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2 H or 3 H replacement, or one or more carbon atoms are 13 C or 14 C-enriched carbon replacement. Positron-emitting isotopes (such as 15 O. 13 N. 11 C and 18 F) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for the compounds of the invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0259] As is known in the art, many chemical entities can adopt a variety of different solid forms, such as amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any such form, including in any solid form. In some embodiments, the compounds described or illustrated herein can be provided or used in the form of a hydrate or solvate.

[0260] Non-limiting examples of compounds of the present invention that may contain one or more deuterium-substituted moieties (wherein "R" at any position may be deuterium (D)) include

[0261]

[0262] At various positions in this specification, substituents of compounds of the present disclosure are disclosed as groups or in ranges. The disclosure is specifically intended to include every individual subcombination of members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually. Furthermore, where a compound includes multiple positions where substituents are disclosed as groups or in ranges, unless otherwise indicated, the disclosure is intended to cover individual compounds and groups of compounds (e.g., classes and subclasses) containing every individual subcombination of members at each position.

[0263] The term "optionally substituted X" (e.g., "optionally substituted alkyl") is intended to be equivalent to "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). The feature "X" (e.g., alkyl) itself is not intended to mean that it is optional. As described herein, certain compounds of interest may contain one or more "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, such as any of the substituents or groups described herein. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents at each position may be the same or different. For example, in the term "optionally substituted C1-C6 alkyl-C2-C9 heteroaryl," the alkyl portion, the heteroaryl portion, or both may be optionally substituted. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are not substantially altered when subjected to conditions that allow for the compound's production, detection, and, in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0264] Suitable monovalent substituents on the substitutable carbon atoms of the "optionally substituted" group may independently be deuterium; halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o ;-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2)0- 4SR o ; -(CH2) 0-4 Ph, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substitution; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be R o substituted; 4-11 membered saturated or unsaturated heterocycloalkyl (e.g., 4-8 membered saturated or unsaturated heterocycloalkyl (e.g., pyridyl)), which may be further optionally substituted (e.g., substituted with methyl); 3-8 membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ; -(CH2) 0-4 C(O)R o ;-C(S)R o ; -(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 -C(O)-N(R o )2;-(CH2) 0-4 -C(O)-N(R o )-S(O)2-R o ;-C(NCN)NRo 2;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR o ;-SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-(CH2) 0- 4OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NOR o )NR o 2;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-P(O)(OR o )2;-OP(O)R o 2;-OP(O)(OR o )2;-OP(O)(ORo )R o , -SiR o 3;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, -C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 3-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o Together with their one or more intermediate atoms, they form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below. In some embodiments, the substituent of a suitable carbon is -N3, for example for the purpose of click chemistry reactions, as described herein.

[0265] R o (or by two independent occurrences of R o Suitable monovalent substituents on the ring formed together with one or more of its intermediate atoms are independently halogen, -(CH2) 0-2 R · 、-(halogenated R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2;-O(halogenated R · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2)0-2SR · 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR ·3. -C(O)SR · 、-(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · , where each R · is unsubstituted or, when preceded by "halo", is substituted only by one or more halogens, and is independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0266] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2-3 S-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1-6 an aliphatic group or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0267] R * Suitable substituents on the aliphatic group include halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR ·2 or -NO2, where each R · is unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and is independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0268] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include Each of these are independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh or an unsubstituted 3-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of Together with their intervening atom(s), they form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0269] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · is unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and is independently C 1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0270] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0271] As used herein, the term "acyl" refers to the group -C(O)-R, where R is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, or heteroaryl, each of which is as defined herein. Optionally substituted acyl is an acyl group that is optionally substituted as defined herein for each group.

[0272] As used herein, the term "alkoxy" refers to -O-C1-C 20 Alkyl groups, wherein the alkoxy group is attached to the rest of the compound through an oxygen atom.

[0273] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon radical containing from 1 to 20 (e.g., from 1 to 10 or from 1 to 6) carbon atoms. In some embodiments, the alkyl group is unbranched (i.e., straight-chain); in some embodiments, the alkyl group is branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n- and isopropyl, n-, sec-, iso-, and tert-butyl, and neopentyl.

[0274] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group derived from a straight-chain or branched saturated hydrocarbon by removing two hydrogen atoms, and examples are methylene, ethylene, isopropylene, etc. The term "C x -C y "Alkylene" means an alkylene group having x to y carbons. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C 10 、C2-C 20 , C2-C6, C2-C 10 or C2-C 20 In some embodiments, the alkylene group may be further substituted with 1, 2, 3, or 4 substituents as defined herein.

[0275] Unless otherwise indicated, as used herein, the term "alkenyl" refers to a monovalent straight or branched chain group of 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds and examples are ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl includes both cis and trans isomers. Unless otherwise indicated, as used herein, the term "alkenylene" refers to a divalent straight or branched chain group of 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0276] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl and 1-propynyl.

[0277] As used herein, the term "alkynyl sulfone" refers to a group comprising the following structure: wherein R is any chemically feasible substituent described herein.

[0278] As used herein, the term "amino" refers to For example -NH2 and -N(CH3)2.

[0279] As used herein, the term "aminoalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties.

[0280] As described herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), wherein the amino acid is connected to a parent molecular group via a side chain, an amino group, or an acid group (e.g., a side chain). As used herein, the term "amino acid" broadly refers to any compound or substance that can be incorporated into a polypeptide chain, for example, by forming one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid. "Standard amino acid" refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0281] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system formed from carbon atoms, wherein the ring connected to the side group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. The aromatic ring can be connected to its side group at any heteroatom or carbocyclic atom that produces a stable structure, and unless otherwise indicated, any one of the ring atoms can be optionally substituted.

[0282] As used herein, the term "CO" represents a bond. For example, the term -N(C(O)-(CO-C5 alkylene-H)- includes -N(C(O)-(CO alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0283] As used herein, the terms "carbocycle" and "carbocyclyl" refer to a monovalent optionally substituted C3-C 12 Monocyclic, bicyclic or tricyclic structures, the ring structure can be a bridged ring, a condensed ring or a spirocycle, wherein all rings are formed by carbon atoms and at least one ring is non-aromatic.Carbocyclic ring structures include cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of carbocyclic groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decahydronaphthyl etc. Carbocyclic ring can be connected to its side group at any ring atom producing a stable structure, and unless otherwise specified, any one of the ring atoms can be optionally substituted.

[0284] As used herein, the term "carbonyl" refers to a C(O) group, which may also be represented as C=O.

[0285] As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH or the unprotonated counterpart.

[0286] As used herein, the term "cyano" refers to a -CN group.

[0287] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon group which may be bridged, fused or spirocyclic, having from three to eight ring carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloheptyl.

[0288] As used herein, the term "cycloalkenyl" refers to a non-aromatic, saturated cyclic hydrocarbon group, which may be bridged, fused, or spiro, having from three to eight ring carbons, unless otherwise specified, and containing one or more carbon-carbon double bonds.

[0289] As used herein, the term "diastereomers" refers to stereoisomers that are not mirror images of each other and are not superimposable on each other.

[0290] As used herein, the term "enantiomer" means each individual optically active form of a compound of the invention having an optical purity or enantiomeric excess of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98% (as determined by methods standard in the art).

[0291] As used herein, the term "haloacetyl" refers to an acetyl group in which at least one hydrogen has been replaced by a halogen.

[0292] As used herein, the term "haloalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more halogen moieties, which may be the same or different.

[0293] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine or fluorine.

[0294] As used herein, the term "heteroalkyl" refers to an "alkyl" as defined herein, wherein at least one carbon atom has been replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom may be present in the middle or at the end of the group. As used herein, the term "heteroalkylene" refers to a divalent alkylene linear or branched group having from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons), unless otherwise specified, wherein at least one carbon atom has been replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom may be present in the middle or at the end of the group.

[0295] As used herein, the term "heteroalkenyl" refers to an "alkenyl" as defined herein, wherein at least one carbon atom has been replaced by a heteroatom (e.g., O, N, or S atom). The heteroatom may be present in the middle or at the terminal end of the group.

[0296] As used herein, the term "heteroalkynyl" refers to an "alkynyl" as defined herein, wherein at least one carbon atom has been replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom may be present in the middle or at the terminal end of the group.

[0297] As used herein, the term "heteroaryl" refers to a monovalent monocyclic or polycyclic structure containing at least one fully aromatic ring: that is, it contains 4n+2 π electrons within the monocyclic or polycyclic ring system and contains at least one ring heteroatom selected from N, O or S in the aromatic ring. Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10 or 2 to 9) carbon atoms. The term "heteroaryl" includes bicyclic, tricyclic and tetracyclic groups, wherein any of the above heteroaromatic rings is fused to one or more aromatic or carbocyclic rings, such as a phenyl ring or a cyclohexane ring. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl and 4-azaindolyl. The heteroaryl ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted. In some embodiments, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents.

[0298] As used herein, the term "heterocycloalkyl" refers to a monocyclic, bicyclic or polycyclic ring system that can be bridged, fused or spirocyclic, wherein at least one ring is non-aromatic and wherein the non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has zero to two double bonds, and the 6-membered and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocycloalkyls have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbon atoms. The term "heterocycloalkyl" also refers to a heterocyclic compound having a bridged polycyclic structure in which one or more carbon atoms or heteroatoms bridge two non-adjacent members of the monocyclic ring, such as quinuclidine. The term "heterocycloalkyl" includes bicyclic, tricyclic and tetracyclic groups, wherein any of the above heterocycles is fused to one or more aromatic rings, carbocyclic rings, heteroaromatic rings or heterocyclic rings, such as aromatic rings, cyclohexane rings, cyclohexene rings, cyclopentane rings, cyclopentene rings, pyridine rings or pyrrolidine rings. Examples of heterocycloalkyls are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine and decahydronaphthyridine. The heterocycloalkyl ring can be connected to its side group at any ring atom that produces a stable structure, and unless otherwise indicated, any of the ring atoms can be optionally substituted.

[0299] The term "heterocyclenyl" as used herein refers to a non-aromatic, saturated cyclic heterocyclic group which may be bridged, fused or spirocyclic, having from 5 to 10 ring atoms, unless otherwise specified, containing one or more carbon-carbon double bonds, and containing one, two, three or four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.

[0300] The term "heterocycloalkynyl" as used herein refers to a non-aromatic, saturated cyclic heterocyclic group which may be bridged, fused or spiro, having from 8 to 10 ring atoms, unless otherwise specified, containing one or more carbon-carbon triple bonds, and containing one, two, three or four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.

[0301] As used herein, the term "hydroxy" refers to an -OH group.

[0302] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more -OH moieties.

[0303] As used herein, the term "isomer" means any tautomer, stereoisomer, atropisomer, enantiomer or diastereomer of any compound of the present invention. It should be recognized that the compounds of the present invention may have one or more chiral centers or double bonds and therefore exist as stereoisomers (e.g., double bond isomers, i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures shown herein and therefore the compounds of the present invention include all corresponding stereoisomers (i.e., stereoisomerically pure forms, e.g., geometrically pure, enantiomerically pure or diastereomerically pure) as well as enantiomers and stereoisomer mixtures, such as racemates. Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can generally be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0304] As used herein, the term "linker" refers to a divalent organic moiety that connects a first moiety (eg, a macrocyclic moiety) to a second moiety (eg, a cross-linking group).

[0305] "Macrocyclic moiety" or "macrocycle" refers to a compound or a portion of a compound having a ring of at least 10 atoms, e.g., at least 12, at least 14, at least 16, 10 to 40, 12 to 40, or 12 to 30. In some embodiments, the macrocycle has at least 12 atoms. In some embodiments, the macrocycle has at least 14 atoms.

[0306] In some embodiments, the linker comprises 20 or fewer straight-chain atoms. In some embodiments, the linker comprises 15 or fewer straight-chain atoms. In some embodiments, the linker comprises 10 or fewer straight-chain atoms. In some embodiments, the linker has a molecular weight of less than 500 g / mol. In some embodiments, the linker has a molecular weight of less than 400 g / mol. In some embodiments, the linker has a molecular weight of less than 300 g / mol. In some embodiments, the linker has a molecular weight of less than 200 g / mol. In some embodiments, the linker has a molecular weight of less than 100 g / mol. In some embodiments, the linker has a molecular weight of less than 50 g / mol.

[0307] As used herein, the term "stereoisomers" refers to all possible different isomeric and conformational forms that a compound (e.g., a compound of any formula described herein) may possess, specifically all possible stereochemical and conformational isomeric forms of the basic molecular structure, all diastereomers, enantiomers, or conformers, including atropisomers. Some compounds of the present invention may exist in different tautomeric forms, all of which are encompassed within the scope of the present invention.

[0308] As used herein, the term "sulfonyl" refers to a -S(O)2- group.

[0309] As used herein, the term "thiocarbonyl" refers to a -C(S)- group.

[0310] Those of ordinary skill in the art reading this disclosure will understand that certain compounds described herein may be provided or used in any of a variety of forms, such as salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, and the like. In some embodiments, reference to a particular compound may relate to a particular form of that compound. In some embodiments, reference to a particular compound may relate to any form of that compound. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound than a racemic mixture of the compound; a particular salt of a compound may be considered a different form than another salt form of the compound; a preparation of one conformational isomer ((Z) or (E)) containing a double bond may be considered a different form than the form of the other conformational isomer ((E) or (Z)) containing a double bond; a preparation in which one or more atoms are different isotopes than those present in a reference preparation may be considered a different form.

[0311] Chemical substituents can "stabilize positive charge or partial positive charge" or "carbocation stabilization" in a manner known to those skilled in the art of organic chemistry. For example, substituents can stabilize positive charge through resonance effects (delocalization of electron density in adjacent orbitals), hyperconjugation (e.g., interaction of electrons in a sigma orbital with adjacent non-bonding p orbitals), and inductive effects (changes in electron density due to electron-withdrawing or electron-donating groups in the molecule).

[0312] As used herein, the term "complex" refers to a group of two or more compounds and / or proteins bound together by binding interactions (e.g., covalent bonds or non-covalent interactions, such as hydrophobic effect interactions, electrostatic interactions, van der Waals interactions, or π effect interactions). Examples of complexes are "presenting protein / compound complexes," which include a compound of the present invention bound to a presenting protein, and "compound / target protein complexes," which include a compound of the present invention bound to a target protein.

[0313] The term "presenting protein" refers to a protein that combines with a small molecule to form a complex that binds to a target protein (e.g., a eukaryotic target protein, such as a mammalian target protein or a fungal target protein or a prokaryotic target protein, such as a bacterial target protein) and regulates the activity of the target protein. In some embodiments, the presenting protein is a relatively abundant protein (e.g., the presenting protein is abundant enough that participation in the ternary complex does not significantly affect the biological effect of the presenting protein in the cell and / or the viability or other properties of the cell). In certain embodiments, the presenting protein is a protein with molecular chaperone activity in the cell. In some embodiments, the presenting protein is a protein with multiple natural interaction partners in the cell. In certain embodiments, the presenting protein is a protein known to combine with a small molecule to form a binary complex that is known or suspected to bind to the target protein and regulate the biological activity of the target protein.

[0314] The term "presenter protein binding portion" refers to a group of ring atoms and moieties attached thereto (e.g., atoms within 20 atoms of the ring atoms, such as atoms within 15 atoms of the ring atoms, atoms within 10 atoms of the ring atoms, atoms within 5 atoms of the ring atoms) that participate in binding to a presenter protein such that the compound specifically binds to the presenter protein, e.g., with a K of less than 10 μM (e.g., less than 5 μM, less than 1 μM, less than 500 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 25 nM, less than 10 nM). D , or inhibiting the peptidyl prolyl isomerase activity of a presenting protein, for example, with an IC of less than 1 μM (e.g., less than 0.5 μM, less than 0.1 μM, less than 0.05 μM, less than 0.01 μM). 50. It should be understood that the presenting protein binding portion does not necessarily include all the atoms in the compound that interacts with the presenting protein. It should also be understood that one or more atoms of the presenting protein binding portion may be located within the target protein interaction portion (e.g., a eukaryotic target protein interaction portion, such as a mammalian target protein interaction portion or a fungal target protein interaction portion, or a prokaryotic target protein interaction portion, such as a bacterial target protein interaction portion). In some embodiments, the presenting protein binding portion has a molecular weight of less than 1000 g / mol. In some embodiments, the presenting protein binding portion has a molecular weight of less than 750 g / mol. In some embodiments, the presenting protein binding portion has a molecular weight of less than 500 g / mol. In some embodiments, the presenting protein binding portion has a molecular weight of less than 400 g / mol. In some embodiments, the presenting protein binding portion has a molecular weight of less than 300 g / mol. In some embodiments, the presenting protein binding portion has a molecular weight of less than 200 g / mol. In some embodiments, the presenting protein binding portion has a molecular weight of less than 100 g / mol. In some embodiments, the presenting protein binding portion has a molecular weight of less than 50 g / mol.

[0315] It will be understood that the term "binding," as used herein, generally refers to an association (e.g., non-covalent or covalent) between two or more entities. "Direct" binding involves physical contact between the entities or moieties; indirect binding involves physical interaction through physical contact with one or more intermediate entities. Binding between two or more entities can generally be assessed under any of a variety of circumstances—including studying the interacting entities or moieties in isolation, or in the context of a more complex system (e.g., covalently or otherwise associated with a carrier entity and / or in a biological system or cell).

[0316] The affinity of a molecule X for its partner Y can usually be described using the dissociation constant (K D ) is represented by a affinity. Affinity can be measured by conventional methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below. As used herein, the term "K D " is intended to refer to the dissociation equilibrium constant for a particular compound-protein or complex-protein interaction. Typically, the compounds of the present invention dissociate at a constant constant of less than about 10 -6 M, such as less than about 10 -7 M, 10 -8 M, 10 -9 M or 10 -10 M or even lower dissociation equilibrium constant (K D) is bound to a presenting protein, for example, when assayed by surface plasmon resonance (SPR) technology using the presenting protein as the analyte and the compound as the ligand. The presenting protein / compound complex of the present invention is bound to a target protein (e.g., a eukaryotic target protein, such as a mammalian target protein, or a fungal target protein or a prokaryotic target protein, such as a bacterial target protein) at a kinetic energy of less than about 10 -6 M, such as less than about 10 -7 M, 10 -8 M, 10 -9 M or 10 -10 M or even lower dissociation equilibrium constant (K D ) binding, for example when the assay is performed by surface plasmon resonance (SPR) technology using the target protein as analyte and the complex as ligand.

[0317] As used herein, the term "target protein interacting portion" refers to a group of ring atoms and moieties attached thereto (e.g., atoms within 20 atoms of the ring atoms, such as atoms within 15 atoms of the ring atoms, atoms within 10 atoms of the ring atoms, atoms within 5 atoms of the ring atoms), which specifically binds to a target protein (e.g., a eukaryotic target protein, such as a mammalian target protein or a fungal target protein, or a prokaryotic target protein, such as a bacterial target protein) when the compound is complexed with a presenting protein.

[0318] The term "modulator" is used to refer to an entity, and the presence or level of the entity is associated with the change in the level and / or properties of the activity in a system in which an activity of interest is observed, compared to the change observed under other similar conditions when the modulator is not present. In some embodiments, the modulator is an activator because the activity is increased in its presence compared to the activity observed under other similar conditions when the modulator is not present. In some embodiments, the modulator is an antagonist or inhibitor because the activity is reduced in its presence compared to other similar conditions when the modulator is not present. In some embodiments, the modulator interacts directly with the target entity of interest in the activity. In some embodiments, the modulator interacts indirectly with the target entity of interest in the activity (i.e., directly with an intermediate compound that interacts with the target entity). In some embodiments, the modulator affects the level of the target entity of interest; optionally or additionally, in some embodiments, the modulator affects the activity of the target entity of interest without affecting the level of the target entity. In some embodiments, the modulator affects the level and activity of the target entity of interest, so that the observed activity difference cannot be fully explained by the observed level difference or is disproportionate to the observed level difference. In some embodiments, the modulator is an allosteric modulator, such as an allosteric agonist.

[0319] The term "presenting protein" refers to a protein that combines with a small molecule to form a complex that binds to a target protein (e.g., a eukaryotic target protein, such as a mammalian target protein or a fungal target protein or a prokaryotic target protein, such as a bacterial target protein) and regulates the activity of the target protein. In some embodiments, the presenting protein is a relatively abundant protein (e.g., the presenting protein is abundant enough that participation in the ternary complex does not significantly affect the biological effect of the presenting protein in the cell and / or the viability or other properties of the cell). In certain embodiments, the presenting protein is a protein with molecular chaperone activity in the cell. In some embodiments, the presenting protein is a protein with multiple natural interaction partners in the cell. In certain embodiments, the presenting protein is a protein known to combine with a small molecule to form a binary complex that is known or suspected to bind to the target protein and regulate the biological activity of the target protein.

[0320] The term "substantially" refers to the qualitative condition of exhibiting all or nearly all of the degree or range of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completion or achieve or avoid an absolute result. Therefore, the term "substantially" is used herein to capture the potential incompleteness inherent in many biological and chemical phenomena.

[0321] As used herein, the term "does not substantially bind" to a particular protein can be expressed as, for example, a molecule or a portion of a molecule having a 10 -4 M or larger, or 10 -5 M or larger, or 10 -6 M or larger, or 10 -7 M or larger, or 10 -8 M or larger, or 10 -9 M or larger, or 10 -10 M or larger, or 10 -11 M or larger, or 10 -12 M or larger K D , or in 10 -4 M to 10 -12 M or 10 -6 M to 10 -10 M or 10 -7 M to 10 -9 K in the M range D .

[0322] The term "target protein" refers to a protein that binds to a small molecule or presenting protein / compound complex described herein. In some embodiments, the target protein does not substantially bind to a small molecule or presenting protein alone. In some embodiments, the small molecule / presenting protein / compound complex does not substantially bind to mTOR or calcineurin. In some embodiments, the target protein is involved in a biological pathway associated with a disease, disorder, or condition. In some embodiments, the target protein is a naturally occurring protein; in some such embodiments, the target protein is naturally present in certain mammalian cells (e.g., mammalian target proteins), fungal cells (e.g., fungal target proteins), bacterial cells (e.g., bacterial target proteins), or plant cells (e.g., plant target proteins). In some embodiments, the target protein is characterized by a natural interaction with one or more naturally presenting proteins / natural small molecule complexes. In some embodiments, the target protein is characterized by a natural interaction with a variety of different naturally presenting proteins / natural small molecule complexes; in some such embodiments, some or all of the complexes utilize the same presenting protein (and different small molecules). In some embodiments, the target protein does not substantially bind to a complex of cyclosporine, rapamycin or FK506 and a presenting protein (e.g., FKBP). The target protein may be naturally occurring, such as wild-type. Alternatively, the target protein may differ from the wild-type protein but still retain biological function, such as as an allelic variant, splice mutant, or biologically active fragment. Exemplary mammalian target proteins are GTPases; GTPase-activating proteins; guanine nucleotide exchange factors; heat shock proteins; ion channels; coiled-coil proteins; kinases; phosphatases; ubiquitin ligases; transcription factors; chromatin modifiers / remodelers; proteins with classic protein-protein interaction domains and motifs; or any other protein involved in a biological pathway associated with a disease, disorder, or condition.

[0323] The term "target protein interacting portion" refers to a group of atoms in a compound that participates in binding to a target protein (e.g., a eukaryotic target protein, such as a mammalian target protein or a fungal target protein, or a prokaryotic target protein, such as a bacterial target protein). In some embodiments, the compound binds to the target protein when the compound forms a complex with the presenting protein. It should be understood that the target protein interacting portion does not necessarily contain all the atoms in the compound that interact with the presenting protein. It should also be understood that one or more atoms of the presenting protein binding portion may also be present in the target protein interacting portion. In some embodiments, the target protein interacting portion is a cross-linking group.

[0324] The term "small molecule" refers to an organic and / or inorganic compound of low molecular weight. Generally speaking, a "small molecule" is a molecule having a size of less than about 5 kilodaltons (kD). In some embodiments, a small molecule is less than about 4kD, 3kD, about 2kD, or about 10kD. In some embodiments, a small molecule is less than about 800 daltons (D), about 600D, about 500D, about 400D, about 300D, about 200D, or about 100D. In some embodiments, a small molecule is less than about 2000g / mol, less than about 1500g / mol, less than about 1000g / mol, less than about 800g / mol, or less than about 500g / mol. In some embodiments, a small molecule is not a polymer. In some embodiments, a small molecule does not include a polymeric portion. In some embodiments, a small molecule is not a protein or polypeptide (e.g., not an oligopeptide or peptide). In some embodiments, a small molecule is not a polynucleotide (e.g., not an oligonucleotide). In some embodiments, a small molecule is not a polysaccharide. In some embodiments, the small molecule does not comprise a polysaccharide (e.g., is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, the small molecule is not a lipid. In some embodiments, the small molecule is a regulatory compound. In some embodiments, the small molecule has biological activity. In some embodiments, the small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, the small molecule is a therapeutic agent. DETAILED DESCRIPTION

[0325] Compound

[0326] The present disclosure provides compounds capable of forming complexes and / or cross-linking with a target (e.g., a target protein). Also disclosed are synthetic intermediates for preparing such compounds and complexes formed by reacting with the compounds.

[0327] synthetic intermediates

[0328] The compounds of the present disclosure may contain an aziridine moiety. The compounds of the present disclosure may contain an aziridine and a group capable of reacting with a second moiety, thereby allowing the aziridine to be incorporated into another moiety. The compounds may, for example, be capable of reacting with nucleophiles (e.g., esters). Thus, the compounds may have a structure of Formula I:

[0329]

[0330] or a pharmaceutically acceptable salt thereof; wherein

[0331] Z is

[0332] M + It is a cation;

[0333] R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0334] R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0335] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0336] R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0337] or

[0338] R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0339] or

[0340] R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a );

[0341] or

[0342] R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0343] or

[0344] R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0345] or

[0346] R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4 are each independently cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0347] or

[0348] R 2 and R 4 Combining to form optionally substituted C3-C10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R are each independently cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0349] R 3 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0350] R 1a 、R 2a 、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0351] R 2bis hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0352] R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0353] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0354] In some embodiments, R and R 4 At least one of them is not hydrogen.

[0355] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ia:

[0356]

[0357] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ib:

[0358]

[0359] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Ic:

[0360]

[0361] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula Id:

[0362]

[0363] In some embodiments, R3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted C6-C 10 In some embodiments, R 3 is an optionally substituted C1-C6 alkyl. 3 is methyl, ethyl or benzyl.

[0364] In some embodiments, M + For Li + .

[0365] In some embodiments, R 3 for:

[0366]

[0367] In some embodiments, Z is

[0368] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof, or an alternative pharmaceutically acceptable salt, or a stereoisomer thereof:

[0369] Table 1

[0370]

[0371]

[0372]

[0373] Aziridine-containing compounds

[0374] The present disclosure also provides compounds containing an aziridine moiety combined with a monovalent organic moiety. Those skilled in the art are familiar with organic moieties. The monovalent organic moiety can be or can include, for example, a small molecule (e.g., a macrocyclic small molecule), a polymer, a nucleic acid (e.g., a DNA or RNA oligonucleotide), a peptide, a polypeptide, an oligosaccharide, an organometallic, a degradation agent, a macrocyclic compound, or a protein (such as a mutant protein). The organic moiety can be combined with the aziridine moiety disclosed herein in a variety of ways, and those skilled in the art are familiar with methods for installing the synthetic intermediates containing aziridine as described herein in the monovalent organic moiety. Non-limiting examples include the following schemes:

[0375] Scheme A. Exemplary General Synthesis of Aziridine-Containing Compounds

[0376]

[0377] As shown in Scheme A, compounds of this type can be prepared by reacting an appropriate amine-substituted monovalent organic moiety (1) with a carboxylate-substituted aziridine (2) in the presence of a standard amide coupling reagent to provide the final compound (3).

[0378] Scheme B. Exemplary General Synthesis of Aziridine-Containing Compounds

[0379]

[0380] As shown in Scheme B, compounds of this type can be prepared by reacting the appropriate amine-substituted monovalent organic moiety (1) with an activated ester-containing aziridine (2) in the presence of a basic amine to provide the final compound (3).

[0381] In some embodiments, the compound containing an aziridine moiety bound to a monovalent organic moiety can have the structure of Formula II:

[0382]

[0383] or a pharmaceutically acceptable salt thereof,

[0384] Among them A 1 For the unit price organic part;

[0385] Q is

[0386] R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0387] R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0388] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0389] R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5- to 10-membered heteroaryl or -Si(R 1a )3;

[0390] or R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0391] or

[0392] R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R 4are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a );

[0393] or

[0394] R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0395] or

[0396] R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0397] or

[0398] R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4 are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0399] or

[0400] R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0401] R 1a 、R 2a 、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0402] R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0403] R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0404] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0405] In some embodiments, R and R 4 At least one of them is not hydrogen.

[0406] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIa:

[0407]

[0408] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIb:

[0409]

[0410] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIc:

[0411]

[0412] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IId:

[0413]

[0414] In some embodiments, Q is

[0415] In some embodiments, the organic moiety can be combined with the aziridine in an alternative manner, such as with R, R 1 、R 2 or R 4 combination.

[0416] In some embodiments, A 1 is or comprises a peptide. In some embodiments, A 1 is or comprises a protein. In some embodiments, A 1 is or comprises a nucleic acid. In some embodiments, A 1 is a small molecule. In some embodiments, A 1 It is or contains a macrocyclic small molecule.

[0417] In some embodiments, one or more compounds in WO 2023 / 141300 may be excluded from any embodiment herein. In some embodiments, one or more compounds in WO 2022 / 271658 may be excluded from any embodiment herein. In some embodiments, one or more compounds in WO 2023 / 208005 may be excluded from any embodiment herein.

[0418] In some embodiments, the compound is not a compound disclosed in WO 2021 / 091967. In some embodiments, the compound is not a compound in Table 2.

[0419] Table 2

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441] Presenting protein binding portion

[0442] In some embodiments of the above compounds, A 1It is a presenting protein binding portion. This portion may include a group of ring atoms (e.g., 5 to 20 ring atoms, 5 to 10 ring atoms, 10 to 20 ring atoms) and a portion attached thereto (e.g., an atom within 20 atoms of the ring atom, such as an atom within 15 atoms of the ring atom, an atom within 10 atoms of the ring atom, an atom within 5 atoms of the ring atom) that participates in binding to the presenting protein such that the provided compound specifically binds to the presenting protein, for example, with a K of less than 10 μM (e.g., less than 5 μM, less than 1 μM, less than 500 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 25 nM, less than 10 nM). D , or inhibiting the peptidyl prolyl isomerase activity of a presenting protein, for example, with an IC of less than 1 μM (e.g., less than 0.5 μM, less than 0.1 μM, less than 0.05 μM, less than 0.01 μM). 50 In some embodiments, the presenter protein binding portion does not comprise all atoms in the provided compounds that interact with the presenter protein. In some embodiments, one or more atoms of the presenter protein binding portion may be located within the target protein interacting portion (e.g., a eukaryotic target protein interacting portion, such as a mammalian target protein interacting portion or a fungal target protein interacting portion, or a prokaryotic target protein interacting portion, such as a bacterial target protein interacting portion). In certain embodiments, one or more atoms of the presenter protein binding portion do not interact with the presenter protein.

[0443] In some embodiments, the presenting protein binding portion comprises an N-acyl proline moiety, an N-acyl-piperacyl acid moiety, an N-acyl 3-morpholino-carboxylic acid moiety, and / or an N-acyl piperazinoic acid moiety (e.g., acylated on any nitrogen atom). In certain embodiments, the presenting protein binding portion comprises an N-acyl-piperacyl acid moiety. In some embodiments, the presenting protein binding portion comprises an N-acyl proline moiety. In certain embodiments, the presenting protein binding portion comprises an N-acyl 3-morpholino-carboxylic acid moiety. In certain embodiments, the presenting protein binding portion comprises an N-acyl piperazinoic acid moiety.

[0444] In some embodiments, at least one atom of the presenting protein binding moiety is involved in binding to one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) of Tyr27, Phe37, Asp 38, Arg41, Phe47, Gln54, Glu55, Val 56, Ile 57, Trp 60, Ala 82, Try 83, His88, Ile 92, and / or Phe 100 of FKBP12. In some embodiments, at least one of the presenting protein binding moieties is involved in binding to at least one (e.g., two, three, or four) of Arg 41, Gln 54, Glu 55, and / or Ala 82 of FKBP12.

[0445] In some embodiments, the presenting protein binding moiety has the structure of Formula IV:

[0446]

[0447] where the dashed lines represent zero, one, two, three, or four non-adjacent double bonds;

[0448] A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is connected to -CH(R 10 )-, an optionally substituted C2-C4 alkylene, an optionally substituted C1-C4 heteroalkylene or an optionally substituted C2-C4 alkenylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene or an optionally substituted 5- to 10-membered heteroarylene;

[0449] X 1 is an optionally substituted C1-C2 alkylene, NR, O or S(O) n ;

[0450] X 2 is O or NH;

[0451] X 3 N or CH;

[0452] n is 0, 1, or 2;

[0453] R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2;

[0454] Each R ’are independently H or optionally substituted C1-C4 alkyl;

[0455] Y 1 is C, CH or N;

[0456] Y 2 、Y 3 、Y 4 and Y 7 are independently C or N;

[0457] Y 5 is CH, CH2 or N;

[0458] Y 6 is C(O), CH, CH2 or N;

[0459] R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or

[0460] R 1 and R 2 and, taken together with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0461] R 2 R is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; 3 does not exist, or

[0462] R 2 and R 3 and the atoms to which it is attached form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl;

[0463] R 4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens;

[0464] R 5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl;

[0465] R 6 is hydrogen or methyl; R 7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or

[0466] R 6 and R 7 and, in combination with the carbon atoms to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0467] R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0468] R 7 and R 8 Combined with the carbon atom to which it is connected to form C=CR 7’ R 8’ ; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;

[0469] R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or, in combination with the carbon to which they are attached, form a carbonyl;

[0470] R 7’ is hydrogen, halogen or optionally substituted C1-C3 alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or

[0471] R 7’ and R 8’ and, in combination with the carbon atoms to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;

[0472] R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or

[0473] R 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl;

[0474] R 9’ is hydrogen or an optionally substituted C1-C6 alkyl group;

[0475] R 10 is hydrogen, halogen, hydroxy, C1-C3 alkoxy or C1-C3 alkyl;

[0476] R 10a is hydrogen or halogen;

[0477] R 11 is hydrogen or C1-C3 alkyl; and

[0478] R 34 Each hydrogen in the compound of formula IV is optionally isotopically enriched with deuterium.

[0479] In some embodiments, the presenting protein binding moiety has the structure of Formula V:

[0480]

[0481] wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene;

[0482] X 1 is CH2 or O;

[0483] m is 1 or 2;

[0484] n is 0 or 1;

[0485] R 1 is hydrogen or an optionally substituted 3- to 10-membered heterocycloalkyl;

[0486] R 2 is an optionally substituted C1-C6 alkyl group; and

[0487] R 3 is an optionally substituted C1-C6 alkyl group or an optionally substituted 3- to 6-membered cycloalkyl group.

[0488] In some embodiments, the presenting protein binding moiety has the structure of Formula VI:

[0489]

[0490] wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene;

[0491] X 1 、X 2 and X 3Each independently selected from CH2, CHF, CF2, C=O or O;

[0492] m is 1 or 2;

[0493] n is 0 or 1;

[0494] R 1 is hydrogen, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl;

[0495] R 2 is an optionally substituted C1-C6 alkyl group; and

[0496] R 3 is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted heterocycloalkyl group,

[0497] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0498] In some embodiments, the presenting protein binding moiety has a structure of one of Formulas VII, VIII, and IX:

[0499]

[0500] wherein o and p are independently 0, 1 or 2;

[0501] q is an integer between 0 and 7;

[0502] r is an integer between 0 and 4;

[0503] X 4 and X 5 Each independently absent, CH2, O, S, SO, SO2 or NR 11 ;

[0504] R 6 and R 7 and each is independently hydrogen, hydroxy, optionally substituted amino, halogen, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10arylC1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroarylC1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C9 heterocyclylC1-C6 alkyl, or R 6 and R 7 Combines with the carbon atom to which it is bound to form C=O;

[0505] Each R 8 are independently hydroxy, optionally substituted amino, halogen, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10 Aryl C1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroaryl C1-C6 alkyl, optionally substituted C2-C9 heterocyclyl or optionally substituted C2-C9 heterocyclyl C1-C6 alkyl, or two R 8 Combining to form optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl;

[0506] R 9 is optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10 ArylC1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroarylC1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclylC1-C6 alkyl;

[0507] R 10 is an optionally substituted C1-C6 alkyl group;

[0508] Each R 11are independently hydroxy, cyano, optionally substituted amino, halogen, thiol, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C 10 Carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C6-C 10 ArylC1-C6 alkyl, optionally substituted C2-C9 heteroaryl, optionally substituted C2-C9 heteroarylC1-C6 alkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heterocyclylC1-C6 alkyl; and

[0509] R 12 and R 13 are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, C3-C7 carbocyclyl, optionally substituted C6-C 10 aryl C1-C6 alkyl and optionally substituted C3-C7 carbocyclyl C1-C6 alkyl.

[0510] In some embodiments, the presenting protein binding moiety has the following structure:

[0511]

[0512]

[0513] or a stereoisomer thereof.

[0514] In certain embodiments, the presenting protein binding moiety has the following structure:

[0515]

[0516] Activity-based probes

[0517] Certain aziridine-containing probes are known in the art and can be used in conjunction with the methods disclosed herein. These compounds can be used to form any of the complexes described herein. Exemplary aziridine-containing activity-based probes are shown below. Such probes can be modified using methods disclosed herein and known in the art to incorporate an aziridine moiety disclosed herein, for example, to replace the original aziridine.

[0518]

[0519]

[0520] Compound characteristics

[0521] Pharmacokinetic parameters

[0522] For example, an in vivo rat early pharmacokinetic (EPK) study design can be used to assess the initial exposure profile of a compound to demonstrate bioavailability. For example, male Sprague-Dawley rats can be dosed with a specific formulation via oral (PO) gavage. Blood samples can then be collected from the animals at six time points within four hours of dosing. Pharmacokinetic analysis can then be performed on the LC-MS / MS measured concentrations of each compound at each time point.

[0523] Cell permeability

[0524] In some embodiments, the compound is cell permeable.To determine the permeability of a compound, any method known in the art can be used, such as the biosensor assays described herein.

[0525] protein

[0526] Presenting protein

[0527] Presenting protein can be combined with small molecules to form a complex, and the complex can be combined with a target protein (e.g., a eukaryotic target protein, such as a mammalian target protein or a fungal target protein or a prokaryotic target protein, such as a bacterial target protein) and regulate the activity of the target protein. In some embodiments, the presenting protein is a mammalian presenting protein (e.g., a human presenting protein). In some embodiments, the presenting protein is a fungal presenting protein. In certain embodiments, the presenting protein is a bacterial presenting protein. In some embodiments, the presenting protein is a plant presenting protein. In some embodiments, the presenting protein is a relatively abundant protein (e.g., the presenting protein is abundant enough that participating in the ternary complex does not have a substantial negative impact on the biological effect of the presenting protein in the cell and / or the viability or other properties of the cell). In some embodiments, the presenting protein is more abundant than the target protein. In certain embodiments, the presenting protein is a protein with molecular chaperone activity in the cell. In some embodiments, the presenting protein has multiple natural interaction partners in the cell. In certain embodiments, the presenting protein is a protein known to be combined with a small molecule to form a binary complex, and the binary complex is known or suspected to be combined with the target protein and regulate the biological activity of the target protein. Immunophilins are a class of presenting proteins known to have these functions and include FKBP and cyclophilins.

[0528] In some embodiments, the reference presenting protein exhibits peptidyl prolyl isomerase activity; in some embodiments, the presenting protein exhibits activity comparable to that of the reference presenting protein. In certain embodiments, the presenting protein is a member of the FKBP family (e.g., FKBP12, FKBP12.6, FKBP13, FKBP19, FKBP22, FKBP23, FKBP25, FKBP36, FKBP38, FKBP51, FKBP52, FKBP60, FKBP65, and FKBP133), a member of the cyclophilin family (e.g., PP1A, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, PPWD1, PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, or PPIAL4G), or PIN1. The "FKBP family" is a family of proteins that have prolyl isomerase activity and act as protein folding chaperones for proteins containing proline residues. Genes encoding proteins in this family include AIP, AIPL1, FKBP1A, FKBP1B, FKBP2, FKBP3, FKBP4, FKBP5, FKBP6, FKBP7, FKBP8, FKBP9, FKBP9L, FKBP10, FKBP11, FKBP14, FKBP15, and LOC541473.

[0529] The "cyclophilin family" is a family of proteins that bind to cyclosporine. Genes encoding proteins in this family include PPIA, PPIB, PPIC, PPID, PPIE, PPIF, PPIG, PPIH, SDCCAG-10, PPIL1, PPIL2, PPIL3, PPIL4, P270, PPWD1, and COAS-2. Exemplary cyclophilins include PP1A, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, PPWD1, PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, and PPIAL4G.

[0530] In some embodiments, the presenting protein is a chaperone protein, such as GRP78 / BiP, GRP94, GRP170, calnexin, calreticulin, HSP47, ERp29, protein disulfide isomerase (PDI), and ERp57.

[0531] In some embodiments, the presenting protein is an allelic variant or splice variant of FKBP or cyclophilin disclosed herein.

[0532] In some embodiments, a presenting protein is a polypeptide whose amino acid sequence i) shows significant identity to the amino acid sequence of a reference presenting protein; ii) includes a portion that shows significant identity to the corresponding portion of the reference presenting protein; and / or iii) includes at least one signature sequence found in a presenting protein. In many embodiments, identity is considered "significant" for the purposes of defining a presenting protein if the identity is greater than 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more. In some embodiments, portions showing substantial identity have at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 500, 550, 600, 7 ...

[0533] Representative presentation proteins are encoded by genes listed in Table 3 or homologs thereof; in some embodiments, reference presentation proteins are encoded by genes listed in Table 3. In addition, one of ordinary skill in the art can readily identify characteristic sequences of general presentation proteins and / or characteristic sequences of specific presentation protein subgroups with reference to Table 3.

[0534] Table 3. Genes encoding selected presentation proteins

[0535]

[0536]

[0537] target protein

[0538] A target protein (e.g., a eukaryotic target protein, such as a mammalian target protein or a fungal target protein, or a prokaryotic target protein, such as a bacterial target protein) is a protein that mediates a disease state or a symptom of a disease state. Therefore, by modulating (inhibiting or increasing) its activity, a desired therapeutic effect can be achieved. Target proteins useful in the complexes and methods of the present invention include those that do not naturally bind to the presenting protein, for example, those that have an affinity for the presenting protein of greater than 1 μM, preferably greater than 5 μM, and more preferably greater than 10 μM in the absence of a binary complex with the compound of the present invention. Alternatively, a target protein that does not naturally bind to the presenting protein is one that has an affinity for the compound of the present invention of greater than 1 μM, preferably greater than 5 μM, and more preferably greater than 10 μM in the absence of a binary complex. In another alternative, a target protein that does not naturally bind to the presenting protein is one that has an affinity for a binary complex of cyclosporine, rapamycin, or FK506 with a presenting protein (e.g., FKBP) of greater than 1 μM, preferably greater than 5 μM, and more preferably greater than 10 μM. In another alternative, the target protein that does not naturally bind to the presenting protein is a protein other than calcineurin or mTOR. The selection of a suitable target protein for the complexes and methods of the present invention may depend on the presenting protein. For example, a target protein with a low affinity for cyclophilin may have a high affinity for FKBP and would not be used with the latter.

[0539] The target protein can be naturally occurring, such as wild-type. Alternatively, the target protein can differ from the wild-type protein while still retaining biological function, such as as an allelic variant, splice mutant, or biologically active fragment.

[0540] In some embodiments, the target protein is a transmembrane protein. In some embodiments, the target protein has a coiled-coil structure. In certain embodiments, the target protein is a protein that is a dimeric complex.

[0541] In some embodiments, the target protein of the present invention includes one or more surface sites (e.g., flat surface sites), characterized in that, in the absence of a presenting protein / compound complex, small molecules typically exhibit low or undetectable binding to the site. In some embodiments, the target protein includes one or more surface sites (e.g., flat surface sites), in the absence of a presenting protein / compound complex, a specific small molecule (e.g., compound) exhibits low or undetectable binding (e.g., binding at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100 times or more compared to the binding observed for a presenting protein / compound complex involving the same compound). In some embodiments, the target protein has a surface characterized in that one or more sites (and in some embodiments, the entire surface) lack any traditional binding pockets, e.g., cavities or pockets on a protein structure whose physicochemical and / or geometric properties are comparable to proteins whose activity has been regulated by one or more small molecules. In certain embodiments, the target protein has sites for traditional binding pockets and protein-protein interactions. In some embodiments, the target protein is an undruggable target, e.g., the target protein is not a member of a protein family known to be targeted by drugs and / or does not have a binding site that is expected (e.g., according to art-recognized understanding, as discussed herein) to be suitable for binding to a small molecule.

[0542] In some embodiments, the target protein is a GTPase such as DIRAS1, DIRAS2, DIRAS3, ERAS, GEM, HRAS, KRAS, MRAS, NKIRAS1, NKIRAS2, NRAS, RALA, RALB, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, RASD1, RASD2, RASL10A, RASL10B, RASL11A, RASL11B, RASL12, REM1, REM2, RERG, RERGL, RRAD, RRAS, RRAS2, RHOA, RHOB, RHOBTB1, RHOBTB2, R HOBTB3, RHOC, RHOD, RHOF, RHOG, RHOH, RHOJ, RHOQ, RHOU, RHOV, RND1, RND2, RND3, RAC1, RAC2, RAC3, CDC42, RAB1A, RAB1B, RAB2, RAB3A, RAB3B, RAB3C , RAB3D, RAB4A, RAB4B, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B, RAB6C, RAB7A, RAB7B, RAB7L1, RAB8A, RAB8B, RAB9, RAB9B, RABL2A, RABL2B, RABL4, RAB10, RAB11A, RAB11B, RAB12, RAB13, RAB14, RAB15, RAB17, RAB18, RAB19, RAB20, RAB21, RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28, RAB 2B, RAB30, RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37, RAB38, RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, RAB41, RAB42, RAB 43. RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, ARF1, ARF3, ARF4, ARF5, ARF6, ARL1, ARL2, ARL3, ARL4, ARL5, ARL5C, ARL6, ARL7, ARL8, ARL9, ARL10A, ARL10B , ARL10C, ARL11, ARL13A, ARL13B, ARL14, ARL15, ARL16, ARL17, TRIM23, ARL4D, ARFRP1, ARL13B, RAN, RHEB, RHEBL1, RRAD, GEM, REM, REM2, RIT1, RIT2,In some embodiments, the target protein is a GTPase activating protein such as NF1, IQGAP1, PLEXIN-B1, RASAL1, RASAL2, ARHGAP5, ARHGAP8, ARHGAP12, ARHGAP22, ARHGAP25, BCR, DLC1, DLC2, DLC3, GRAF, RALBP1, RAP1GAP, SIPA1, TSC2, AGAP2, ASAP1, or ASAP3. In some embodiments, the target protein is a guanine nucleotide exchange factor such as CNRASGEF, RASGEF1A, RASGRF2, RASGRP1, RASGRP4, SOS1, RALGDS, RGL1, RGL2, RGR, ARHGEF10, ASEF / ARHGEF4, ASEF2, DBS, ECT2, GEF-H1, LARG, NET1, OBSCURIN, P-REX1, P-REX2, PDZ-RHOGEF, TEM4, TIAM1, TRIO, VAV1, VAV2, VAV3, DOCK1, DOCK2, DOCK3, DOCK4, DOCK8, DOCK10, C3G, BIG2 / ARFGEF2, EFA6, FBX8, or GEP100. In certain embodiments, the target protein is a protein having a protein-protein interaction domain such as: ARM; BAR; BEACH; BH; BIR; BRCT; BROMO; BTB; C1; C2; CARD; CC; CALM; CH; CHROMO; CUE; DEATH; DED; DEP; DH; EF-hand; EH; ENTH; EVH1; F-box; FERM; FF; FH2; FHA; FYVE; GAT; GEL; GLUE; GRAM; GRIP; GYF; HEAT ; HECT; IQ; LRR; MBT; MH1; MH2; MIU; NZF; PAS; PB1; PDZ; PH; POLO-Box; PTB; PUF; PWWP; PX; RGS; RING; SAM; SC; SH2; SH3; SOCS; SPRY; START; SWIRM; TIR; TPR; TRAF; SNARE; TUBBY; TUDOR; UBA; UEV; UIM; VHL; VHS; WD40; WW; SH2; SH3; TRAF; bromodomain; or TPR. In some embodiments, the target protein is a heat shock protein such as: Hsp20, Hsp27, Hsp70, Hsp84, αB crystal, TRAP-1, hsf1, or Hsp90. In certain embodiments, the target protein is an ion channel such as: Cav2.2, Cav3.2, IKACh, Kv1.5, TRPA1,NAv1.7, Nav1.8, Nav1.9, P2X3 or P2X4. In some embodiments, the target protein is a coiled-coil protein such as synaptonemal, SPAG4, VAV1, MAD1, ROCK1, RNF31, NEDP1, HCCM, EEA1, Vimentin, ATF4, Nemo, SNAP25, Syntaxin1a, FYCO1 or CEP250. In certain embodiments, the target protein is a kinase such as ABL, ALK, AXL, BTK, EGFR, FMS, FAK, FGFR1, 2, 3, 4, FLT3, HER2 / ErbB2, HER3 / ErbB3, HER4 / ErbB4, IGF1R, INSR, JAK1, JAK2, JAK3, KIT, MET, PDGFRA, PDGFRB, RETRON, ROR1, ROR2, ROS, SRC, SYK, TIE1, TIE2, TRKA, TRKB, KDR, AKT1, AKT2, A KT3, PDK1, PKC, RHO, ROCK1, RSK1, RKS2, RKS3, ATM, ATR, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, ERK1, ERK2, ERK3, ERK4, GSK3A, GSK3B, JNK1, JNK2, JNK3, AurA, ARuB, PLK1, PLK2, PLK3, PLK4, IKK, KIN1, cRaf, PKN3, c-Src, Fak, PyK2 or AMPK. In some embodiments, the target protein is a phosphatase such as WIP1, SHP2, SHP1, PRL-3, PTP1B or STEP. In certain embodiments, the target protein is a ubiquitin ligase, such as BMI-1, MDM2, NEDD4-1, Beta-TRCP, SKP2, E6AP, or APC / C. In some embodiments, the target protein is a chromatin modifier / remodeler, such as a chromatin modifier / remodeler encoded by the genes BRG1, BRM, ATRX, PRDM3, ASH1L, CBP, KAT6A, KAT6B, MLL, NSD1, SETD2, EP300, KAT2A, or CREBBP. In some embodiments, the target protein is a transcription factor, such as the transcription factors encoded by the following genes: EHF, ELF1, ELF3, ELF4, ELF5, ELK1, ELK3, ELK4, ERF, ERG, ETS1, ETV1, ETV2, ETV3, ETV4, ETV5, ETV6, FEV, FLI1, GAVPA, SPDEF, SPI1, SPIC, SPIB, E2F1, E2F2, E2F3, E2F4, E2F7, E2F8,ARNTL、BHLHA15、BHLHB2、BHLBHB3、BHLHE22、BHLHE23、BHLHE41、CLOCK、FIGLA、HAS5、HES7、HEY1、HEY2、ID4、MAX、MESP1、MLX、MLXIPL、MNT、MSC、MYF6、NEUROD2、NEUROG2、NHLH1、OLIG1、OLIG2、OLIG3、SREBF2、TCF3、TCF4、TFAP4、TFE3、TFEB、TFEC、USF1、ARF4、ATF7、BATF3、CEBPB、CEBPD、CEBPG、CREB3、CREB3L1、DBP、HLF、JDP2、MAFF、MAFG、MAFK、NRL、NFE2、NFIL3、TEF、XBP1、PROX1、TEAD1、TEAD3、TEAD4、ONECUT3、ALX3、ALX4、ARX、BARHL2、BARX、BSX、CART1、CDX1、CDX2、DLX1、DLX2、DLX3、DLX4、DLX5、DLX6、DMBX1、DPRX、DRGX、DUXA、EMX1、EMX2、EN1、EN2、ESX1、EVX1、EVX2、GBX1、GBX2、GSC、GSC2、GSX1、GSX2、HESX1、HMX1、HMX2、HMX3、HNF1A、HNF1B、HOMEZ、HOXA1、HOXA10、HOXA13、HOXA2、HOXAB13、HOXB2、HOXB3、HOXB5、HOXC10、HOXC11、HOXC12、HOXC13、HOXD11、HOXD12、HOXD13、HOXD8、IRX2、IRX5、ISL2、ISX、LBX2、LHX2、LHX6、LHX9、LMX1A、LMX1B、MEIS1、MEIS2、MEIS3、MEOX1、MEOX2、MIXL1、MNX1、MSX1、MSX2、NKX2-3、NKX2-8、NKX3-1、NKX3-2、NKX6-1、NKX6-2、NOTO、ONECUT1、ONECUT2、OTX1、OTX2、PDX1、PHOX2A、PHOX2B、PITX1、PITX3、PKNOX1、PROP1、PRRX1、PRRX2、RAX、RAXL1、RHOXF1、SHOX、SHOX2、TGIF1、TGIF2、TGIF2LX、UNCX、VAX1、VAX2、VENTX、VSX1、VSX2、CUX1、CUX2、POU1F1、POU2F1、POU2F2、POU2F3、POU3F1、POU3F2, POU3F3, POU3F4, POU4F1, POU4F2, POU4F3, POU5F1P1, POU6F2, RFX2, RFX3, RFX4, RFX5, TFAP2A, TFAP2B, TFAP2C, GRHL1, TFCP2, NFIA, NFIB, NFIX, GCM1, GCM2, HSF1, HSF2, HSF4, HSFY2, EBF1, IRF3, IRF4, IRF5, IRF7, IRF8, IRF9, MEF2A, MEF2B, MEF2D, SRF, NRF1, CPEB1, GMEB2, MYBL1, MYBL2, SMAD3, CENPB, PAX1, PAX2, PAX9, PAX3, PAX4, PAX5, PAX6, PAX7, BCL6B, EGR1, EGR2, EGR3, EGR4, GLIS1, GLIS2, GLI2, GLIS3, HIC2, HINFP1, KLF13, KLF14, KLF16, MTF1, PRDM1, PRDM4, SCRT1, SCRT2, SNAI2, SP1, SP3, SP4, SP8, YY1, YY2, ZBED1, ZBTB7A, ZBTB7B, ZBTB7C, ZIC1, ZIC3, ZIC4, ZNF143, ZNF232, ZNF238, ZNF282, ZNF306, ZNF410, ZNF435, ZBTB49, ZNF524, ZNF713, ZNF740, ZNF75A, ZNF784, ZSCAN4, CTCF, LEF1, SOX10, SOX14, SOX15, SOX18, SOX2, SOX21, SOX4, SOX7, SOX8, SOX9, SRY, TCF7L1, FOXO3, FOXB1, FOXC, FOXC2, FOXD2, FOXD3, FOXG1, FOXI1, FOXJ2, FOXJ3, FOXK, FOXL1, FOXO1, FOXO4, FOXO6, FOXP3, EOMES, MGA, NFAT5, NFATC1, NFKB1, NFKB2, TP63, RUNX2, RUNX3, T, TBR1, TBX1, TBX15, TBX19, TBX2, TBX20, TBX21, TBX4, TBX5, AR, ESR1, ESRRA, ESRRB, ESRRG, HNF4A, NR2C2, NR2E1, NR2F1, NR2F6, NR3C1, NR3C2, NR4A2, RARA, RARB, RARG, RORA, RXRA, RXRB, RXRG, THRA, THRB, VDR, GATA3, GATA4 or GATA5; or C-myc, Max,Stat3, androgen receptor, C-Jun, C-Fox, N-Myc, L-Myc, MITF, Hif-1α, Hif-2α, Bcl6, E2F1, NF-κB, Stat5 or ER (coact). In certain embodiments, the target protein is TrkA, P2Y14, mPEGS, ASK1, ALK, Bcl-2, BCL-XL, mSIN1, RORγt, IL17RA, eIF4E, TLR7 R, PCSK9, IgER, CD40, CD40L, Shn-3, TNFR1, TNFR2, IL31RA, OSMR, IL12β1,2, Tau, FASN, KCTD 6, KCTD 9, Raptor, Rictor, RALGAPA, RALGAPB, annexin family members, BCOR, NCOR, β-catenin, AAC 11. PLD1, PLD2, Frizzled7, RaLP, MLL-1, Myb, Ezh2, RhoGD12, EGFR, CTLA4R, GCGC (coact), adiponectin R2, GPR81, IMPDH2, IL-4R, IL-13R, IL-1R, IL2-R, IL-6R, IL-22R, TNF-R, TLR4, Nrlp3, or OTR.

[0543] Synthesis method

[0544] The method for synthesizing cyclopropylaziridine disclosed herein is known in the art. Said method may include the method shown in the following scheme.

[0545]

[0546] (2R,3R)-β-phenylaziridine was synthesized using Davis auxiliary (p-toluenesulfenyl imide) (Davis et al., J. Org. Chem. 1994, 59(12), 3243-3245; Davis et al., J. Org. Chem. 1999, 64(20), 7559-7567). See letter A above.

[0547] (2S,3S)-β-Cyclopropylaziridine (letter B in the figure above) can be synthesized using Ellman's auxiliary (tert-butylsulfenyl imide) (Solá et al., Org. Biomol. Chem. 2011, 9(14), 5034).

[0548] β-Cyclopropylaziridines can also be prepared by reacting benzhydryl imine with a diazo ester under acidic conditions (Williams et al., J. Am. Chem. Soc. 2004, 126(6), 1612–1613). However, this method is not asymmetric and produces a mixture of cis- and trans-isomers as well as a mixture of enantiomers.

[0549] Alternatively, β-cyclopropylaziridine can be produced on a large scale using the following scheme:

[0550]

[0551] (2R,3R)-β-Cyclopropylaziridine can be synthesized by the reaction of (R)-p-toluenesulfenyl imine with benzyl 2-bromoacetate and LiHMDS. Removal of the chiral auxiliary is achieved using TFA or a methyl Grignard reagent. Methylation of the aziridine nitrogen is achieved via Chan-Lam coupling with methylboronic acid or alkylation with methyl iodide.

[0552] Complex

[0553] Presenting protein / compound complexes

[0554] In naturally occurring protein-protein interactions, binding events are primarily driven by hydrophobic residues on flat surface sites of the two proteins, whereas many small molecule-protein interactions are driven by interactions between small molecules in cavities or pockets on proteins. Hydrophobic residues on flat surface sites form hydrophobic hotspots on the two interacting proteins, where most binding interactions between two proteins are van der Waals interactions. Small molecules can participate in pseudo-protein-protein interactions (e.g., forming a ternary complex with a target protein) by forming complexes (e.g., presenting protein / compound complexes), thereby acting as portable hotspots for missing proteins (e.g., presenting proteins).

[0555] Many mammalian proteins are able to bind to any of a number of different partners; in some cases, this alternative binding interaction contributes to the biological activity of the protein. Many such proteins adapt to the inherent variability of hotspot protein regions to present the same residues in different structural environments. More specifically, protein-protein interactions can be mediated by a class of natural products produced by a selected group of fungal and bacterial species. These molecules exhibit a common structural organization and the resulting functions, thereby providing the ability to regulate protein-protein interactions. These molecules contain a highly conserved presenting protein binding portion and a target protein interaction portion that exhibits high variability between different natural products. The presenting protein binding portion confers specificity to the presenting protein and allows the molecule to bind to the presenting protein to form a binary complex; the mammalian target protein interaction portion confers specificity to the target protein and allows the binary complex to bind to the target protein, typically regulating (e.g., positively or negatively regulating) its activity.

[0556] These natural products are presented by presenting proteins (such as FKBP and cyclophilin) ​​and as adaptors of diffusible, cell-permeable, orally bioavailable protein-protein interactions.Examples include well-known and clinically relevant molecules, such as rapamycin (sirolimus (Sirolimus)), FK506 (tacrolimus (Tacrolimus)) and cyclosporin.In short, these molecules bind to presenting proteins, FKBP (such as rapamycin and FK506) or cyclophilin (such as diluent) in endogenous cells, and the binary complex of the resulting presenting protein-binding molecule selectively binds and inhibits the activity of the target protein in the cell. The formation of the ternary complex between presenting proteins, molecules and target proteins is driven by protein-molecule and protein-protein interactions, and both are necessary for suppressing target proteins. In the example of FKBP-rapamycin complex, the intracellular target is serine-threonine kinase mTOR, and for FKBP-FK506 complex, the intracellular target is phosphatase calcineurin. Of particular interest in the two preceding examples is that FKBP12 is used as a chaperone presentation protein by both rapamycin and FK506 presentation ligands. Furthermore, the substructural components of rapamycin and FK506 responsible for binding to FKBP12 are closely related in structure, the so-called "conserved regions." However, significant structural differences between rapamycin and FK506 in the non-FKBP12 binding regions, the "variable regions," lead to specific targeting of two different intracellular proteins, mTOR and calcineurin, respectively. In this way, the variable regions of rapamycin and FK506 contribute to the binding energy necessary to achieve presentation protein-target protein interactions.

[0557] In some embodiments, the binding affinity of a presenting protein / compound complex of the invention to the target protein is at least 5-fold (e.g., at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold) greater than the binding affinity of the complex to each of mTOR and / or calcineurin.

[0558] In some embodiments, the binding affinity of a presenting protein / compound complex of the invention to a target protein is at least 5-fold (e.g., at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold) greater than the affinity of the compound for the target protein when the compound is not bound to the presenting protein to form a complex.

[0559] In certain embodiments, the binding affinity of a presenting protein / compound complex of the invention to a target protein is at least 5-fold (e.g., at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold) greater than the affinity of the presenting protein to the target protein when the presenting protein is not bound to the compound to form a complex.

[0560] In some embodiments, the presenting protein / compound complexes of the invention inhibit a naturally occurring interaction between a target protein and a ligand (eg, a protein or small molecule that specifically binds to the target protein).

[0561] In certain embodiments, when the presenting protein is a prolyl isomerase, prolyl isomerase activity is inhibited by formation of a presenting protein / compound complex. In some embodiments of the presenting protein / compound complex of the invention, the compound is present with a K of less than 10 μM (e.g., less than 5 μM, less than 1 μM, less than 500 nM, less than 200 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 25 nM, less than 10 nM). D Specifically bind to the presenting protein, or inhibit the peptidyl prolyl isomerase activity of the presenting protein, for example, with an IC of less than 1 μM (e.g., less than 0.5 μM, less than 0.1 μM, less than 0.05 μM, less than 0.01 μM). 50 .

[0562] Compound / target protein complex

[0563] The compounds of the present disclosure can be used to form complexes with target proteins. Complexes can be formed by non-covalent interactions (e.g., van der Waals interactions or π interactions). Alternatively or in addition, such complexes can be formed by "cross-linking" the target by forming a covalent bond between the compound and the target protein. The compounds described herein may contain an electrophilic aziridine group that can react with nucleophilic residues (e.g., aspartic acid, glutamic acid, cysteine, glutamine, asparagine, lysine or histidine residues) of the target protein.

[0564] Including a carbocation-stabilizing electron-donating group at the β position of the carbonyl substituent may help promote crosslinking with the target protein. For example, a cyclopropyl substituent may facilitate the reaction of the aziridine with nucleophilic residues (e.g., aspartic acid residues). Without being bound by theory, the present inventors speculate that in situ protonation of the weakly basic aziridine nitrogen enhances the reactivity of the aziridine ring. c-c bond) part to the newly formed carbon cation (δ + )p orbitals, further promoting the reaction of the less reactive and highly solvated aspartate anion.

[0565]

[0566] In addition to the β-cyclopropyl group, other moieties may be beneficial for stabilizing the carbocation by hyperconjugation or resonance, including but not limited to aryl, vinyl, alkynyl, and cubic groups.

[0567] In some embodiments, the disclosed compound / target protein complex has the structure of Formula III:

[0568]

[0569] Among them A 1 For the unit price organic part;

[0570] Q is

[0571] P 1 A 2 , and P 2 is hydrogen; or P 1 is a hydroxyl group, and P 2 A 2 ;

[0572] A 2 is the target protein;

[0573] R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0574] R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0575] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0576] R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 Aryl or optionally substituted 5- to 10-membered heteroaryl or -Si(R 1a )3;

[0577] or R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0578] or

[0579] R and R 2Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a );

[0580] or

[0581] R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0582] or

[0583] R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0584] or

[0585] R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4 are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0586] or

[0587] R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0588] R 1a 、R 2a 、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0589] R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0590] R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0591] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0592] In some embodiments, R and R 4 At least one of them is not hydrogen.

[0593] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-1:

[0594]

[0595] Among them A 3 is the remaining portion of the target protein.

[0596] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-2:

[0597]

[0598] Among them A 3 is the remaining portion of the target protein.

[0599] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-3:

[0600]

[0601] Among them A 3 is the remaining portion of the target protein.

[0602] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-4:

[0603]

[0604] Among them A 3 is the remaining portion of the target protein.

[0605] In some embodiments, the compound / target protein complex has the structure of the compound / target protein complex as described in Technical Solution 16, wherein the compound / target protein complex has the structure of Formula IIIb-1:

[0606]

[0607] Among them A 3 is the remaining portion of the target protein.

[0608] In some embodiments, the compound / target protein complex has the structure of Formula IIIb-2:

[0609]

[0610] Among them A 3 is the remaining portion of the target protein.

[0611] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-1:

[0612]

[0613] Among them A 3 is the remaining portion of the target protein.

[0614] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-2:

[0615]

[0616] Among them A 3 is the remaining portion of the target protein.

[0617] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-3:

[0618]

[0619] Among them A 3 is the remaining portion of the target protein.

[0620] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-4:

[0621]

[0622] Among them A 3 is the remaining portion of the target protein.

[0623] In some embodiments, the compound / target protein complex has the structure of Formula IIId-1:

[0624]

[0625] Among them A 3 is the remaining portion of the target protein.

[0626] In some embodiments, the compound / target protein complex has the structure of Formula IIId-2:

[0627]

[0628] Among them A 3 is the remaining portion of the target protein.

[0629] In some embodiments, the compound / target protein complex has the structure of Formula IIIe-1:

[0630]

[0631] Among them A 3 is the remaining portion of the target protein.

[0632] In some embodiments, the compound / target protein complex has the structure of Formula IIIe-1:

[0633]

[0634] Among them A 3 is the remaining portion of the target protein.

[0635] In some embodiments, R is optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 In some embodiments, R is an optionally substituted C2-C6 alkylene group, an optionally substituted C2-C6 alkylene group, or an optionally substituted C2-C6 alkylene group. 10 In some embodiments, R is an optionally substituted cyclopropyl group. In some embodiments, R is In some embodiments, R is In some embodiments, R is an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl. In some embodiments, R is a carbocation-stabilized electron-donating group.

[0636] Ternary complex

[0637] The vast majority of small molecule drugs act by binding to functionally important sites on target proteins, thereby modulating (e.g., positively or negatively regulating) the activity of the protein. For example, the cholesterol-lowering drugs statins bind to the enzymatic active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. The fact that many such drug / target interaction pairs are known may have misled some people into believing that, given reasonable time, effort, and resources, small molecule modulators for most (if not all) proteins could be discovered. This is far from the truth. Current estimates suggest that only approximately 10% of all human proteins are targetable by small molecules. The other 90% are currently considered refractory or intractable to small molecule drug discovery. Such targets are often referred to as "undruggable." These undruggable targets include a large number of human proteins of important medical significance that have yet to be developed. Therefore, there is great interest in discovering new molecular patterns that can modulate the function of such undruggable targets.

[0638] The present invention recognizes that the targeting ability of small molecules is generally limited because their interaction with the target is driven by adhesion forces, the strength of which is roughly proportional to the contact surface area. Due to their small size, the only way for small molecules to accumulate sufficient intermolecular contact surface area to effectively interact with the target protein is to be engulfed by the protein. In fact, a large amount of experimental and computational data supports the view that only proteins with hydrophobic "pockets" on their surfaces can bind small molecules. In these cases, binding is achieved through engulfment. There are no examples of small molecules that can bind with high affinity to proteins outside of the hydrophobic pocket.

[0639] Nature has evolved a strategy that allows small molecules to interact with target proteins at locations other than hydrophobic pockets. This strategy is exemplified by the naturally occurring immunosuppressive drugs cyclosporin A, rapamycin, and FK506. The activity of these drugs involves the formation of a high-affinity complex between the small molecule and a small presenting protein. This combined surface of the small molecule and presenting protein then binds to the target. Thus, for example, the binary complex formed between cyclosporin A and cyclophilin A targets calcineurin with high affinity and specificity, whereas neither cyclosporin A nor cyclophilin A alone binds calcineurin with measurable affinity.

[0640] Many important therapeutic targets exert their effects by complexing with other proteins. The protein / protein interaction surface in many of these systems contains a core of hydrophobic side chains surrounded by a broad ring of polar residues. The hydrophobic residues contribute nearly all of the energetically favorable contacts, and thus this cluster is designated a "hotspot" for protein-protein interactions. Importantly, in the aforementioned complexes of natural small molecules with small presenting proteins, the small molecule provides a cluster of hydrophobic functionality resembling the hotspot, while the protein provides a ring composed primarily of polar residues. In other words, the presented small molecule system mimics a surface structure widely employed in natural protein / protein interaction systems.

[0641] The compounds of the present invention (e.g., macrocyclic compounds) can regulate biological processes, for example, by forming a presenting protein / compound complex as described above in combination with a presenting protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1), which is combined with a target protein to form a triple complex. The formation of these triple complexes allows for the regulation of proteins that do not have traditional binding sites and / or are considered undruggable. The presenting protein / compound complex can regulate biological processes by the synergistic binding between the compound and the presenting protein. Both the compound and the presenting protein have low affinity for a single target protein, but the presenting protein / compound complex has high affinity for the target protein. Collaborative binding can be determined by measuring the buried surface area of ​​the target protein including atoms from the compound and / or presenting protein and / or by measuring the free binding energy contribution of the compound and / or presenting protein. If at least one atom of each of the compound and the presenting protein participates in the binding to the target protein, the binding is considered to be synergistic.

[0642] Binding of the target protein / compound complex to the target protein is achieved by forming a combined binding site that includes residues from both the presenting protein and the compound, which allows for increased affinity that is not possible with either the presenting protein or the compound alone. For example, at least 20% (e.g., at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%) of the total buried surface area of ​​the target protein in the ternary complex includes one or more atoms that participate in binding to the compound, and / or at least 20% (e.g., at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%) of the total buried surface area of ​​the target protein in the ternary complex includes one or more atoms that participate in binding to the presenting protein. Alternatively, the compound contributes at least 10% (e.g., at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%) of the total binding free energy of the ternary complex, and / or the presenting protein contributes at least 10% (e.g., at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%) of the total binding free energy of the ternary complex.

[0643] In some embodiments, the presenting protein / compound complex is bound to a flat surface site on the target protein. In some embodiments, the compound (e.g., macrocyclic compound) in the presenting protein / compound complex is bound to a hydrophobic surface site on the target protein, such as a site comprising at least 50% hydrophobic residues. In some embodiments, at least 70% of the binding interactions between one or more atoms of the compound and one or more atoms of the target protein are van der Waals interactions and / or π effect interactions. In certain embodiments, the presenting protein / compound complex is bound to the target protein at a site of naturally occurring protein-protein interactions between a target protein and a protein that specifically binds to the target protein. In some embodiments, the presenting protein / compound complex is not bound at the active site of the target protein. In some embodiments, the presenting protein / compound complex is bound at the active site of the target protein.

[0644] Compounds of the invention that form ternary complexes with a presenting protein and a target protein are characterized by a lack of major structural reorganization in the presenting protein / compound complex compared to the ternary complex. Once the presenting protein / compound complex is formed, the lack of major structural reorganization results in a lower entropic cost to reorganize into a configuration that favors ternary complex formation. For example, PyMOL version 1.7rc1 ( In some embodiments, the structural organization of the compound (i.e., the average three-dimensional configuration of the atoms and bonds of the molecule) is substantially unchanged in the triple complex compared to the compound in the present protein / compound complex before target protein binding. For example, the root mean square deviation (RMSD) of the two aligned structures is less than 1.

[0645] Pharmaceutical compositions and methods of use

[0646] One embodiment of the present invention provides pharmaceutical compositions containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, as well as methods of preparing such compositions using the compound of the present invention.

[0647] As used herein, the term "pharmaceutical composition" refers to a compound, such as a compound of the present invention or a pharmaceutically acceptable salt thereof, formulated together with a pharmaceutically acceptable excipient.

[0648] In some embodiments, the compound is present in a pharmaceutical composition in a unit dose amount suitable for administration in a treatment regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition can be specifically formulated for administration in solid or liquid form, including those suitable for oral administration, such as a drench (aqueous or non-aqueous solution or suspension), tablet (e.g., those targeted for buccal, sublingual, and systemic absorption), bolus, powder, granules, paste for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as, for example, a sterile solution or suspension or a sustained release formulation; topical application, such as in the form of a cream, ointment, or controlled release patch or a spray applied to the skin, lungs, or oral cavity; intravaginal or rectal administration, such as in the form of a pessary, cream, or foam; sublingual; ophthalmic; transdermal; or nasal, transpulmonary, and to other mucosal surfaces.

[0649] As used herein, "pharmaceutically acceptable excipient" refers to any inactive ingredient (e.g., a vehicle capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in a subject. Typical excipients include, for example, anti-adhesive agents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coating agents, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water of hydration. Excipients include, but are not limited to, butylated optionally substituted hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, cross-linked polyvinyl pyrrolidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are familiar with a variety of agents and materials that can be used as excipients. See, e.g., Ansel et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0650] Unless expressly stated to the contrary, whether or not expressly stated, the compounds described herein can be provided or used in salt form (e.g., pharmaceutically acceptable salt form). As used herein, the term "pharmaceutically acceptable salt" refers to salts of compounds described herein that are suitable for use in contact with the tissues of humans and other animals without excessive toxicity, irritation, allergic reactions, etc., and that meet reasonable benefit / risk ratios, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., J.Pharmaceutical Sciences 66: 1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (P.H. Stahl and C.G. Wermuth eds.), Wiley-VCH, 2008 describe pharmaceutically acceptable salts. Salts can be prepared in situ during the final separation and purification of the compounds described herein or prepared separately by reacting the free base group with a suitable organic acid.

[0651] The compounds of the present invention may have an ionizable group so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts relating to inorganic or organic acids, or in the case of an acidic form of the compounds of the present invention, the salts may be prepared by inorganic or organic bases. In some embodiments, the compound is prepared into a pharmaceutically acceptable salt or is used in the form of a pharmaceutically acceptable salt, which is prepared into an addition product of a pharmaceutically acceptable acid or base. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid or tartaric acid for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, etc. for forming alkaline salts. The method for preparing suitable salts is well known in the art.

[0652] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-optionally substituted hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0653] As used herein, the term "subject" refers to any member of the animal kingdom. In some embodiments, a "subject" refers to a person at any stage of development. In some embodiments, a "subject" refers to a human patient. In some embodiments, a "subject" refers to a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cattle, primate, or pig). In some embodiments, the subject includes, but is not limited to, mammals, birds, reptiles, amphibians, fish, or worms. In some embodiments, the subject can be a transgenic animal, a genetically engineered animal, or a clone.

[0654] As used herein, the term "dosage form" refers to a physical discrete unit of a compound (e.g., a compound of the present invention) for administration to a subject. Each unit contains a predetermined amount of compound. In some embodiments, such an amount is a unit dose amount (or its entire portion) suitable for administration according to a dosage regimen that has been determined to be relevant to the desired or beneficial results when administered to a relevant group (i.e., using a therapeutic dosage regimen). It is understood by those skilled in the art that the total amount of the therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms. As used herein, the term "dosage regimen" refers to a group of unit doses (usually more than one) that are typically administered separately to a subject in separate time periods. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dosage regimen that may involve one or more doses. In some embodiments, the dosage regimen includes multiple doses, each of which is separated by a time period of the same length; in some embodiments, the dosage regimen includes multiple doses and at least two different time periods separating individual doses. In some embodiments, all doses within the dosage regimen have the same unit dose amount. In some embodiments, different doses within the dosage regimen have different amounts. In some embodiments, a dosing regimen comprises a first dose of a first dose amount, followed by one or more additional doses of a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose of a first dose amount, followed by one or more additional doses of a second dose amount that is the same as the first dose amount. In some embodiments, a dosing regimen is associated with a desired or beneficial outcome when administered in a relevant population (i.e., is a therapeutic dosing regimen).

[0655] A "therapeutic regimen" refers to a regimen of dosages whose administration in the relevant population is associated with desired or beneficial therapeutic outcomes.

[0656] The term "treatment" (as well as "treat" or "treating") broadly refers to any administration of a substance (e.g., a compound of the present invention) that partially or completely alleviates, ameliorates, alleviates, suppresses, delays the onset of, reduces the severity of, or reduces the incidence of one or more symptoms, features, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment may be administered to a subject who does not show signs of the relevant disease, disorder, or condition, or to a subject who shows only early signs of the disease, disorder, or condition. Alternatively or additionally, in some embodiments, treatment may be administered to a subject who shows one or more established signs of the relevant disease, disorder, or condition. In some embodiments, treatment may be treatment of a subject who has been diagnosed with the relevant disease, disorder, or condition. In some embodiments, treatment may be treatment of a subject who is known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, disorder, or condition.

[0657] The term "therapeutically effective amount" means an amount sufficient to treat the disease, disorder or illness when administered to a population suffering from or susceptible to the disease, disorder or illness according to a therapeutic dosing regimen. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence or severity of one or more symptoms of the disease, disorder or illness or delays its onset. Those of ordinary skill in the art will understand that the term "therapeutically effective amount" does not actually require successful treatment in a particular individual. On the contrary, a therapeutically effective amount can be an amount that provides a specific desired pharmacological response in a large number of subjects when administered to a patient in need of such treatment. In particular, it should be understood that a particular subject may actually be "refractory" to a "therapeutically effective amount". In some embodiments, reference to a therapeutically effective amount may refer to an amount measured in one or more specific tissues (e.g., tissues affected by a disease, disorder or illness) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, a therapeutically effective amount can be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount can be formulated or administered in multiple doses, for example, as part of a dosing regimen.

[0658] In order to be used as the treatment of a subject, the compound of the present invention or its pharmaceutically acceptable salt can be formulated into a medicine or veterinary composition. According to the subject to be treated, mode of administration and desired treatment type (such as prevention (prevention / prophylaxis) or treatment), compound or its pharmaceutically acceptable salt is prepared in a manner consistent with these parameters. An overview of such technology can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0659] The composition can be prepared according to conventional mixing, granulation or coating methods, respectively, and the pharmaceutical composition of the present invention can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the compound of the present invention or its pharmaceutically acceptable salt by weight or volume. In some embodiments, the compound described herein or its pharmaceutically acceptable salt can be present in an amount of 1%-95% by weight of the total weight of the composition (such as a pharmaceutical composition).

[0660] Composition can be suitable for intra-articular, oral, parenteral (such as intravenous, intramuscular), per rectum, percutaneous, subcutaneous, through surface, through dermal, sublingual, per nasal, per vaginal, intracapsular, intraurethral, ​​intrathecal, epidural, through ear or through eye administration or by injection, suction or with the dosage form of nose, urogenital, reproduction or oral mucosa direct contact provide.Therefore, pharmaceutical composition can be in such as tablet, capsule, pill, powder, granule, suspension, emulsion, solution, comprise the gel of hydrogel, paste, ointment, emulsifiable paste, plaster, drench medicine, osmotic delivery device, suppository, enema, injection, implant, spray, be suitable for the preparation sent by iontophoresis or the form of aerosol.Composition can be prepared according to conventional medicine practice.

[0661] As used herein, the term "administering" refers to administering a composition (e.g., a compound, or a formulation comprising a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be performed by any appropriate route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreous.

[0662] The formulation can be suitable for systemic administration or prepared in a manner suitable for topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or can be prepared for transdermal, transmucosal, or oral administration. The formulation will typically include a diluent and, in some cases, an adjuvant, a buffer, a preservative, etc. The compound or its pharmaceutically acceptable salt can also be administered in a liposomal composition or in a microemulsion.

[0663] For injection, the preparation can be prepared into a liquid solution or suspension form in a conventional manner, or into a solid form suitable for dissolving or suspending in a liquid before injection, or into an emulsion. Suitable excipients include, for example, water, saline, glucose, glycerol, etc. Such compositions can also contain a certain amount of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitan monolaurate, etc.

[0664] Various sustained-release systems for drugs have also been designed. See, for example, U.S. Pat. No. 5,624,677.

[0665] Systemic administration can also include relatively non-invasive methods such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or pharmaceutically acceptable salts thereof. As understood in the art, suitable forms include syrups, capsules, and tablets.

[0666] Each compound as described herein or its pharmaceutically acceptable salt can be formulated in a variety of ways known in the art. For example, the first and second doses of the combination therapy can be formulated together or separately. Other modes of combination therapy are described herein.

[0667] Individual or individually formulated agents can be packaged together into a medicine box. Non-limiting examples include, but are not limited to, medicine boxes containing, for example, two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The medicine box may include optional components that help administer a unit dose to the subject, such as a vial for reconstitution of the powder form, a syringe for injection, a custom IV delivery system, an inhaler, etc. In addition, the unit dose medicine box may contain instructions for preparing and administering the composition. The medicine box may be manufactured into a unit dose for a single use by a subject, for multiple use by a specific subject (with a constant dose or wherein the efficacy of an individual compound or its pharmaceutically acceptable salt may change with the progress of therapy); or the medicine box may contain multiple doses suitable for administration to multiple subjects ("batch packaging"). The medicine box components may be assembled in cartons, blister packs, bottles, tubes, etc.

[0668] Formulations for oral use include tablets containing one or more active ingredients in admixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch (including potato starch), calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrants (e.g., cellulose derivatives including microcrystalline cellulose, starch including potato starch, cross-linked sodium carboxymethyl cellulose, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinyl pyrrolidone, or polyethylene glycol); and lubricants, glidants, and anti-adherents (e.g., magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may be colorants, flavorings, plasticizers, wetting agents, buffers, and the like.

[0669] Two or more compounds can be mixed together in tablets, capsules or other vehicles, or can be separated. In one example, the first compound is contained inside the tablet, and the second compound is outside, so that most of the second compound is released before the first compound is released.

[0670] Formulations for oral use can also be provided as chewable tablets; or hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin); or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil). Powders, granules, and pellets can be prepared in a conventional manner using, for example, a mixer, fluidized bed apparatus, or spray drying apparatus using the ingredients mentioned above under tablets and capsules.

[0671] Dissolution or diffusion controlled release can be achieved by coating the tablets, capsules, pellets or granules of the compound, or by incorporating the compound or its pharmaceutically acceptable salt into a suitable matrix. The controlled release coating can include one or more of the coating materials mentioned above or, for example, shellac, beeswax, glucose wax (glycowax), castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethylacrylate, methacrylate hydrogel, 1,3-butylene glycol, ethylene glycol methacrylate or polyethylene glycol. In controlled release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, tristearin, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0672] Liquid forms in which the compounds of the invention or pharmaceutically acceptable salts thereof and compositions can be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0673] Typically, when administered to a person, the oral dose of any one of the compound of the present invention or its pharmaceutically acceptable salt will depend on the properties of the compound, and can be easily determined by those skilled in the art. Dosage can be, for example, from about 0.001 mg to about 2000 mg per day, from about 1 mg to about 1000 mg per day, from about 5 mg to about 500 mg per day, from about 100 mg to about 1500 mg per day, from about 500 mg to about 1500 mg per day, from about 500 mg to about 2000 mg per day, or any range available therein. In some embodiments, the daily dose range of oral administration can be, for example, in the range of from about 0.001 mg to about 2000 mg / kg human body weight, administered in single doses or divided doses. On the other hand, it may be necessary to use a dosage exceeding these limits in some cases.

[0674] In some embodiments, the pharmaceutical composition may also include another compound with antiproliferative activity. Depending on the mode of administration, the compound or its pharmaceutically acceptable salt will be formulated into a suitable composition to allow for easy delivery. Each compound or its pharmaceutically acceptable salt of the combination therapy can be formulated in a variety of ways known in the art. For example, the first and second doses of the combination therapy can be formulated together or separately. Ideally, the first and second doses are formulated together so that the doses are administered simultaneously or nearly simultaneously.

[0675] It will be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapies, i.e., the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, before, or after one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutics or procedures) used in a combination regimen will take into account the compatibility of the desired therapeutic agents or procedures with the desired therapeutic effect to be achieved. It will also be understood that the therapies used may achieve the desired effect for the same condition, or they may achieve different effects (e.g., control any adverse effects).

[0676] Administration of each drug in the combination therapy as described herein can independently be from once to four times daily for one day to one year, and may even continue for the lifetime of the subject. Chronic, long-term administration may be indicated.

[0677] How to use

[0678] The compounds and complexes of the present disclosure can be used in various methods. For example, the present disclosure provides a method for regulating a target protein by contacting the target protein with a compound as described herein or presenting a protein / compound complex. The method may include suppressing the target protein by contacting the target protein with a compound as described herein or presenting a protein / compound complex, or activating the target protein by contacting the target protein with a compound as described herein or presenting a protein / compound complex. Regulation (for example, inhibition or activation) can make the compound and / or complex useful for treating various diseases or conditions. Therefore, the compound and complex can be used for treating a disease or condition of a subject in need by administering a therapeutically effective amount of a compound as described herein to the subject. In some embodiments, the subject has previously received treatment with a previous therapy. In some embodiments, the subject has developed resistance to a previous therapy.

[0679] The present disclosure also relates to the synthesis of the various complexes disclosed.For example, the present disclosure provides methods for forming the ternary complex described herein by contacting a target protein with a presenting protein / compound complex described herein.

[0680] In some embodiments of the aforementioned methods, upon contact with the target protein, the target protein forms a covalent bond with the compound or presenting protein / compound complex. In some embodiments, upon contact with the target protein, an aspartic acid, glutamic acid, cysteine, glutamine, asparagine, lysine, or histidine residue of the target protein forms a covalent bond with the compound or complex. In some embodiments, upon contact with the target protein, an aspartic acid, glutamic acid, cysteine, glutamine, or asparagine residue of the target protein forms a covalent bond with the compound or complex.

[0681] In one embodiment, the present disclosure provides a method of cross-linking a compound described herein to a second moiety by contacting the second moiety with the compound under conditions sufficient to form a covalent bond between the compound and the second moiety. In some embodiments, the second moiety is a target protein.

[0682] The present disclosure also provides methods of forming a presenting protein / compound complex described herein by contacting a presenting protein with a compound described herein under conditions sufficient to allow complex formation. In some embodiments, the complex is formed by non-covalent interactions.

[0683] In another embodiment, the present disclosure provides a method of forming the ternary complex described herein, comprising the steps of:

[0684] a) contacting a presenting protein with a compound described herein under conditions sufficient to allow formation of a presenting protein / compound complex; and

[0685] b) contacting the presenting protein / compound complex with the target protein under conditions that allow formation of a ternary complex.

[0686] In some embodiments, the binding affinity of the presenting protein / compound complex to the target protein is at least 5-fold higher than that of the presenting protein or compound alone. In some embodiments, the presenting protein or compound does not substantially bind to the target protein without forming a presenting protein / compound complex.

[0687] The compounds of the present invention can be used in methods including click chemistry. Those skilled in the art will be familiar with how to make the compounds disclosed herein suitable for click chemistry applications. See, for example, Jewett et al., J.Am.Chem.Soc.2010, 132, 3688-3690; Gui et al., ChemRxiv 2022, 1-11; and Scinto et al., Nature Reviews Methods Primers 2021, 1, 1-23. The compounds of the present invention are also suitable for antibody-drug conjugates and degradation agent applications. It is also contemplated that the aziridine moiety described herein may be incorporated into known modulators (e.g., RAS inhibitors). Exemplary scaffolds suitable for such modifications include known RAS scaffolds and compounds disclosed in the art, such as WO 2022152233, WO 2022148422, WO 2022148421, WO 2022135346, WO 2022133731, WO 2022133038, WO 2022133345, WO 2022132200, WO 2022119748, WO 2022109487, WO 2022109485, WO 2022105859, WO 2022105857, WO 2022098625, WO 2022098625, WO 2022093856, WO 2022087335, WO 2022083569, WO 2022078470, WO 2022078414, WO 2022072783, WO 2022066805, WO 2022066646, WO 2022048545, WO 2022047093, WO 2022042630, WO 2022031678, WO 2022028492, WO 2022015375, WO 2022002102, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, 2021173923, WO 2021169990, WO2021169963, WO 2021168193, WO 2021158071, WO 2021155716, WO 2021152149, WO2021150613, WO 2021147967, WO 2021147965, WO 2021143693, WO 2021142252, WO2021141628, WO 2021139748, WO 2021139678, WO 2021129824, WO 2021129820, WO2021127404, WO2021126816, WO 2021126799, WO 2021124222, WO 2021121371, WO2021121367, WO 2021121330, WO 2021108643, WO 2020050890, WO 2020047192, WO2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO2019217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO2018217651, WO 2018218071, WO 2018218069, WO 2018206539, WO 2018143315, WO2018140600, WO 2018140599, WO 2018140598, WO 2018140514, WO 2018140513, WO2018140512, WO 2018119183, WO 2018112420, WO 2018068017, WO 2018064510, WO2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO 2017058807, WO2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768, WO2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO2016049524, WO 2015054572, WO 2014152588, WO 2014143659, WO 2013155223Japan PCT / US2022 / 027773, hereafter included in the text.

[0688] The compounds of the present invention can be used to treat subjects, such as mammals (e.g., mice, rats, dogs, and humans) suffering from a disease or condition. The disease or condition can be, for example, cancer, diabetes, cardiovascular disease, nervous system disorders, viral diseases, infectious diseases, autoimmune diseases, arthritis, allergic disorders, inflammation, hormone-related diseases, organ transplant-related disorders (e.g., transplant rejection), immunodeficiency disorders, bone disorders, or proliferative disorders.

[0689] Reagent test kit

[0690] The present invention also provides kits comprising (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound or complex of the invention), and (b) a package insert with instructions for performing any of the methods described herein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound or complex of the invention), (b) one or more additional therapies (e.g., non-drug therapies or therapeutic agents), and (c) a package insert with instructions for performing any of the methods described herein.

[0691] Since one aspect of the present invention encompasses treating a disease or a symptom associated therewith with a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit may comprise two separate pharmaceutical compositions: a compound of the present invention, and one or more additional therapies. The kit may comprise a container for accommodating a separate composition, such as a separate bottle or a separate foil packet. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions for use of separate components. When separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosing intervals, or when a prescribing healthcare professional needs to titrate the individual components of the combination, the kit form is particularly advantageous.

[0692] Listed implementation plans

[0693] The following are some specific embodiments. The embodiments listed below should not be interpreted as limiting the scope of the present disclosure. Instead, the following are some examples of the practicality of the present disclosure.

[0694] 1. A compound having the structure of Formula I:

[0695]

[0696] or a pharmaceutically acceptable salt thereof; wherein

[0697] M + It is a cation;

[0698] Z is

[0699] R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0700] R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0701] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0702] R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0703] or

[0704] R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0705] or

[0706] R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a );

[0707] or

[0708] R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0709] or

[0710] R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0711] or

[0712] R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0713] or

[0714] R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0715] Where R and R 4 At least one of is not hydrogen;

[0716] R 3 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C3-C10 Cycloalkyl, optionally substituted C3-C 10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0717] R 1a 、R 2a 、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0718] R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0719] R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0720] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0721] 2. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ia:

[0722]

[0723] 3. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ib:

[0724]

[0725] 4. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ic:

[0726]

[0727] 5. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Id:

[0728]

[0729]

[0730] 6. A compound as described in any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl.

[0731] 7. A compound as described in any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 3 is an optionally substituted C1-C6 alkyl group.

[0732] 8. A compound as described in any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl, ethyl or benzyl.

[0733] 9. A compound as described in any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein M + For Li + .

[0734] 10. A compound as described in any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

[0735]

[0736] 11. A compound as described in any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Z is

[0737] 12. A compound having the structure of Formula II:

[0738]

[0739]

[0740] or a pharmaceutically acceptable salt thereof,

[0741] Among them A 1 For the unit price organic part;

[0742] Q is

[0743] R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0744] R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0745] R 2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0746] R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0747] or R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0748] or

[0749] R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R1a );

[0750] or

[0751] R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0752] or

[0753] R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10Cycloalkenyl, optionally substituted C8-C 10 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0754] or

[0755] R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0756] or

[0757] R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0758] Where R and R 4 At least one of is not hydrogen;

[0759] R 1a 、R 2a 、R 2c 、R 2d and R 2eare each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0760] R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0761] R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0762] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0763] 13. The compound according to embodiment 12 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IIa:

[0764]

[0765] 14. The compound according to embodiment 12 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IIb:

[0766]

[0767] 15. The compound according to embodiment 12 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IIc:

[0768]

[0769] 16. The compound according to embodiment 12 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IId:

[0770]

[0771]

[0772] 17. A compound as described in any one of embodiments 12 to 16, or a pharmaceutically acceptable salt thereof, wherein Q is

[0773] 18. A compound / target protein complex or a pharmaceutically acceptable salt thereof, wherein the compound / target protein complex has a structure of Formula IIIa or Formula IIIb:

[0774]

[0775] Among them A 1 For the unit price organic part;

[0776] Q is

[0777] P 1 A 2 , and P 2 is hydrogen; or P 1 is a hydroxyl group, and P 2 A 2 ;

[0778] A 2 is the target protein;

[0779] R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a)3;

[0780] R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0781] R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0782] R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0783] or

[0784] R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl, and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0785] or

[0786] R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a );

[0787] or

[0788] R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0789] or

[0790] R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0791] or

[0792] R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl or optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4 are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0793] or

[0794] R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;

[0795] Where R and R 4 At least one of is not hydrogen;

[0796] R 1a 、R 2a 、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl;

[0797] R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and

[0798] R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl,

[0799] and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

[0800] 19. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIa-1:

[0801]

[0802] Among them A 3 is the remaining portion of the target protein.

[0803] 20. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIa-2:

[0804]

[0805] Among them A 3 is the remaining portion of the target protein.

[0806] 21. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIa-3:

[0807]

[0808] Among them A 3 is the remaining portion of the target protein.

[0809] 22. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIa-4:

[0810]

[0811] Among them A 3 is the remaining portion of the target protein.

[0812] 23. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIb-1:

[0813]

[0814] Among them A 3 is the remaining portion of the target protein.

[0815] 24. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIb-2:

[0816]

[0817] Among them A 3 is the remaining portion of the target protein.

[0818] 25. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIc-1:

[0819]

[0820] Among them A 3 is the remaining portion of the target protein.

[0821] 26. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIc-2:

[0822]

[0823] Among them A 3 is the remaining portion of the target protein.

[0824] 27. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIc-3:

[0825]

[0826] Among them A 3 is the remaining portion of the target protein.

[0827] 28. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIc-4:

[0828]

[0829] Among them A 3 is the remaining portion of the target protein.

[0830] 29. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIId-1:

[0831]

[0832] Among them A 3 is the remaining portion of the target protein.

[0833] 30. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIId-2:

[0834]

[0835] Among them A 3 is the remaining portion of the target protein.

[0836] 31. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIe-1:

[0837]

[0838] Among them A 3 is the remaining portion of the target protein.

[0839] 32. The compound / target protein complex of embodiment 18, wherein the compound / target protein complex has the structure of Formula IIIe-2:

[0840]

[0841] Among them A 3 is the remaining portion of the target protein.

[0842] 33. A compound or pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 17, or a compound / target protein complex as described in any one of embodiments 18 to 33, wherein R is an optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl.

[0843] 34. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to embodiment 33, wherein R is an optionally substituted C3-C 10 Cycloalkyl.

[0844] 35. The compound or compound / target protein complex of embodiment 34, or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted cyclopropyl group.

[0845] 36. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to embodiment 35, wherein R is

[0846] 37. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to embodiment 36, wherein R is

[0847] 38. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof as described in embodiment 33, wherein R is an optionally substituted C2-C6 alkenyl or an optionally substituted C2-C6 alkynyl.

[0848] 39. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to embodiment 38, wherein R is

[0849] 40. The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or the compound / target protein complex of any one of embodiments 18 to 33, wherein R is a carbocation-stabilized electron-donating group.

[0850] 41. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 40, wherein R 1 For hydrogen.

[0851] 42. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 41, wherein R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl.

[0852] 43. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to embodiment 42, wherein R 2 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C3-C 10 cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl.

[0853] 44. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to embodiment 43, wherein R 2 is an optionally substituted C1-C6 cycloalkyl group.

[0854] 45. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to embodiment 43, wherein R 2 is optionally substituted C3-C 10 Cycloalkyl.

[0855] 46. ​​The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to embodiment 43, wherein R 2 is a 3- to 10-membered heterocycloalkyl group.

[0856] 47. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 41, wherein R 2 for:

[0857]

[0858] 48. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to embodiment 47, wherein R 2 for:

[0859]

[0860] 49. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to embodiment 48, wherein R 2 It is a methyl group.

[0861] 50. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof as described in an...

Claims

1. A compound having the structure of Formula I: or a pharmaceutically acceptable salt thereof; wherein M + It is a cation; Z is R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ); or R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; or R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; or R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4 are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; Where R and R 4 At least one of is not hydrogen; R 3 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 cycloalkenyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; R 1a 、R 2a 、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl, and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 is an optionally substituted C1-C6 alkyl group.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl, ethyl or benzyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein M + For Li + .

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 3 for:

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Z is 8. A compound having the structure of Formula II: or a pharmaceutically acceptable salt thereof, Among them A 1 For the unit price organic part; Q is R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ); or R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; or R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; or R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4 are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; Where R and R 4 At least one of is not hydrogen; R 1a 、R 2a 、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl, and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein Q is 10. A compound / target protein complex or a pharmaceutically acceptable salt thereof, wherein the compound / target protein complex has a structure of Formula IIIa or Formula IIIb: Among them A 1 For the unit price organic part; Q is P 1 A 2 , and P 2 is hydrogen; or P 1 is a hydroxyl group, and P 2 A 2 ; A 2 is the target protein; R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl, and R 4 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R 4 are each independently hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ); or R and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R 1 is hydrogen, halogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; or R 1 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 acyl, -C(O)2R 2a 、-C(O)N(R 2b )2、-S(O)2R 2c 、-S(O)2N(R 2d )2、-S(O)2OR 2e , optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; or R 1 and R 2 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl or optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl or optionally substituted 8- to 10-membered heterocycloalkynyl, and R and R 4 are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 Combining to form optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and R 1 and R are each independently hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; Where R and R 4 At least one of is not hydrogen; R 1a 、R 2a 、R 2c 、R 2d and R 2e are each independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; R 2b is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 cycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl; and R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Cycloalkenyl, optionally substituted C8-C 10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C6-C 10 aryl or optionally substituted 5- to 10-membered heteroaryl, and wherein each hydrogen is independently, optionally isotopically enriched with deuterium.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, or the compound / target protein complex according to claim 10, wherein R is an optionally substituted C3-C 10 Cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C6 alkenyl or optionally substituted C2-C6 alkynyl.

12. The compound or compound / target protein complex according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted C3-C 10 Cycloalkyl.

13. The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to claim 12, wherein R is an optionally substituted cyclopropyl group. 14 . The compound or compound / target protein complex or a pharmaceutically acceptable salt thereof according to claim 11 , wherein R is an optionally substituted C 2 -C 6 alkenyl group or an optionally substituted C 2 -C 6 alkynyl group.

15. The compound or compound / target protein complex according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 1 For hydrogen.

16. The compound or compound / target protein complex according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 cycloalkyl or optionally substituted 3- to 10-membered heterocycloalkyl.

17. The compound or compound / target protein complex according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 For hydrogen.

18. The compound or compound / target protein complex according to any one of claims 8 to 17, or a pharmaceutically acceptable salt thereof, wherein A 1 Proteins, nucleic acids or small molecules.

19. The compound / target protein complex of any one of claims 10 to 18, wherein the target protein is a GTPase, a GTPase-activating protein, a guanine nucleotide exchange factor, a heat shock protein, an ion channel, a coiled-coil protein, a kinase, a phosphatase, a ubiquitin ligase, a transcription factor, a chromatin modifier / remodeler, a protease, or a protein with a canonical protein-protein interaction domain and motif.

20. A presenting protein / compound complex comprising a presenting protein and a compound according to any one of claims 8, 9, and 11 to 18, or a pharmaceutically acceptable salt thereof.

21. A method of modulating a target protein, the method comprising contacting the target protein with a compound according to any one of claims 8 to 18 or a presenting protein / compound complex according to claim 20.

22. A triple complex comprising a presenting protein, a compound according to any one of claims 8 to 18 or a pharmaceutically acceptable salt thereof, and a target protein.

23. A method of forming the ternary complex of claim 22, comprising contacting a target protein with the presenting protein / compound complex of claim 20.

24. A method of cross-linking a compound as claimed in any one of claims 8 to 18 and a second moiety, the method comprising contacting the moiety with the compound under conditions sufficient to form a covalent bond between the compound as claimed in any one of claims 8 to 18 and the second moiety.

25. A method of forming a presenting protein / compound complex as claimed in claim 20, comprising contacting a presenting protein with a compound as claimed in any one of claims 8 to 18 under conditions sufficient to allow formation of a complex.

26. A method of forming the ternary complex of claim 22, comprising: a) contacting a presenting protein with a compound according to any one of claims 8 to 18 under conditions sufficient to allow formation of a presenting protein / compound complex; as well as b) contacting the presenting protein / compound complex with the target protein under conditions that allow formation of a ternary complex.

27. A method of treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 8 to 18.

Images