Compounds, conjugates, and methods for preparing and using them

Abstract

The present invention features compounds containing an aziridine moiety and methods for synthesizing the same. The compounds can be linked to a monovalent organic moiety and can be used to bind to a target (e.g., a target protein), e.g., by crosslinking to the target. In some embodiments, the monovalent organic moiety is capable of binding to a presenter protein. Also disclosed are complexes containing the compounds (e.g., presenter protein / compound complexes, compound / target protein complexes, or ternary complexes). Also disclosed are methods of forming the complexes and methods of modulating biological processes using the compounds and complexes.

Description

[Background technology]

[0001] The majority of small molecule drugs act by binding to functionally important cavities on target proteins, thereby modulating their activity. For example, cholesterol-lowering drugs known as statins bind to the enzyme active site of HMG-CoA reductase, thus preventing the enzyme from engaging its substrate. The fact that many such drug / target interaction pairs are known may lead one to believe that small molecule modulators could be discovered for most, if not all, proteins, given a reasonable amount of time, effort, and resources. This is far from the truth. Current estimates suggest that only approximately 10% of all human proteins are amenable to small molecule targeting (Bojadzic and Buchwald, Curr Top Med Chem 18:674-699 (2019)). The other 90% are currently considered intractable or intractable for small molecule drug discovery as described above. Such targets are commonly referred to as "undruggable." These undruggable targets include a large, largely unused reservoir of medically important human proteins. Therefore, there is great interest in discovering new molecular modalities that have the ability to modulate the function of such undruggable targets. In particular, there is a need for new compounds that have the ability to form complexes with targets of interest (e.g., target proteins). Summary of the Invention

[0002] In general, the disclosure features compounds capable of complexing with and / or crosslinking a target (e.g., a target protein). Also disclosed are synthetic intermediates used in the preparation of such compounds, conjugates formed by reaction with the compounds, methods of synthesizing the compounds and conjugates, and methods of using the compounds and conjugates.

[0003] In a first aspect, the present disclosure provides a compound having the structure of Formula I: [ka] or a pharmaceutically acceptable salt thereof, [Here, Z is [ka] and; M + is a cation; 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 1 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ) and; or R and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C3-C6 heteroalkynyl ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-C 10 R and R form a cycloalkynyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. 4 are each independently selected from 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-C6 10Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 each R is 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; where: R and R 4 at least one of which 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-C6 10 Cycloalkyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; Each R 1a , R 2a , R 2c , R 2d and R 2e are 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 C-C 10 aryl, or optionally substituted 5-10 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; where: Each hydrogen is independently, optionally, isotopically enriched with deuterium. The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0004] In some embodiments, the compound or pharmaceutically acceptable salt thereof has the structure of Formula Ia: [ka] It has.

[0005] In some embodiments, the compound or pharmaceutically acceptable salt thereof has the structure of Formula Ib: [ka] It has.

[0006] In some embodiments, the compound or pharmaceutically acceptable salt thereof has the structure of Formula Ic: [ka] It has.

[0007] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Id: [ka] It has.

[0008] 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 aryl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R 3 is an optionally substituted C1-C6 alkyl. In some embodiments, R 3 is methyl, ethyl or benzyl.

[0009] In some embodiments, M + Li + is.

[0010] In some embodiments, R 3 teeth, [ka] is.

[0011] In some embodiments, Z is [ka] is.

[0012] In another embodiment, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, [Here, A 1 is a monovalent organic moiety; Q is [ka] and; 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 1 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R and R 1 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ) and; or R and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C3-C6 heteroalkynyl ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-C 10 R and R form a cycloalkynyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. 4 are each independently selected from 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-C6 10Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 each R is 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; where: R and R 4 at least one of which is not hydrogen; Each R 1a , R 2a , R 2c , R 2d and R 2e are 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; R 5 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C 10Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; where: Each hydrogen is independently, optionally, isotopically enriched with deuterium. The present invention provides a compound or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIa: [ka] It has.

[0014] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIb: [ka] It has.

[0015] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIc: [ka] It has.

[0016] In some embodiments, the compound of formula II or a pharmaceutically acceptable salt thereof has the structure of formula IId: [ka] It has.

[0017] In some embodiments, Q is [ka] is.

[0018] In a further aspect, the present disclosure provides a compound having the structure of formula III: [ka] or a pharmaceutically acceptable salt thereof, [Here, A 1 is a monovalent organic moiety; Q is [ka] and; P 1 is A 2 and P 2 is hydrogen; or P 1 is hydroxyl and P 2 is A 2 and; 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R1a )3; R 1 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ) and; or R and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C3-C6 heteroalkynyl ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-C 10 R and R form a cycloalkynyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. 4 are each independently selected from 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 each R is 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; where: R and R 4 at least one of which is not hydrogen; Each R 1a , R 2a , R 2c , R 2d and R 2e are 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 C-C 10 aryl, or optionally substituted 5-10 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 10Cycloalkyl, 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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; where: Each hydrogen is independently, optionally, isotopically enriched with deuterium. A compound / target protein complex, or a pharmaceutically acceptable salt thereof, is provided.

[0019] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-1: [ka] where A 3 is the remainder of the target protein.

[0020] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-2: [ka] where A 3 is the remainder of the target protein.

[0021] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-3: [ka] where A 3 is the remainder of the target protein.

[0022] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-4: [ka] where A 3 is the remainder of the target protein.

[0023] In some embodiments, the compound / target protein complex has the structure of the compound / target protein complex of claim 16, wherein the compound / target protein complex has the structure of Formula IIIb-1: [ka] where A 3 is the remainder of the target protein.

[0024] In some embodiments, the compound / target protein complex has the structure of Formula IIIb-2: [ka] where A 3 is the remainder of the target protein.

[0025] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-1: [ka] where A 3 is the remainder of the target protein.

[0026] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-2: [ka] where A 3 is the remainder of the target protein.

[0027] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-3: [ka] where A 3 is the remainder of the target protein.

[0028] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-4: [ka] where A 3 is the remainder of the target protein.

[0029] In some embodiments, the compound / target protein complex has the structure of formula IIId-1: [ka] where A 3 is the remainder of the target protein.

[0030] In some embodiments, the compound / target protein complex has the structure of Formula IIId-2: [ka] where A 3 is the remainder of the target protein.

[0031] In some embodiments, the compound / target protein complex has the structure of Formula IIIe-1: [ka] where A 3 is the remainder of the target protein.

[0032] In some embodiments, the compound / target protein complex has the structure of Formula IIIe-2: [ka] where A 3 is the remainder of the target protein.

[0033] 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 C-C 10 In some embodiments, R is an optionally substituted C-C alkyl group, an optionally substituted C-C alkynyl group, an optionally substituted C-C aryl group, an optionally substituted C-C alkenyl group, or an optionally substituted C-C alkynyl group. 10 In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is [ka] In some embodiments, R is [ka] In some embodiments, R is an optionally substituted C2-C6 alkenyl or an optionally substituted C2-C6 alkynyl. In some embodiments, R is [ka] In some embodiments, R is an electron donating group that stabilizes a carbocation, i.e., R is a substituent that has the ability to stabilize the positive charge or partial positive charge of the carbon to which it is attached.

[0034] In some embodiments of any of the compounds or compound / target protein complexes described herein, R 1 is hydrogen.

[0035] 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 cycloalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, 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. In some embodiments, R 2 is an optionally substituted C1-C6 alkyl. In some embodiments, R 2 is an optionally substituted C3-C 10 In some embodiments, R 2 is an optionally substituted 3-10 membered heterocycloalkyl. In some embodiments, R 2 teeth, [ka] is.

[0036] In some embodiments, R 2 teeth, [ka] is.

[0037] In some embodiments, R 2 is methyl.

[0038] In some embodiments of any of the compounds or compound / target protein complexes described herein, R 4 is hydrogen.

[0039] 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. 1 is or comprises a small molecule. 1 is or comprises a macrocyclic small molecule. 1 is or comprises a degradation inducer.

[0040] In some embodiments, A 1 has the structure of formula IV: [ka] where The dashed lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10)-], optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and; X 2 is O or NH; X 3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); each R' is independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH or N; Y 2 , Y 3 , Y 4 and Y 7 are independently C or N; Y 5 is CH, CH2 or N; Y 6 is C(O), CH, CH2 or N; 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 R 1 and R 2 and, combined with the atom(s) to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 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, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or R 2 and R 3 and, in combination with the atoms to which they are attached, form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl; or 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; R 8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, 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 R 7 and R 8 and combine with the carbon atoms bonded to them 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; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, 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 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; 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 R 9 and L, combined with the atom(s) to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo; R 11 is hydrogen or C1-C3 alkyl; R 34 is hydrogen or C1-C3 alkyl, where: Each hydrogen is independently, optionally, isotopically enriched with deuterium.

[0041] In some embodiments, A 1 is a structure of formula V: [ka] where 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; X 1 is CH2 or O; m is 1 or 2; n is 0 or 1; R 1 is hydrogen or an optionally substituted 3- to 10-membered heterocycloalkyl; R 2is an optionally substituted C1-C6 alkyl; R 3 is an optionally substituted C1-C6 alkyl or an optionally substituted 3- to 6-membered cycloalkyl; where: Each hydrogen is independently, optionally, isotopically enriched with deuterium.

[0042] In some embodiments, A 1 has the structure of formula VI: [ka] where 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; X 1 , X 2 , and X 3 are each independently selected from CH, CHF, CF, C=O, or O; m is 1 or 2; n is 0 or 1; R 1 is hydrogen, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3-10 membered heterocycloalkyl; R 2 is an optionally substituted C1-C6 alkyl; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted heterocycloalkyl; where: Each hydrogen is independently, optionally isotopically enriched with deuterium.

[0043] In some embodiments, A 1has the structure of any one of formulas VII, VIII and IX: [ka] where o and p are independently 0, 1 or 2; q is an integer from 0 to 7; r is an integer from 0 to 4; X 4 and X 5 are each independently absent, CH, O, S, SO, SO, or NR 11 and; Each R 6 and R 7 are independently hydrogen, hydroxyl, 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-C6 heteroalkyl, optionally substituted C3 ... 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C-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 and combine with the carbon atoms to which they are attached to form C=O; Each R 8are independently selected from hydroxyl, 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-C6 heteroalkyl, optionally substituted C3 ... 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C-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, or two R 8 in combination with optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 forming an aryl or an optionally substituted C2-C9 heteroaryl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C2-C6 heteroalkenyl, an optionally substituted C2-C6 heteroalkynyl, an optionally substituted C3-C6 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C-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; R 10 is an optionally substituted C1-C6 alkyl; Each R 11 are independently selected from hydroxyl, 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-C6 heteroalkyl, optionally substituted C3 ...alkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C-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; 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 arylC1-C6 alkyl, and optionally substituted C3-C7 carbocyclylC1-C6 alkyl.

[0044] In yet another aspect, the present disclosure provides a ternary complex, the ternary complex comprising a presenter protein, a compound described herein, and a target protein.

[0045] 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 classical protein-protein interaction domains and motifs.

[0046] The following are the names of the graphics DIRAS1, DIRAS2, DIRAS3, ERAS, GEM, HRAS, and KRAS. MRAS、NKIRAS1、NKIRAS2、NRAS、RALA、RALB、RAP1A、RAP1B、RAP2A、RAP2B、R AP2C, 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 RN D3, RAC1, RAC2, RAC3, CDC42, RAB1A, RAB1B, RAB2, RAB3A, RAB3B, RAB3C, RAB 3D RAB4A、RAB4B、RAB5A、RAB5B、RAB5C、RAB6A、RAB6B、RAB6C、RAB7A、RAB7 B、RAB7L1、RAB8A、RAB8B、RAB9、RAB9B、RABL2A、RABL2B、RABL4、RAB10、RAB1 1A、RAB11B、RAB12、RAB13、RAB14、RAB15、RAB17、RAB18、RAB19、RAB20、RAB 21, RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28, RAB2B AB30, RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37, RAB38 RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, RAB41, RAB42, RAB43, RA P1A、RAP1B、RAP2A、RAP2B、RAP2C、ARF1、ARF3、ARF4、ARF5、ARF6、ARL1、ARL 2, ARL3, ARL4, ARL5, ARL5C, ARL6, ARL7, ARL8, ARL9, ARL10A, ARL10B, ARL10 C、ARL11、ARL13A、ARL13B、ARL14、ARL15、ARL16、ARL17、TRIM23、ARL4D、AR FRP1, ARL13B, RAN, RHEB, RHEBL1, RRAD, GEM, REM, REM2, RIT1, RIT2, RHOT1and 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 mutated HRAS, mutated KRAS, or mutated NRAS. In some embodiments, the target protein is not a RAS (e.g., not HRAS, not KRAS, or not NRAS, e.g., not mutated HRAS, not mutated KRAS, or not mutated NRAS). In some embodiments, the target protein is KRAS. In some embodiments, the target protein is a GTPase activator selected from NF1, IQGAP1, PLEXIN-B1, RASAL1, RASAL2, ARHGAP5, ARHGAP8, ARHGAP12, ARHGAP22, ARHGAP25, BCR, DLC1, DLC2, DLC3, GRAF, RALBP1, RAP1GAP, SIPA1, TSC2, AGAP2, ASAP1, and ASAP3.

[0047] In some embodiments, the target protein is a guanine nucleotide exchange factor selected from CNRASGEF, RASGEFlA, RASGRF2, RASGRPl, RASGRP4, SOSl, RALGDS, RGLl, RGL2, RGR, ARHGEF10, ASEF / ARHGEF4, ASEF2, DBS, ECT2, GEF-Hl, LARG, NETl, OBSCURIN, P-REXl, P-REX2, PDZ-RHOGEF, TEM4, TIAMl, TRIO, VAVl, VAV2, VAV3, DOCKl, DOCK2, DOCK3, DOCK4, DOCK8, DOCK10, C3G, BIG2 / ARFGEF2, EFA6, FBX8, and GEP100.

[0048] In some embodiments, the target protein is 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, The protein has a protein-protein interaction domain selected from 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, and TPR.

[0049] In some embodiments, the target protein is a heat shock protein selected from Hsp20, Hsp27, Hsp70, Hsp84, alpha B crystallin, TRAP-1, hsf1, and Hsp90.

[0050] In some embodiments, the target protein is an ion channel selected from Cav2.2, Cav3.2, IKACh, Kv1.5, TRPA1, NAv1.7, Nav1.8, Nav1.9, P2X3, or P2X4.

[0051] In some embodiments, the target protein is a coiled-coil protein selected from geminin, SPAG4, VAV1, MAD1, ROCK1, RNF31, NEDP1, HCCM, EEA1, vimentin, ATF4, Nemo, SNAP25, syntaxin1a, FYCO1, and CEP250.

[0052] In some embodiments, the target protein is 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, RET The kinase is selected from RON, ROR1, ROR2, ROS, SRC, SYK, TIE1, TIE2, TRKA, TRKB, KDR, AKT1, AKT2, AKT3, 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.

[0053] In some embodiments, the target protein is a phosphatase selected from WIP1, SHP2, SHP1, PRL-3, PTP1B, and STEP.

[0054] In some embodiments, the target protein is a ubiquitin ligase selected from BMI-1, MDM2, NEDD4-1, beta-TRCP, SKP2, E6AP, and APC / C.

[0055] In some embodiments, the target protein is a chromatin modifier / remodeler encoded by a gene selected from BRG1, BRM, ATRX, PRDM3, ASH1L, CBP, KAT6A, KAT6B, MLL, NSD1, SETD2, EP300, KAT2A, and CREBBP.

[0056] In some embodiments, target proteins are 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、ES X1、EVX1、EVX2、GBX1、GBX2、GSC、GSC2、GSX1、GSX2、HESX1、HMX1、HMX2、HMX3、HNF1A、HNF1B、HOMEZ、HOXA1、HOXA10、HOXA13、HOXA2、HOXA13、HOXA2、HOXA13 3、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、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、The transcription factor is encoded by a gene selected from 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-1 alpha, Hif-2 alpha, Bcl6, E2F1, NF-kappa B, Stat5, and ER(coact).

[0057] In some embodiments, the target protein is 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, IL12beta1,2, tau, FASN, KCTD6, KCTD9, Raptor, Rictor, RALGAPA, RALGAPB, annexin family members, BCOR, NCOR, beta-catenin, AAC11, 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.

[0058] In another aspect, the disclosure provides a presenter protein / compound complex comprising a presenter protein and a compound described herein.

[0059] In some embodiments of the ternary complexes or presenter protein / compound complexes described herein, the presenter protein is a proline isomerase. In some embodiments, the presenter protein is a member of the FKBP family, a member of the cyclophilin family, or PIN1. In some embodiments, the presenter protein is a member of the 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 presenter protein is a member of the cyclophilin family selected from 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 cyclophilin family is PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, or PPIAL4G.

[0060] In another aspect, the disclosure provides methods of modulating a target protein by contacting the target protein with a compound or a presenter protein / compound complex described herein.

[0061] In a further aspect, the disclosure provides methods of inhibiting a target protein by contacting the target protein with a compound or a presenter protein / compound complex described herein.

[0062] In yet another aspect, the disclosure provides methods for activating a target protein by contacting the target protein with a compound or a presenter protein / compound complex described herein.

[0063] In another aspect, the disclosure provides methods of forming a ternary complex described herein by contacting a target protein with a presenter protein / compound complex described herein.

[0064] In some embodiments of the above method, upon contacting the target protein, the target protein forms a covalent bond with the compound or the presenter protein / compound complex. In some embodiments, upon contacting 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 the complex. In some embodiments, upon contacting 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 the complex.

[0065] In another aspect, the present disclosure provides a method for crosslinking 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. 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 assays. In some embodiments, the second moiety is a target protein.

[0066] In another aspect, the present disclosure provides a method for forming a presenter protein / compound complex as described herein, by contacting the presenter protein with the compound described herein under sufficient conditions to allow the formation of the complex.In some embodiments, the complex is formed by non-covalent interaction.The method for measuring such interaction is known in the art, for example, using FRET.

[0067] In another aspect, the present disclosure provides a method of forming a ternary complex as described herein, comprising the steps of: a) contacting a presenter protein with a compound described herein under conditions sufficient to allow the formation of a presenter protein / compound complex; and b) contacting the presenter protein / compound complex with the target protein under conditions that allow for the formation of a ternary complex; The method includes:

[0068] In some embodiments, the presenter protein / compound complex binds to the target protein with at least 5-fold greater affinity than the presenter protein or compound alone, hi some embodiments, the presenter protein or compound does not substantially bind to the target protein in the absence of the formation of the presenter protein / compound complex.

[0069] In yet another aspect, the present disclosure provides methods of treating a disease or disorder in a subject in need thereof by administering a therapeutically effective amount of a compound described herein to the subject. In some embodiments, the subject has previously been treated with a prior therapy, e.g., a cancer therapy. In some embodiments, the subject has developed resistance to treatment with the prior therapy, e.g., a cancer therapy.

[0070] It is specifically contemplated that any limitation stated with respect to one embodiment of this disclosure may apply to any other embodiment of this disclosure. Furthermore, any compound or composition of this disclosure may be used in any method of this disclosure, and any method of this disclosure may be used to make or utilize any compound or composition of this disclosure.

[0071] Definitions and Chemical Terms As used herein, unless otherwise clear from the context, (i) the term "a" means "one or more"; (ii) the term "or" is used to mean "and / or" unless expressly indicated to refer only to alternatives or the alternatives are mutually exclusive, although this disclosure supports definitions that refer only to alternatives and "and / or"; (iii) the terms "comprising" and "including" are understood to encompass listed elements or steps, whether presented by themselves or together with one or more additional elements or steps; and (iv) when ranges are provided, the endpoints are included.

[0072] As used herein, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. In certain embodiments, the term "about" refers to a range of values ​​that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less on either side of (above or below) the specified value, unless otherwise stated or apparent from the context (e.g., where such number would exceed 100% of the possible values).

[0073] As used herein, the term "adjacent" in the context of describing adjacent atoms refers to divalent atoms that are directly linked by a covalent bond.

[0074] As used herein, "compounds of the invention," "compounds disclosed herein," or "compounds described herein," and similar terms refer to compounds of Formula I or Formula II, and formulae substituting therein, and compounds in Table 3, and salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof, whether or not explicitly stated.

[0075] The term "wild-type" refers to an entity having a structure or activity found in a "normal" state or relationship in nature (as opposed to a mutant, affected, modified, etc.). Those skilled in the art will appreciate that wild-type genes and polypeptides often exist in several alternative forms (e.g., alleles).

[0076] It will be appreciated by those of ordinary skill in the art that certain compounds described herein may exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., forms in which one or more atoms are replaced by another isotope of that atom, e.g., hydrogen for deuterium). Unless otherwise indicated or apparent from the context, the depicted structures can be understood to represent any such isomeric or isotopic forms individually or in combination.

[0077] The compounds described herein can be asymmetric (e.g., they can have one or more stereocenters). Unless otherwise specified, all stereoisomers, e.g., enantiomers and diastereomers, are contemplated. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also exist in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as a mixture of isomers or as separate isomeric forms.

[0078] In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. Reference to such a compound encompasses all such tautomeric forms unless expressly excluded, as will be clear from the context. In some embodiments, tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a proton tautomer, which is an isomeric protonation state having the same empirical formula and total charge as the referenced form. Examples of moieties having proton tautomeric forms are ketone-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 more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. In some embodiments, tautomeric forms may be in equilibrium or may be sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion.

[0079] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Illustrative isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H, 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 Isotopically labeled compounds (e.g.,3 H and 14 C) can be useful in tissue distribution assays of compounds or substrates. 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful due to their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e., 2 H) can provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) resulting from greater metabolic stability. In some embodiments, one or more hydrogen atoms can be replaced by 2 H or 3 H or one or more carbon atoms 13 C enriched or 14 C-enriched carbon is substituted. Positron-emitting isotopes, e.g. 15 O. 13 N, 11 C and 18 F is useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically labeled compounds is known in the art. For example, isotopically labeled compounds can generally be prepared by following procedures similar to those disclosed for the compounds of the present invention described herein, by using an isotopically labeled reagent instead of a non-isotopically labeled reagent.

[0080] As known to those skilled in the art, many chemical entities can exist in various solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates), etc. In some embodiments, the compounds of the present invention can be utilized in any such form, including any solid form. In some embodiments, the compounds described or depicted herein can be provided or utilized in the form of a hydrate or solvate.

[0081] Non-limiting examples of moieties in the compounds of the present invention that may contain one or more deuterium substitutions include: [ka] Examples include:

[0082] At various places herein, substituents for compounds of the present disclosure are disclosed as groups or ranges. It is specifically intended that the disclosure include any and all individual subcombinations of the members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, when a compound contains multiple positions where substituents are disclosed as groups or ranges, the disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing any and all individual subcombinations at each position, unless otherwise indicated.

[0083] The term "optionally substituted X" (e.g., "optionally substituted alkyl") is intended to be synonymous with "X, optionally substituted with said X" (e.g., "alkyl, optionally substituted with said alkyl"). It is not intended to imply that the "X" (e.g., alkyl) feature itself is optional. As described herein, particular compounds of interest may contain one or more "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent, e.g., 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 the specified groups, the substituents at every position may be the same or different. For example, in the term "optionally substituted C-C alkyl-C-C heteroaryl," the alkyl portion, the heteroaryl portion, or both, can 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" means that the compound remains substantially unchanged when exposed to conditions that allow for its production, detection, and, in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0084] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently deuterium; halogen; -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R o ;-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4SR°; optionally substituted with R° -(CH2) 0-4 Ph; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 Ph; optionally substituted with R° -CH=CHPh; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 -pyridyl; 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., by methyl); 3-8 membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 -C(O)-N(R°)2;-(CH2) 0-4 -C(O)-N(R°)-S(O)2-R°;-C(NCN)NR°2;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NOR°)NR°2;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-P(O)(OR°)2;-OP(O)R°2;-OP(O)(OR°)2;-OP(O)(OR°)R°,-SiR°3;-(linear or branched C 1-4 alkylene) ON(R°)2; or -(linear or branched C 1-4 alkylene)C(O)ON(R°), where each R° may be optionally substituted as defined below and independently represents hydrogen, —C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 3- to 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°, taken together with the intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl 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, for example, for purposes of click chemistry reactions described herein, a preferred carbon substituent is -N3.

[0085] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° together with the intervening atom(s)) are independently halogen, —(CH) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(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 ● , -(linear or branched C 1-4 alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, if preceded by "halo", is substituted with one or more halogens only, and independently represents C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include ═O and ═S.

[0086] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =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 independently occurring R * is hydrogen, optionally substituted as defined below1-6 A 5- to 6-membered unsubstituted saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from aliphatic, nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2-3 O-, where each R * is hydrogen, optionally substituted as defined below 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0087] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with one or more halogens only, and independently represents C 1-4 Aliphatic, -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.

[0088] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR† 2. -C(NH)NR † 2, or -N(R † )S(O)2R † where each R † are independently hydrogen, optionally substituted as defined below, C 1-6 an 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 definition, two independently occurring R † together with the intervening atom(s) 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.

[0089] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, if preceded by "halo", is substituted with one or more halogens only, and independently represents C 1-4 Aliphatic, -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. † Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0090] The term "acetyl," as used herein, refers to a -C(O)CH group.

[0091] The term "acyl," as used herein, 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 as defined herein. An optionally substituted acyl is an acyl optionally substituted as defined herein for each group.

[0092] The term "alkoxy" as used herein means -O-C-C 20 It refers to an alkyl group, and an alkoxy group is attached to the remainder of the compound through an oxygen atom.

[0093] The term "alkyl," as used herein, refers to a saturated, straight-chain or branched, monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10 or 1 to 6) carbons. In some embodiments, an alkyl group is unbranched (i.e., linear); in some embodiments, an alkyl group is branched. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n- and iso-propyl, n-, sec-, iso-, and tert-butyl, and neopentyl.

[0094] The term "alkylene," as used herein, refers to a saturated divalent hydrocarbon group derived from a straight- or branched-chain saturated hydrocarbon by the removal of two hydrogen atoms, examples of which include methylene, ethylene, isopropylene, and the like. x -C y The term "alkylene" refers to an alkylene group having x to y carbon atoms. Exemplary values ​​of x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​of 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 20In some embodiments, the alkylene may be further substituted with 1, 2, 3, or 4 substituents, as defined herein.

[0095] As used herein, the term "alkenyl" refers to a monovalent straight- or branched-chain group containing one or more carbon-carbon double bonds and, unless otherwise specified, having 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms); examples include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl includes both cis and trans isomers. As used herein, the term "alkenylene" refers to a divalent straight- or branched-chain group containing one or more carbon-carbon double bonds and, unless otherwise specified, having 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms).

[0096] The term "alkynyl," as used herein, 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 carbon atoms) containing a carbon-carbon triple bond, examples of which include ethynyl and 1-propynyl.

[0097] The term "alkynyl sulfone," as used herein, refers to a group having the structure [ka] where R is any chemically feasible substituent described herein.

[0098] The term “amino” as used herein refers to —N(R † )2, for example, -NH2 and -N(CH3)2.

[0099] As used herein, the term "aminoalkyl" refers to an alkyl moiety substituted at one or more carbon atoms with one or more amino moieties.

[0100] The term "amino acid," as used herein, refers to a molecule having a side chain, an amino group, and an acid group (e.g., —COH or —SOH), where the amino acid is attached to the parent molecular group by the side chain, the amino group, or the acid group (e.g., the side chain). As used herein, the term "amino acid," in its broadest sense, refers to any compound or substance that can be incorporated into a polypeptide chain, for example, by the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure HN-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. A "standard amino acid" refers to any of the 20 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 hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0101] The term "aryl," as used herein, refers to a monovalent, monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms, wherein the ring attached to the pendant group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. An aryl ring may be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure, and any ring atom may be optionally substituted unless otherwise specified.

[0102] The term "C" as used herein represents a bond. For example, part of the term -N(C(O)-(C-C alkylene-H)- includes -N(C(O)-(C alkylene-H)-, which is also represented as -N(C(O)-H)-.

[0103] The terms "carbocyclic" and "carbocyclyl" as used herein refer to a monovalent, optionally substituted C-C 12 "Carbocyclic" refers to a monocyclic, bicyclic, or tricyclic ring system, which may be bridged, fused, or spirocyclic, in which all rings are formed by carbon atoms and at least one ring is non-aromatic. Carbocyclic systems include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups include cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like. A carbocyclic ring may be attached to its pendant group at any ring atom that results in a stable structure, and any ring atom may be optionally substituted unless otherwise specified.

[0104] The term "carbonyl" as used herein refers to a C(O) group, which may also be depicted as C=O.

[0105] The term "carboxyl," as used herein, means -COH, (C=O)(OH), COOH, or C(O)OH, or deprotonated counterparts.

[0106] The term "cyano," as used herein, refers to a --CN group.

[0107] The term "cycloalkyl," as used herein, refers to a saturated cyclic hydrocarbon group, which, unless otherwise specified, may be bridged, fused, or spirocyclic, having from 3 to 8 ring carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0108] The term "cycloalkenyl," as used herein, refers to a non-aromatic saturated cyclic hydrocarbon group, which, unless otherwise specified, has 3 to 8 ring carbon atoms, and which may be bridged, fused, or spirocyclic, and which contains one or more carbon-carbon double bonds.

[0109] The term "diastereomers," as used herein, means stereoisomers that are not mirror images of each other and are not superimposable with respect to one another.

[0110] The term "enantiomer," as used herein, refers to each individual optically active form of a compound of the present invention having an optical purity or enantiomeric excess (as determined by standard methods in the art) of at least 80% (i.e., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%.

[0111] The term "haloacetyl," as used herein, refers to an acetyl group in which at least one of the hydrogens has been replaced with a halogen.

[0112] As used herein, the term "haloalkyl" refers to an alkyl moiety substituted at one or more carbon atoms with one or more of the same or different halogen moieties.

[0113] The term "halogen", as used herein, refers to a halogen selected from bromine, chlorine, iodine or fluorine.

[0114] The term "heteroalkyl," as used herein, refers to an "alkyl" group, as defined herein, in which at least one carbon atom is replaced with a heteroatom (e.g., an O, N, or S atom). The heteroatom may occur internally or at the terminus of the radical. The term "heteroalkylene," as used herein, refers to a divalent alkylene straight- or branched-chain group, having 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms), unless otherwise specified, in which at least one carbon atom is replaced with a heteroatom (e.g., an O, N, or S atom). The heteroatom may occur internally or at the terminus of the radical.

[0115] As used herein, the term "heteroalkenyl" refers to an "alkenyl" group, as defined herein, in which at least one carbon atom is replaced with a heteroatom (e.g., an O, N, or S atom). The heteroatom may occur internally or at the terminus of the radical.

[0116] As used herein, the term "heteroalkynyl" refers to an "alkynyl" group, as defined herein, in which at least one carbon atom is replaced with a heteroatom (e.g., an O, N, or S atom). The heteroatom may occur at the interior or terminal end of the radical.

[0117] As used herein, the term "heteroaryl" refers to a monovalent monocyclic or polycyclic ring system containing at least one ring that is fully aromatic, i.e., containing 4n+2 pi electrons in the monocyclic or polycyclic ring system, and containing at least one ring heteroatom selected from N, O, or S in the aromatic ring. Exemplary unsubstituted heteroaryl groups are those containing 1 to 12 carbon atoms (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9). The term "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings are fused to one or more aryl or carbocyclic rings, such as phenyl or cyclohexane rings. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl. A heteroaryl ring may be attached to its pendant group at any ring atom that results in a stable structure, and any ring atom may be optionally substituted unless otherwise specified. In some embodiments, a heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0118] The term "heterocycloalkyl," as used herein, refers to a monocyclic, bicyclic, or polycyclic ring system, which may be bridged, fused, or spirocyclic, in which at least one ring is non-aromatic and the non-aromatic ring contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered rings have 0 to 2 double bonds, and six- and seven-membered rings have 0 to 3 double bonds. Exemplary unsubstituted heterocycloalkyl groups are those containing 1 to 12 carbon atoms (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9). The term "heterocycloalkyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbon or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as a quinuclidinyl group. The term "heterocycloalkyl" includes cyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused with one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, a pyridine ring, or a pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthyridinyl. A heterocycloalkyl ring may be attached to its pendant group at any ring atom that results in a stable structure, and any ring atom may be optionally substituted unless otherwise specified.

[0119] As used herein, the term "heterocycloalkenyl" refers to a non-aromatic saturated heterocyclic group, which, unless otherwise specified, may be bridged, fused, or spirocyclic, containing 5 to 10 ring atoms, containing one or more carbon-carbon double bonds, and containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

[0120] As used herein, the term "heterocycloalkynyl" refers to a non-aromatic saturated heterocyclic group, which unless otherwise specified, may be bridged, fused, or spirocyclic, containing 8 to 10 ring atoms, containing a carbon-carbon triple bond, and containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

[0121] The term "hydroxy" as used herein refers to an --OH group.

[0122] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety substituted at one or more carbon atoms with one or more --OH moieties.

[0123] The term "isomer," as used herein, refers to any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention may have one or more chiral centers or double bonds and may 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). In accordance with the present invention, the chemical structures depicted herein, and thus the compounds of the invention, encompass all corresponding stereoisomers, i.e., stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure), as well as both enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can typically be resolved into their constituent enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase 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 stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0124] 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 bridging group).

[0125] A "macrocyclic moiety" or "macrocycle" refers to a compound or portion of a compound having a ring with at least 10 atoms (e.g., at least 12, at least 14, at least 16, 10-40, 12-40, or 12-30). In some embodiments, the macrocycle has at least 12 atoms. In some embodiments, the macrocycle has at least 14 atoms.

[0126] In some embodiments, the linker comprises 20 or fewer linear chain atoms. In some embodiments, the linker comprises 15 or fewer linear chain atoms. In some embodiments, the linker comprises 10 or fewer linear 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.

[0127] The term "stereoisomer," as used herein, refers to all possible different isomeric and conformational forms that a compound (e.g., a compound of any formula described herein) may possess, in particular all possible stereochemical and conformational isomeric forms of the basic molecular structure, all diastereomers, enantiomers, or conformational isomers, including atropisomers. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.

[0128] The term "sulfonyl," as used herein, refers to a -S(O)2- group.

[0129] The term "thiocarbonyl," as used herein, refers to a -C(S)- group.

[0130] Those skilled in the art will appreciate, upon reading this disclosure, that certain compounds described herein may be provided or utilized in various forms, such as salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a unique form of that compound. In some embodiments, reference to a particular compound may refer to that compound in any form. 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 containing one conformational isomer of the double bond ((Z) or (E)) may be considered a different form than one containing the other conformational isomer of the double bond ((E) or (Z)); a preparation in which one or more atoms are isotopically different from those present in a reference preparation may be considered a different form.

[0131] A chemical substituent may be one that is "capable of stabilizing a positive charge or partial positive charge" or "stabilizes a carbocation," as known to those skilled in the art of organic chemistry. For example, a substituent may have the ability to stabilize a positive charge through resonance effects (delocalization of electron density across adjacent orbitals), hyperconjugation (e.g., interaction of electrons in a sigma orbital with an adjacent non-bonding p orbital), or inductive effects (changes in electron density due to electron-withdrawing or electron-donating groups in a molecule).

[0132] 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 "presenter protein / compound complexes" comprising a compound of the invention bound to a presenter protein, and "compound / target protein complexes" comprising a compound of the invention bound to a target protein.

[0133] The term "presenter protein" refers to a protein that binds to a small molecule to form a complex that binds to and regulates the activity of 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 presenter protein is a relatively abundant protein (e.g., the presenter protein is sufficiently abundant that its incorporation into a ternary complex does not substantially affect the biological role of the presenter protein in the cell and / or the viability or other attributes of the cell). In certain embodiments, the presenter protein is a protein that has chaperone activity within the cell. In some embodiments, the presenter protein is a protein that has multiple natural interaction partners within the cell. In certain embodiments, the presenter protein is known to bind to a small molecule to form a binary complex that is known or suspected to bind to and regulate the biological activity of the target protein.

[0134] The term "presenter protein binding moiety" refers to a compound that binds to the presenter protein with a K of, for example, 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). Dspecifically binds to or inhibits the peptidyl prolyl isomerase activity of the presenter protein with an IC of, for example, 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 "A" refers to a group of ring atoms and their attached moieties (e.g., atoms within 20 atoms of the ring atom, e.g., atoms within 15 atoms of the ring atom, atoms within 10 atoms of the ring atom, atoms within 5 atoms of the ring atom) that participate in binding to the presenter protein in a manner that inhibits binding. It will be understood that a presenter protein-binding moiety does not necessarily encompass all atoms in a compound that interacts with a presenter protein. It will also be understood that one or more atoms of a presenter protein-binding moiety may be included in a target protein-interacting moiety (e.g., a eukaryotic target protein-interacting moiety, e.g., a mammalian target protein-interacting moiety or a fungal target protein-interacting moiety, or a prokaryotic target protein-interacting moiety, e.g., a bacterial target protein-interacting moiety). In some embodiments, the presenter protein-binding moiety has a molecular weight of less than 1000 g / mol. In some embodiments, the presenter protein-binding moiety has a molecular weight of less than 750 g / mol. In some embodiments, the presenter protein-binding moiety has a molecular weight of less than 500 g / mol. In some embodiments, the presenter protein-binding moiety has a molecular weight of less than 400 g / mol. In some embodiments, the presenter protein-binding moiety has a molecular weight of less than 300 g / mol. In some embodiments, the presenter protein-binding moiety has a molecular weight of less than 200 g / mol. In some embodiments, the presenter protein-binding moiety has a molecular weight of less than 100 g / mol. In some embodiments, the presenter protein-binding moiety has a molecular weight of less than 50 g / mol.

[0135] It will be understood that the term "binding," as used herein, typically refers to an association (e.g., a non-covalent or covalent association between or among two or more entities). "Direct" binding involves physical contact between the entities or moieties; indirect binding involves a physical interaction through physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts, including those in which the interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g., while associated with a carrier entity, such as by a covalent bond, and / or while within a biological system or cell).

[0136] The affinity of a molecule X for its partner Y is usually expressed as the dissociation constant (K D Affinity can be measured by common methods known in the art, for example, the methods described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below. D The term "" as used herein is intended to refer to the dissociation equilibrium constant of a particular compound-protein or complex-protein interaction. Typically, the compounds of the invention have a dissociation equilibrium constant of about 10 as determined, for example, by surface plasmon resonance (SPR) techniques using a presenter protein as the analyte and the compound as the ligand. -6 Less than M, for example, approximately 10 -7 Under M, 10 -8 Under M, 10 -9 Less than M or 10 -10 The dissociation equilibrium constant (K) is less than M or an even lower value. D The presenter protein / compound complex of the present invention binds to the presenter protein at a concentration of about 10 as determined by surface plasmon resonance (SPR) technology using the target protein as the analyte and the complex as the ligand. -6 Less than M, for example, approximately 10 -7 Under M, 10 -8 Under M, 10 -9 Less than M or 10 -10The dissociation equilibrium constant (K) is less than M or an even lower value. D ) 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).

[0137] As used herein, the term "target protein interacting moiety" refers to a group of ring atoms and attached moieties (e.g., atoms within 20 atoms of the ring atom, e.g., atoms within 15 atoms of the ring atom, atoms within 10 atoms of the ring atom, atoms within 5 atoms of the ring atom) that specifically binds to a target protein (e.g., a eukaryotic target protein, e.g., a mammalian target protein or a fungal target protein, or a prokaryotic target protein, e.g., a bacterial target protein) when the compound is in a complex with a presenter protein.

[0138] The term "modulator" is used to refer to an entity whose presence or level in a system in which an activity of interest is observed correlates with a change in the level and / or nature of the activity when compared to the activity observed under otherwise equivalent conditions in the absence of the modulator. In some embodiments, a modulator is an activator, in that in its presence, the activity is increased compared to the activity observed under otherwise equivalent conditions in the absence of the modulator. In some embodiments, a modulator is an antagonist or inhibitor, in that in its presence, the activity is decreased compared to otherwise equivalent conditions in the absence of the modulator. In some embodiments, a modulator directly interacts with a target entity whose activity is of interest. In some embodiments, a modulator interacts indirectly with a target entity whose activity is of interest (i.e., directly with an intermediate compound that interacts with the target entity). In some embodiments, a modulator affects the level of a target entity of interest; alternatively, or in addition, in some embodiments, a modulator affects the activity of a target entity of interest without affecting the level of the target entity. In some embodiments, the modulator affects both the level and activity of the target entity of interest such that the difference in activity observed is not fully explained by or commensurate with the difference in level observed, hi some embodiments, the modulator is an allosteric modulator, e.g., an allosteric agonist.

[0139] The term "presenter protein" refers to a protein that binds to a small molecule to form a complex that binds to and regulates the activity of 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 presenter protein is a relatively abundant protein (e.g., the presenter protein is sufficiently abundant that its incorporation into a ternary complex does not substantially affect the biological role of the presenter protein in the cell and / or the viability or other attributes of the cell). In certain embodiments, the presenter protein is a protein that has chaperone activity within the cell. In some embodiments, the presenter protein is a protein that has multiple natural interaction partners within the cell. In certain embodiments, the presenter protein is known to bind to a small molecule to form a binary complex that is known or suspected to bind to and regulate the biological activity of the target protein.

[0140] The term "substantially" refers to the qualitative state of exhibiting a property or characteristic of interest to a perfect or near-perfect degree or extent. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, are perfect and / or move toward perfection or achieve or avoid absolute results. The term "substantially" is therefore used herein to capture the possible lack of perfection inherent in many biological and chemical phenomena.

[0141] As used herein, the term "does not substantially bind" to a particular protein refers to, for example, a protein that does not bind to a target. D is 10 -4 M or more, or 10 -5 M or more, or 10 -6 M or more, or 10 -7 M or more, or 10 -8 M or more, or 10 -9 M or more, or 10-10 M or more, or 10 -11 M or more, or 10 -12 M or greater, or K D is 10 -4 M~10 -12 M or 10 -6 M~10 -10 M or 10 -7 M~10 -9 M can be a molecule or a portion of a molecule.

[0142] The term "target protein" refers to a protein that binds to a small molecule or a presenter protein / compound complex described herein. In some embodiments, the target protein does not substantially bind to either the small molecule or the presenter protein alone. In some embodiments, the small molecule / presenter 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 one that is naturally found in a particular mammalian cell (e.g., a mammalian target protein), fungal cell (e.g., a fungal target protein), bacterial cell (e.g., a bacterial target protein), or plant cell (e.g., a plant target protein). In some embodiments, the target protein is characterized by a natural interaction with one or more natural presenter protein / native small molecule complexes. In some embodiments, the target protein is characterized by a natural interaction with multiple different natural presenter proteins / native small molecule complexes; in some such embodiments, some or all of the complexes utilize the same presenter protein (and different small molecules). In some embodiments, the target protein does not substantially bind to a complex of cyclosporine, rapamycin, or FKFK506 and a presenter protein (e.g., FKBP). The target protein can be naturally occurring, e.g., wild-type. Alternatively, the target protein can be different from the wild-type protein but still retain biological function, e.g., an allelic variant, splice variant, 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 classical protein-protein interaction domains and motifs, or any other proteins involved in a biological pathway associated with a disease, disorder, or condition.

[0143] The term "target protein interacting moiety" refers to a group of atoms in a compound that participates in binding 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). In some embodiments, a compound binds to a target protein when the compound is in a complex with a presenter protein. It will be understood that a target protein interacting moiety does not necessarily encompass all atoms in a compound that interact with a target protein. It will also be understood that one or more atoms of a presenter protein binding moiety may be present in the target protein interacting moiety. In some embodiments, a target protein interacting moiety is a bridging group.

[0144] The term "small molecule" refers to a low molecular weight organic and / or inorganic compound. Generally, a "small molecule" is a molecule less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, less than 3 kD, less than about 2 kD, or less than about 1 kD. In some embodiments, a small molecule is less than about 800 daltons (D), less than about 600 D, less than about 500 D, less than about 400 D, less than about 300 D, less than about 200 D, or less than about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer. In some embodiments, a small molecule does not comprise a polymeric moiety. In some embodiments, a small molecule is not a protein or polypeptide (e.g., not an oligopeptide or peptide). In some embodiments, the small molecule is not a polynucleotide (e.g., not an oligonucleotide). In some embodiments, the 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 OF THE INVENTION

[0145] compound The present disclosure provides compounds capable of forming complexes and / or cross-linking to targets (e.g., target proteins), as well as synthetic intermediates used in the preparation of such compounds and the complexes formed by reaction with the compounds.

[0146] Synthetic Intermediates The compounds of the present disclosure may contain an aziridine moiety. The compounds of the present invention may contain an aziridine and a group capable of reacting with a second moiety, allowing the aziridine to be incorporated into another moiety. The compounds may, for example, be capable of reacting with a nucleophile (e.g., an ester). Thus, the compounds may have the formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: Z is [ka] and; M + is a cation; 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 1is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ) and; or R and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C3-C6 heteroalkynyl ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-C 10 R and R form a cycloalkynyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. 4 each independently represents 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 each R is independently selected from 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-C6 heteroalkyl, optionally substituted C3 ...alkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyn 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; 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-C6 10 Cycloalkyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; Each R 1a , R 2a , R 2c , R 2d and R 2e are independently an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C 10Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, optionally substituted 8- to 10-membered heterocycloalkynyl, optionally substituted C-C 10 aryl, or optionally substituted 5-10 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; where: Each hydrogen is independently, optionally, isotopically enriched with deuterium.

[0147] In some embodiments, R and R 4At least one of is not hydrogen.

[0148] In some embodiments, the compound or pharmaceutically acceptable salt thereof has the structure of Formula Ia: [ka] It has.

[0149] In some embodiments, the compound or pharmaceutically acceptable salt thereof has the structure of Formula Ib: [ka] It has.

[0150] In some embodiments, the compound or pharmaceutically acceptable salt thereof has the structure of Formula Ic: [ka] It has.

[0151] In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure of formula Id: [ka] It has.

[0152] 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 aryl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R 3 is an optionally substituted C1-C6 alkyl. In some embodiments, R 3 is methyl, ethyl or benzyl.

[0153] In some embodiments, M + Li + is.

[0154] In some embodiments, R 3 teeth, [ka] is.

[0155] In some embodiments, Z is [ka] is.

[0156] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof or an alternative pharmaceutically acceptable salt thereof, or a stereoisomer thereof. [Table 1-1] [Table 1-2] [Table 1-3]

[0157] Aziridine-containing compounds The present disclosure also features compounds containing an aziridine moiety linked to a monovalent organic moiety. Those of ordinary skill in the art are familiar with organic moieties. The monovalent organic moiety can be or 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 decomposition inducer, a macrocycle, or a protein, e.g., a mutant protein. The organic moiety can be linked to the aziridine moieties disclosed herein in a variety of ways, and those of ordinary skill in the art are familiar with the methodology for incorporating the aziridine-containing synthetic intermediates described herein into monovalent organic moieties. Non-limiting examples include the following scheme:

[0158] Scheme A. Exemplary General Synthesis of Aziridine-Containing Compounds [ka] 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 give the final compound (3).

[0159] Scheme B. Exemplary General Synthesis of Aziridine-Containing Compounds [ka] As shown in Scheme B, compounds of this type can be prepared by reacting an appropriate amine-substituted monovalent organic moiety (1) with an aziridine containing an activated ester (2) in the presence of a basic amine to give the final compound (3).

[0160] In some embodiments, the compound containing an aziridine moiety attached to a monovalent organic moiety has Formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: A 1 is a monovalent organic moiety; Q is [ka] and; 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 1 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ) and; or R and R 4 and optionally substituted C3-C 10Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C3-C6 heteroalkynyl ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-C 10 R and R form a cycloalkynyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. 4 are each independently selected from 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 each R is 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; Each R 1a , R 2a , R 2c , R 2d and R 2e are 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 C-C10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; 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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; where: Each hydrogen is independently, optionally, isotopically enriched with deuterium.

[0161] In some embodiments, R and R 4 At least one of is not hydrogen.

[0162] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIa: [ka] It has.

[0163] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIb: [ka] It has.

[0164] In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof has the structure of Formula IIc: [ka] It has.

[0165] In some embodiments, the compound of formula II or a pharmaceutically acceptable salt thereof has the structure of formula IId: [ka] It has.

[0166] In some embodiments, Q is [ka] is.

[0167] In some embodiments, the organic moiety may be attached to the aziridine in other ways, for example, R, R 1 , R 2 or R 4 , may be bound to.

[0168] In some embodiments, A1 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. 1 is a small molecule. In some embodiments, A 1 is or comprises a macrocyclic small molecule.

[0169] In some embodiments, one or more compounds described in WO2023 / 141300 may be excluded from any embodiment herein. In some embodiments, one or more compounds described in WO2022 / 271658 may be excluded from any embodiment herein. In some embodiments, one or more compounds described in WO2023 / 208005 may be excluded from any embodiment herein.

[0170] In some embodiments, the compound is not a compound disclosed in WO2021 / 091967. In some embodiments, the compound is not a compound in Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 [Table 2-21] [Table 2-22] [Table 2-23] [Table 2-24] [Table 2-25] [Table 2-26] [Table 2-27] [Table 2-28]

[0171] Displayer protein-binding moiety In some embodiments of the above compounds, A 1 is a presenter protein-binding moiety. This moiety is capable of binding to the presenter protein with a K of, for example, 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 binds to or inhibits the peptidyl prolyl isomerase activity of the presenter protein with an IC of, for example, 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). 50The presenter protein-binding moiety may include a group of ring atoms (e.g., 5-20 ring atoms, 5-10 ring atoms, 10-20 ring atoms) and a moiety attached thereto (e.g., atoms within 20 atoms of the ring atoms, e.g., 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 the presenter protein in a manner that inhibits binding. In some embodiments, the presenter protein-binding moiety does not encompass all atoms in a provided compound that interacts with a presenter protein. In some embodiments, one or more atoms of the presenter protein-binding moiety may be included in the target protein-interacting moiety (e.g., a eukaryotic target protein-interacting moiety, e.g., a mammalian target protein-interacting moiety or a fungal target protein-interacting moiety, or a prokaryotic target protein-interacting moiety, e.g., a bacterial target protein-interacting moiety). In certain embodiments, one or more atoms of the presenter protein-binding moiety do not interact with the presenter protein.

[0172] In some embodiments, the presenter protein-binding moiety is an N-acylproline moiety, an N-acyl-pipecolic acid moiety, an N-acyl 3-morpholino-carboxylic acid moiety, and / or an N-acylpiperazine acid moiety (e.g., where either nitrogen atom is acylated). In certain embodiments, the presenter protein-binding moiety comprises an N-acyl-pipecolic acid moiety. In some embodiments, the presenter protein-binding moiety comprises an N-acylproline moiety. In certain embodiments, the presenter protein-binding moiety comprises an N-acyl 3-morpholino-carboxylic acid moiety. In some embodiments, the presenter protein-binding moiety comprises an N-acylpiperazine acid moiety.

[0173] In some embodiments, at least one atom of the presenter protein-binding moiety participates in binding to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) of Tyr 27, Phe 37, Asp 38, Arg 41, Phe 47, Gln 54, Glu 55, Val 56, Ile 57, Trp 60, Ala 82, Try 83, His 88, Ile 92, and / or Phe 100 of FKBP12. In some embodiments, at least one atom of the presenter protein-binding moiety participates in binding to at least one (e.g., 2, 3, or 4) of Arg 41, Gln 54, Glu 55, and / or Ala 82 of FKBP12.

[0174] In some embodiments, the presenter protein-binding moiety has Formula IV: [ka] wherein: The dashed lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-], optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and; X 2 is O or NH; X 3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); each R' is independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH or N; Y 2 , Y 3 , Y 4 and Y 7 are independently C or N; Y 5 is CH, CH2 or N; Y 6 is C(O), CH, CH2 or N; 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 R 1 and R 2 and, combined with the atom(s) to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 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, optionally substituted 5- or 6-membered heteroaryl; R 3 is absent, or R 2 and R 3and, in combination with the atoms to which they are attached, form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl; or 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; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, 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 R 7 and R 8 and combine with the carbon atoms bonded to them 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; R 7a and R 8aare independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, 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 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; 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 R 9 and L, combined with the atom(s) to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo; R 11 is hydrogen or C1-C3 alkyl; R 34is hydrogen or C1-C3 alkyl. Each hydrogen in the compound of formula IV is optionally isotopically enriched with deuterium.

[0175] In some embodiments, the presenter protein-binding moiety has the structure of Formula V: [ka] where 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; X 1 is CH2 or O; m is 1 or 2; n is 0 or 1; R 1 is hydrogen or an optionally substituted 3- to 10-membered heterocycloalkyl; R 2 is an optionally substituted C1-C6 alkyl; R 3 is an optionally substituted C1-C6 alkyl or an optionally substituted 3- to 6-membered cycloalkyl.

[0176] In some embodiments, the presenter protein-binding moiety has the structure of Formula VI: [ka] where 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; X 1 , X 2 , and X 3 are each independently selected from CH, CHF, CF, C=O, or O; m is 1 or 2; n is 0 or 1; R 1 is hydrogen, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3-10 membered heterocycloalkyl; R 2 is an optionally substituted C1-C6 alkyl; R 3 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted heterocycloalkyl; where: Each hydrogen is independently, optionally isotopically enriched with deuterium.

[0177] In some embodiments, the presenter protein-binding moiety has the structure of any one of Formulas VII, VIII, and IX: [ka] where o and p are independently 0, 1 or 2; q is an integer from 0 to 7; r is an integer from 0 to 4; X 4 and X 5 are each independently absent, CH, O, S, SO, SO, or NR 11 and; Each R 6 and R 7 are independently hydrogen, hydroxyl, 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-C6 heteroalkyl, optionally substituted C3 ... 10Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C-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 and combine with the carbon atoms to which they are attached to form C=O; Each R 8 are independently selected from hydroxyl, 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-C6 heteroalkyl, optionally substituted C3 ... 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C-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, or two R 8 in combination with optionally substituted C3-C 10 Carbocyclyl, optionally substituted C-C 10 forming an aryl or an optionally substituted C2-C9 heteroaryl; R 9is an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C2-C6 heteroalkenyl, an optionally substituted C2-C6 heteroalkynyl, an optionally substituted C3-C6 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C-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; R 10 is an optionally substituted C1-C6 alkyl; Each R 11 are independently selected from hydroxyl, 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-C6 heteroalkyl, optionally substituted C3 ...alkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally 10 Carbocyclyl, optionally substituted C-C 10 Aryl, optionally substituted C-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; R 12 and R 13are 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 arylC1-C6 alkyl, and optionally substituted C3-C7 carbocyclylC1-C6 alkyl.

[0178] In some embodiments, the presenter protein-binding moiety is [ka] [ka] [ka] [ka] or the structure of a stereoisomer thereof.

[0179] In certain embodiments, the presenter protein-binding moiety is [ka] It has the following structure.

[0180] Activity Probes Certain aziridine-containing probes are known in the art and can be used with the methods of the present disclosure. These compounds can be useful in forming any of the conjugates described herein. Exemplary aziridine-containing activity 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, replacing the original aziridine. [ka] [ka]

[0181] Compound properties Pharmacokinetic parameters The preliminary exposure profile of a compound can be evaluated, for example, using an in vivo rat early phase pharmacokinetic (EPK) study design to demonstrate bioavailability. For example, a specific formulation can be administered to male Sprague-Dawley rats by oral gavage (PO). Blood samples can then be collected from the animals at six time points up to 4 hours after administration. Pharmacokinetic analysis can then be performed on the concentrations of each compound measured by LC-MS / MS at each time point.

[0182] cell permeability In some embodiments, the compound is cell-permeable. Any method known in the art can be employed to determine the permeability of a compound, such as the biosensor assays described herein.

[0183] protein Presentation protein A display protein can bind to a small molecule to form a complex that can bind to and regulate the activity of 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 display protein is a mammalian display protein (e.g., a human display protein). In some embodiments, the display protein is a fungal display protein. In certain embodiments, the display protein is a bacterial display protein. In some embodiments, the display protein is a plant display protein. In some embodiments, the display protein is a relatively abundant protein (e.g., the display protein is sufficiently abundant that incorporation into a ternary complex does not substantially adversely affect the biological role of the display protein in the cell and / or the viability or other attributes of the cell). In some embodiments, the display protein is more abundant than the target protein. In certain embodiments, the display protein is a protein that has chaperone activity within the cell. In some embodiments, the display protein has multiple natural interaction partners within the cell. In certain embodiments, the presenter protein is one that has been shown to bind to a small molecule to form a binary complex that is known or suspected to bind to and modulate the biological activity of a target protein. Immunophilins are a class of presenter proteins known to have these functions, including FKBPs and cyclophilins.

[0184] In some embodiments, the reference display protein exhibits peptidyl prolyl isomerase activity; in some embodiments, the display protein exhibits activity equivalent to the reference display protein. In certain embodiments, the presenter 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 with proline isomerase activity that function 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.

[0185] 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.

[0186] In some embodiments, the presenter protein is a chaperone protein, such as GRP78 / BiP, GRP94, GRP170, calnexin, calreticulin, HSP47, ERp29, protein disulfide isomerase (PDI), and ERp57.

[0187] In some embodiments, the presenter protein is an allelic variant or splice variant of an FKBP or cyclophilin disclosed herein.

[0188] In some embodiments, a display protein is a polypeptide whose amino acid sequence i) shows significant identity to the amino acid sequence of a reference display protein; ii) includes a portion that shows significant identity to a corresponding portion of the reference display protein; and / or iii) includes at least one characteristic sequence found in the display protein. In many embodiments, for purposes of defining a display protein, identity is considered "significant" if it is greater than 80%, greater than 81%, greater than 82%, greater than 83%, greater than 84%, greater than 85%, greater than 86%, greater than 87%, greater than 89%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or more. In some embodiments, the portion showing significant identity is 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, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 300, 350, 450, 500, 550, 600, or more amino acids in length.

[0189] Representative display proteins are encoded by genes listed in Table 3 or homologs thereof; in some embodiments, a reference display protein is encoded by a gene set forth in Table 3. Moreover, by referring to Table 3, one of skill in the art can readily identify sequences that are characteristic of display proteins in general and / or particular subsets of display proteins. [Table 3]

[0190] Target protein Target proteins (e.g., eukaryotic target proteins, such as mammalian target proteins or fungal target proteins, or prokaryotic target proteins, such as bacterial target proteins) are proteins that mediate disease states or symptoms of disease states. Therefore, modulating (inhibiting or increasing) their activity can result in desirable therapeutic effects. Target proteins useful in the complexes and methods of the invention include those that do not naturally associate with presenter proteins, e.g., those that have an affinity for presenter proteins 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 a compound of the invention. Alternatively, target proteins that do not naturally associate with presenter proteins have an affinity for compounds of the 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, target proteins that do not naturally associate with presenter proteins have an affinity for a binary complex of cyclosporine, rapamycin, or FK506 with a presenter protein (e.g., FKBP) of greater than 1 μM, preferably greater than 5 μM, and more preferably greater than 10 μM. In yet another alternative, the target protein that is not naturally associated with the presenter protein is other than calcineurin or mTOR. The selection of a target protein suitable for the complex and method of the present invention can depend on the presenter protein. For example, a target protein with low affinity for cyclophilin may have high affinity for FKBP, and will not be used together with the latter.

[0191] A target protein can be naturally occurring, e.g., wild-type, or it can be a protein that differs from the wild-type protein but still retains biological function, e.g., an allelic variant, splice variant, or biologically active fragment.

[0192] 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 one protein of a dimeric complex.

[0193] In some embodiments, target proteins of the invention comprise one or more surface sites (e.g., smooth surface sites) characterized by low or undetectable binding of small molecules to the site(s) in the absence of the formation of a presenter protein / compound complex. In some embodiments, target proteins comprise one or more surface sites (e.g., smooth surface sites) in which low or undetectable binding of a particular small molecule (e.g., the compound) to the site in the absence of the formation of a presenter protein / compound complex (e.g., at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, or less binding compared to the binding observed for a presenter protein / compound complex containing the same compound). In some embodiments, the target protein has a surface (in some embodiments, the entire surface) characterized by one or more sites that lack a traditional binding cavity, e.g., a protein structural cavity or cavity that has physiological and / or geometric characteristics comparable to proteins whose activity is regulated by one or more small molecules. In particular embodiments, the target protein has a traditional binding cavity and a site for protein-protein interaction. In some embodiments, the target protein is a non-druggable target, e.g., the target protein is a member of a protein family that is known to be a drug target and / or does not have a binding site predicted to be suitable for binding to a small molecule (according to art-accepted interpretations as described herein).

[0194] These are GTP-protein, DIRAS1, DIRAS2, DIRAS3, ERAS, and GEM. HRAS、KRAS、MRAS、NKIRAS1、NKIRAS2、NRAS、RALA、RALB、RAP1A、RAP1B、RAP2 A, RAP2B, RAP2C, RASD1, RASD2, RASL10A, RASL10B, RASL11A, RASL11B, RAS L12, REM1, REM2, RERG, RERGL, RRAD, RRAS, RRAS2, RHOA, RHOB, RHOBTB1, RHO BTB2, RHOBTB3, RHOC, RHOD, RHOF, RHOG, RHOJ, RHOQ, RHOU, RHOV, RND 1, RND2, RND3, RAC1, RAC2, RAC3, CDC42, RAB1A, RAB1B, RAB2, RAB3A, RAB3B. RAB3C, RAB3D, RAB4A, RAB4B, RAB5A, RAB5B, RAB5C, RAB6A, RAB6B, RAB6C, RA B7A, RAB7B, RAB7L1, RAB8A, RAB8B, RAB9, RAB9B, RABL2A, RABL2B, RABL4, RA B10, RAB11A, RAB11B, RAB12, RAB13, RAB14, RAB15, RAB17, RAB18, RAB19 AB20, RAB21, RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28 RAB2B, RAB30, RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37 RAB38, RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, RAB41, RAB42 AB43, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, ARF1, ARF3, ARF4, ARF5, ARF6 RL1, ARL2, ARL3, ARL4, ARL5, ARL5C, ARL6, ARL7, ARL8, ARL9, ARL10A, ARL10 B、ARL10C、ARL11、ARL13A、ARL13B、ARL14、ARL15、ARL16、ARL17、TRIM23、AR L4D, ARFRP1, ARL13B, RAN, RHEB, RHEBL1, RRAD, GEM, REM, REM2, RIT1, RIT2In 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, e.g., CNRASGEF, RASGEFlA, RASGRF2, RASGRPl, RASGRP4, SOSl, RALGDS, RGLl, RGL2, RGR, ARHGEFlO, ASEF / ARHGEF4, ASEF2, DBS, ECT2, GEF-Hl, LARG, NETl, OBSCURIN, P-REXl, P-REX2, PDZ-RHOGEF, TEM4, TIAMl, TRIO, VAVl, VAV2, VAV3, DOCKl, DOCK2, DOCK3, DOCK4, DOCK8, DOCKlO, C3G, BIG2 / ARFGEF2, EFA6, FBX8, or GEP100. In certain embodiments, the target protein is 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, In some embodiments, the target protein is a protein having an 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, e.g., Hsp20, Hsp27, Hsp70, Hsp84,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 geminin, 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, e.g., 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, RET RON, ROR1, ROR2, ROS, SRC, SYK, TIE1, TIE2, TRKA, TRKB, KDR, AKT1, AKT2, AKT3, PDK1, PKC, RHO, ROCK1, RSK1, RKS2, RKS3, ATM, ATR, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CD K7, 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 the genes BRG1, BRM, ATRX, PRDM3, ASH1L, CBP, KAT6A, KAT6B, MLL, NSD1, SETD2, EP300,In some embodiments, the target protein is a chromatin modifier / remodeler encoded by KAT2A or CREBBP. In some embodiments, the target protein is a transcription factor, e.g., a gene encoding 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, F IGLA, 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, HOXA 1, HOXA10, HOXA13, HOXA2, HOXAB13, HOXB2, HOXB3, HOXB5, HOXC10, HOXC11, HOXC12, HOXC13, HOXD11, HOXD12, HOXD13, HOXD8, IRX2, IRX5, ISL2, IS X, 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、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, ES RRG, HNF4A, NR2C2, NR2E1, NR2F1, NR2F6, NR3C1, NR3C2, NR4A2, RARA, RARB, RARG, RORA, RXRA, RXRB, RXRG, THR, A, THRB, VDR, GATA3, GATA4, or GATA5 encoded transcription factors; or C-myc, Max, Stat3, androgen receptor, C-Jun, C-Fox, N-Myc, L-Myc, MITF, Hif-1 alpha, Hif-2 alpha, Bcl6, E2F1, NF-kappaB, Stat5, or ER(coact). In certain embodiments, the target protein is TrkA, P2Y14, mPEGS, ASK1, ALK, Bcl-2, BCL-XL, mSIN1, RORγt, IL17RA, eIF4E, TLR7R, PCSK9, IgE R, CD40, CD40L, Shn-3, TNFR1, TNFR2, IL31RA, OSMR, IL12beta1,2, tau, FASN, KCTD6, KCTD9, Raptor, Rictor, RALGAPA, RALGAPB, annexin family members, BCOR, NCOR, beta-catenin, AAC11, 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.

[0195] Synthesis method Methods for synthesizing the cyclopropylaziridines disclosed herein are known in the art and may include those shown in the following schemes: [ka]

[0196] (2R,3R)-beta-phenylaziridine was synthesized using the Davis auxiliary (para-toluenesulfinimide) (Davis et al., J. Org. Chem. 1994, 59(12), 3243-3245; Davis et al., J. Org. Chem. 1999, 64(20), 7559-7567). See A above.

[0197] (2S,3S)-beta-cyclopropylaziridine (B above) can be synthesized using Ellman's auxiliary (tert-butylsulfinimide) (Sola et al., Org. Biomol. Chem. 2011, 9(14), 5034).

[0198] Beta-cyclopropylaziridines can also be prepared by reacting diphenylmethylimines with diazoesters under acidic conditions (Williams, et al., J. Am. Chem. Soc. 2004, 126(6), 1612-1613). However, this method is not asymmetric and results in a mixture of cis and trans isomers, as well as a mixture of enantiomers.

[0199] Alternatively, beta-cyclopropylaziridine can be made on a large scale using the following scheme. [ka] (2R,3R)-beta-cyclopropylaziridine can be synthesized by reacting (R)-para-toluenesulfinimide with 2-bromobenzyl acetate and LiHMDS. Removal of the chiral auxiliary is accomplished using either TFA or methyl Grignard. Methylation of the aziridine nitrogen is achieved either by Chan-Lam coupling with methylboronic acid or by alkylation with methyl iodide.

[0200] Complex Presentation protein / compound complex In contrast to many small molecule-protein interactions, which are driven by small molecule-small molecule interactions in cavities or pockets on proteins, naturally occurring protein-protein interactions are driven primarily by hydrophobic residues on the smooth surface of the two proteins. Hydrophobic residues on the smooth surface form hydrophobic hot spots on two interacting proteins, with most of the binding interaction between the two proteins being van der Waals interactions. Small molecules can be used as portable hot spots for proteins lacking an interaction (e.g., a display protein) by forming a complex (e.g., a display protein / compound complex) to participate in a pseudoprotein-protein interaction (e.g., form a ternary complex with a target protein).

[0201] Many mammalian proteins can bind to any of several different partners; in some cases, such alternative binding interactions contribute to the biological activity of the protein. Many of these proteins adapt the inherent variability of hotspot protein regions to display the same residues in different structural contexts. More specifically, protein-protein interactions can be mediated by a class of natural products produced by a select group of fungal and bacterial species. These molecules not only share a common structural organization, but also exhibit the resulting functionality that confers the ability to regulate protein-protein interactions. These molecules contain a highly conserved displayer protein-binding portion and a highly variable target protein-interacting portion among different natural products. The displayer protein-binding portion confers specificity for the displayer protein, allowing the molecule to bind to the displayer protein and form a binary complex; the mammalian target protein-interacting portion confers specificity for the target protein, allowing the binary complex to bind to the target protein and typically regulate its activity (e.g., positively or negatively).

[0202] These natural products are presented by presenter proteins such as FKBP and cyclophilin, which act as diffusible, cell-permeable, and orally bioavailable adaptors for protein-protein interactions. Examples include well-known, clinically important molecules such as rapamycin (sirolimus), FK506 (tacrolimus), and cyclosporin. Briefly, these molecules bind to endogenous intracellular presenter proteins, such as FKBP (e.g., rapamycin and FK506), or cyclosporin (e.g., diluent), and the resulting presenter protein-binding molecule binary complex selectively binds to and inhibits the activity of intracellular target proteins. The formation of a ternary complex between the presenter protein, molecule, and target protein is facilitated by both protein-molecule and protein-protein interactions, both of which are necessary for target protein inhibition. In the case of the FKBP-rapamycin complex, the intracellular target is the serine-threonine kinase mTOR, whereas in the case of the FKBP-FK506 complex, the intracellular target is the phosphatase calcineurin. What is particularly interesting about these two examples is that both rapamycin and FK506-presented ligands utilize FKBP12 as their partner protein. Furthermore, the structural elements of rapamycin and FK506 that contribute to FKBP12 binding are closely related, i.e., the so-called "conserved regions." However, dramatic structural differences exist between rapamycin and FK506 in their non-FKBP12-binding regions, or "variable regions," resulting in their specific targeting of mTOR and calcineurin, two distinct intracellular proteins, respectively. Thus, the variable regions of rapamycin and FK506 serve as contributors to the binding energy required to enable presenter protein-target protein interactions.

[0203] In some embodiments, a presenter protein / compound complex of the invention binds to a target protein with an affinity that 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 complex binds to mTOR and / or calcineurin, respectively.

[0204] In some embodiments, the present presenter protein / compound complexes bind to a target protein with an affinity that 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 in a complex with the presenter protein.

[0205] In certain embodiments, the present presenter protein / compound complexes bind to a target protein with an affinity that is at least 5 times (e.g., at least 10 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 100 times) higher than the affinity of the presenter protein for the target protein when the presenter protein is not bound in a complex with a compound.

[0206] In some embodiments, presenter protein / compound complexes of the invention inhibit the naturally occurring interaction between a target protein and a ligand, e.g., a protein or small molecule that specifically binds to the target protein.

[0207] In certain embodiments, when the presenter protein is a proline isomerase, proline isomerase activity is inhibited by the formation of a presenter protein / compound complex. In some embodiments of the presenter protein / compound complexes of the present invention, the compound has 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). Dor specifically binds to the presenter protein at 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), or inhibits the peptidyl prolyl isomerase activity of the presenter protein at an IC 50 and inhibits.

[0208] Compound / target protein complex The compounds of the present disclosure can be useful in forming complexes with target proteins. The complexes can be formed through non-covalent interactions (e.g., van der Waals interactions or pi interactions). Alternatively, or in addition, such complexes can be formed by "cross-linking" the target through the formation of a covalent bond between the compound and the target protein. The compounds described herein can contain an electrophilic aziridine group capable of reacting with nucleophilic residues of target proteins (e.g., aspartic acid, glutamic acid, cysteine, glutamine, asparagine, lysine, or histidine residues).

[0209] Inclusion of an electron-donating group at the beta position of the carbonyl substituent that stabilizes the carbocation can be useful in facilitating cross-linking with target proteins. For example, a cyclopropyl substituent can be useful in enabling the aziridine to react with nucleophilic residues (e.g., aspartic acid residues). Without being bound by theory, we hypothesize that in situ protonation of the weakly basic aziridine nitrogen enhances the reactivity of the aziridine ring. The nascent carbocation (δ) at the beta carbon of the aziridine can be used to catalyze cross-linking with target proteins. + ) p orbital to the pseudoaromatic cyclopropyl (σ C-C Stabilization by the (linking) moiety makes it more amenable to reaction with the less reactive, highly solvated aspartate anion. [ka]

[0210] In addition to beta-cyclopropyl groups, additional moieties, including but not limited to aryl, vinyl, ynyl, and cubyl groups, may be beneficial in stabilizing carbocations either by hyperconjugation or resonance.

[0211] In some embodiments, the compound / target protein complex of the disclosure has the structure of Formula III: [ka] where A 1 is a monovalent organic moiety; Q is [ka] and; P 1 is A 2 and P 2 is hydrogen; or P 1 is hydroxyl and P 2 is A 2 and; 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R1a )3; R 1 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ) and; or R and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C3-C6 heteroalkynyl ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-C 10 R and R form a cycloalkynyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. 4 are each independently selected from 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 each R is 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; Each R 1a , R 2a , R 2c , R 2d and R 2e are 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 C-C 10 aryl, or optionally substituted 5-10 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 10Cycloalkyl, 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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; where: Each hydrogen is independently, optionally, isotopically enriched with deuterium.

[0212] In some embodiments, R and R 4 At least one of is not hydrogen.

[0213] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-1: [ka] where A 3 is the remainder of the target protein.

[0214] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-2: [ka] where A 3 is the remainder of the target protein.

[0215] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-3: [ka] where A 3 is the remainder of the target protein.

[0216] In some embodiments, the compound / target protein complex has the structure of Formula IIIa-4: [ka] where A 3 is the remainder of the target protein.

[0217] In some embodiments, the compound / target protein complex has the structure of the compound / target protein complex of claim 16, wherein the compound / target protein complex has the structure of Formula IIIb-1: [ka] where A 3 is the remainder of the target protein.

[0218] In some embodiments, the compound / target protein complex has the structure of Formula IIIb-2: [ka] where A 3 is the remainder of the target protein.

[0219] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-1: [ka] where A 3 is the remainder of the target protein.

[0220] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-2: [ka] where A 3 is the remainder of the target protein.

[0221] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-3: [ka] where A 3 is the remainder of the target protein.

[0222] In some embodiments, the compound / target protein complex has the structure of Formula IIIc-4: [ka] where A 3 is the remainder of the target protein.

[0223] In some embodiments, the compound / target protein complex has the structure of formula IIId-1: [ka] where A 3 is the remainder of the target protein.

[0224] In some embodiments, the compound / target protein complex has the structure of Formula IIId-2: [ka] where A 3 is the remainder of the target protein.

[0225] In some embodiments, the compound / target protein complex has the structure of Formula IIIe-1: [ka] where A 3 is the remainder of the target protein.

[0226] In some embodiments, the compound / target protein complex has the structure of Formula IIIe-1: [ka] where A 3 is the remainder of the target protein.

[0227] In some embodiments, R is an optionally substituted C-C 10 Cycloalkyl, optionally substituted C-C 10 In some embodiments, R is an optionally substituted C-C alkyl group, an optionally substituted C-C alkynyl group, an optionally substituted C-C aryl group, an optionally substituted C-C alkenyl group, or an optionally substituted C-C alkynyl group. 10 In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is [ka] In some embodiments, R is [ka] In some embodiments, R is an optionally substituted C2-C6 alkenyl or an optionally substituted C2-C6 alkynyl. In some embodiments, R is [ka] In some embodiments, R is an electron donating group that stabilizes the carbocation.

[0228] Ternary complex The majority of small molecule drugs act by binding to functionally important sites on target proteins, thereby modulating (e.g., positively or negatively) the activity of those proteins. For example, cholesterol-lowering drugs, statins, bind to the enzyme active site of HMG-CoA reductase, thus preventing the enzyme from engaging its substrate. The fact that many such drug / target interaction pairs are known may lead one to believe that small molecule modulators could be discovered for most, if not all, proteins, given a reasonable amount of time, effort, and resources. This is far from the reality. Current estimates suggest that only about 10% of all human proteins are amenable to small molecule targeting. The other 90% are currently considered intractable or intractable for small molecule drug discovery. Such targets are commonly referred to as "undruggable." These undruggable targets include a large, largely untapped pool of medically important human proteins. Therefore, there is great interest in discovering new molecular modalities capable of modulating the function of such undruggable targets.

[0229] The present invention encompasses the recognition that the targeting ability of small molecules is typically limited because interactions between small molecules and targets are driven by adhesive forces whose strength is roughly proportional to the contact surface area. Due to their small size, the only way for small molecules to establish sufficient intermolecular surface area contact to effectively interact with a target protein is to be literally engulfed by the protein. Indeed, much of both experimental and computational data supports the view that only proteins with hydrophobic "cavities" on their surfaces have the ability to bind small molecules. In these examples, binding is enabled by engulfment. There are no examples of small molecules that bind with high affinity to proteins outside of the hydrophobic cavity.

[0230] Nature has evolved strategies that allow small molecules to interact with target proteins at sites other than the hydrophobic cavity. Examples of this strategy are the naturally occurring immunosuppressants 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 display protein. The complex surface of the small molecule and the display protein then engages the target. Thus, for example, a binary complex formed between cyclosporin A and cyclophilin A targets calcineurin with high affinity and specificity, yet cyclosporin A and cyclophilin A alone do not bind calcineurin with measurable affinity.

[0231] Many important therapeutic targets exert their functions through complex formation with other proteins. In many of these systems, the protein / protein interaction surface contains an inner core of hydrophobic side chains surrounded by a broad ring of polar residues. The hydrophobic residues contribute almost all of the energetically favorable contacts; therefore, this cluster has been called a "hot spot" for engagement in protein-protein interactions. Importantly, in the naturally occurring small molecule-small protein complexes described above, the small molecule provides a cluster of hydrophobic functionality similar to the hot spot, while the protein provides a ring of mostly polar residues. In other words, the displayed small molecule system mimics the surface structural patterns commonly adopted in natural protein / protein interaction systems.

[0232] The compounds (e.g., macrocyclic compounds) of the present invention have the ability to modulate biological processes, for example, by binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) to form the above-mentioned presenter protein / compound complex, which forms a ternary complex that binds to a target protein. The formation of these ternary complexes enables the modulation of proteins that do not have a traditional binding cavity and / or are considered undruggable. The presenter protein / compound complex can modulate biological processes through cooperative binding between the compound and the presenter protein. While both the compound and the presenter protein alone have low affinity for the target protein, the presenter protein / compound complex has high affinity for the target protein. Cooperative binding can be determined by measuring the buried surface area of ​​the target protein, including atoms from the compound and / or the presenter protein, and / or by measuring the free binding energy contributions of the compound and / or the presenter protein. Binding is considered cooperative when at least one atom from each of the compound and the presenter protein participates in binding to the target protein.

[0233] Binding of the presenter protein / compound complex to the target protein is achieved by the formation of a combined binding site that includes residues from both the presenter protein and the compound, allowing for increased affinity not possible with either the presenter 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 with 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 with the presenter 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 presenter 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.

[0234] In some embodiments, the presenter protein / compound complex binds at a smooth surface site on the target protein. In some embodiments, the compound (e.g., a macrocyclic compound) in the presenter protein / compound complex binds at a hydrophobic surface site on the target protein, e.g., 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 and / or π-effect interactions. In certain embodiments, the presenter protein / compound complex binds to the target protein at a site of a protein-protein interaction that naturally occurs between the target protein and a protein that specifically binds to the target protein. In some embodiments, the presenter protein / compound complex does not bind at the active site of the target protein. In some embodiments, the presenter protein / compound complex binds at the active site of the target protein.

[0235] A characteristic of compounds of the present invention that form ternary complexes with a presenter protein and a target protein is that the presenter protein / compound complex does not undergo significant structural rearrangements compared to the ternary complex. This lack of significant structural rearrangements reduces the entropic cost of reorganizing the presenter protein / compound complex into a configuration favorable for ternary complex formation immediately after its formation. For example, a threshold quantification of RMSD can be measured using the align command in PyMOL version 1.7rc1 (Schrödinger Inc.). Alternatively, RMSD can be calculated using the ExecutiveRMS parameter from the LigAlign algorithm (J. Mol. Graphics and Modeling 2010, 29, 93-101). In some embodiments, the structural organization of the compound (i.e., the average three-dimensional configuration of the atoms and bonds of the molecule) in the ternary complex is substantially unchanged compared to the compound in the presenter protein / compound complex before binding to the target protein. For example, the root mean square deviation (RMSD) of the two aligned structures is less than 1.

[0236] Pharmaceutical Compositions and Methods of Use 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, and methods of using a compound of the present invention to prepare such compositions.

[0237] 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.

[0238] In some embodiments, the compound is present in the pharmaceutical composition in a unit dose in an amount suitable for administration in a treatment regimen that, when administered to a relevant population, exhibits a statistically significant probability of producing a predetermined therapeutic effect. In some embodiments, the pharmaceutical composition can be specially formulated for administration in solid or liquid form, including forms suitable for oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets, such as those intended for buccal, sublingual, and systemic absorption, pills, powders, granules, and pastes for application to the tongue; parenteral administration, such as parenteral administration by subcutaneous, intramuscular, intravenous, or epidural injection, for example, as a sterile solution or suspension or sustained-release formulation; topical application, such as a cream, plaster, or sustained-release patch or spray applied to the skin, lung, or oral cavity; vaginal or rectal administration, for example, as a suppository, cream, or foam; intraocular administration; transdermal administration; or administration to the nose, lung, and other mucosal surfaces.

[0239] " Pharmaceutically acceptable excipient " as used herein refers to any inactive ingredient (e.g., a vehicle capable of suspending or dissolving active compounds) that has the properties of being non-toxic and non-inflammatory in subjects. Typical excipients include, for example, anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, pigments (coloring agents), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavorings, fragrances, glidants (flow improvers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or hydration water. Excipients include, but are not limited to, butylated and optionally substituted hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, 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 the variety of agents and materials that are useful 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.

[0240] The compounds described herein may be provided or utilized in salt form, e.g., pharmaceutically acceptable salt form, whether or not explicitly stated, unless expressly stated otherwise. As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound described herein that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977, and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein by reacting the free base group with a suitable organic acid.

[0241] The compounds of the present invention may have ionizable groups, allowing them to be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts, including inorganic or organic acids, or salts may be prepared from inorganic or organic bases when the compounds of the present invention are in their acidic form. In some embodiments, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, including, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid to form acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like to form base salts. Methods for preparing suitable salts are well established in the art.

[0242] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-optionally substituted hydroxyl-ethanesulfonate, and the like. Included are sulfonate, 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, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0243] As used herein, the term "subject" refers to any member of the animal kingdom. In some embodiments, "subject" refers to a human at any stage of development. In some embodiments, "subject" refers to a human patient. In some embodiments, "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, cow, primate, or pig). In some embodiments, the subject includes, but is not limited to, a mammal, a bird, a reptile, an amphibian, a fish, or a worm. In some embodiments, the subject may be a transgenic animal, a genetically engineered animal, or a clone.

[0244] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (e.g., a compound of the invention) for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, such amount is a unit dosage (or a whole fraction thereof) suitable for administration according to a dosing regimen (i.e., using a therapeutic dosing regimen) that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population. Those skilled in the art will appreciate that the total amount of a therapeutic composition or compound to be administered to a particular subject is determined by one or more attending physicians and may include the administration of multiple dosage forms. As used herein, the term "dosage regimen" refers to a set of unit doses (typically more than one) administered individually to a subject, typically separated by a period of time. In some embodiments, a given therapeutic compound (e.g., a compound of the invention) has a recommended dosing regimen that may include one or more doses. In some embodiments, the dosing regimen includes multiple doses, each separated from the other by a period of equal length; in some embodiments, the dosing regimen includes multiple doses and at least two distinct periods separating the individual doses. In some embodiments, all doses within the dosing regimen have the same unit dose amount. In some embodiments, different doses within the dosing regimen have different amounts. In some embodiments, the dosing regimen includes a first dose having an amount equal to the first dose, followed by one or more additional doses having an amount equal to the amount of the first dose. In some embodiments, the dosing regimen includes a first dose having an amount equal to the first dose, followed by one or more additional doses having an amount equal to the amount of the first dose. In some embodiments, the dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0245] A "therapeutic regimen" refers to a dosing regimen whose administration correlates with a desired or beneficial therapeutic outcome across a relevant population.

[0246] The term "treatment" (also "treat" or "treating"), in its broadest sense, refers to any administration of a substance (e.g., a compound of the invention) that partially or completely alleviates, improves, relieves, suppresses, delays the onset of, reduces the severity of, or reduces the incidence of one or more symptoms, characteristics, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment may be administered to a subject who does not exhibit symptoms of the relevant disease, disorder, or condition, or who exhibits only early symptoms of the disease, disorder, or condition. Alternatively, or in addition, in some embodiments, treatment may be administered to a subject who exhibits one or more established symptoms 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 correlated with an increased risk of developing the relevant disease, disorder, or condition.

[0247] The term "therapeutically effective amount" refers to an amount that, when administered to a population suffering from or susceptible to a disease, disorder, or condition according to a therapeutic dosing regimen, is sufficient to treat the disease, disorder, or condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence or severity of, or delays the onset of, one or more symptoms of, a disease, disorder, or condition. Those skilled in the art will appreciate that the term "therapeutically effective amount" does not require that successful treatment actually occur in a particular individual. Rather, a therapeutically effective amount may be an amount that, when administered to subjects in need of such treatment, results in a specific desired pharmacological response in a significant number of subjects. Specifically, it is understood that certain subjects may actually be "refractory" to a "therapeutically effective amount." In some embodiments, reference to a therapeutically effective amount may be a reference to the amount measured in one or more specific tissues (e.g., tissues affected by a disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will appreciate that in some embodiments, a therapeutically effective amount may be formulated or administered as a single dose, while in some embodiments, a therapeutically effective amount may be formulated or administered as multiple doses, for example, as part of a dosing regimen.

[0248] When used to treat a subject, the compounds of the present invention or their pharmaceutically acceptable salts can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy, the compounds or their pharmaceutically acceptable salts are formulated to meet these parameters. An overview of such techniques is provided in Remington: The Science and Practice of Pharmacy, 21 stEdition, Lippincott Williams & Wilkins, (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0249] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions of the present invention can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% by weight or volume of a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds described herein or a pharmaceutically acceptable salt thereof can be present in an amount of 1 to 95% by weight, in total, of the total weight of the composition, such as a pharmaceutical composition.

[0250] The compositions may be provided in a dosage form suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesical, intraurethral, ​​spinal intrathecal, epidural, auricular, or intraocular administration, or for injection, inhalation, or direct contact with nasal, urogenital, genital, or oral mucosa. Thus, pharmaceutical compositions may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels, including hydrogels, pastes, plasters, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice.

[0251] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound described herein or a preparation comprising a compound) to a subject or body. Administration to an animal subject (e.g., a human) can be by any suitable route. For example, in some embodiments, administration can be intrabronchial (including administration by bronchial instillation), buccal, enteral, transdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, spinal intrathecal, intravenous, intraventricular, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, transtracheal (including administration by intratracheal instillation), transdermal, intravaginal, or intravitreal.

[0252] The formulation may be prepared in a manner suitable for systemic administration or local or topical administration. Systemic formulations include formulations designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection), or may be prepared for transdermal, transmucosal, or oral administration. The formulation will generally include a diluent, and optionally, adjuvants, buffers, preservatives, etc. The compound or its pharmaceutically acceptable salt may also be administered in a liposomal composition or as a microemulsion.

[0253] For injection, the preparations can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving or suspending in liquid prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol, etc. Such compositions may also contain amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like, for example, sodium acetate, sorbitan monolaurate, and the like.

[0254] Various sustained release systems for drugs have also been devised, see, for example, U.S. Patent No. 5,624,677.

[0255] Systemic administration can also include the use of relatively non-invasive methods, such as suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or their pharmaceutically acceptable salts. Suitable forms include syrups, capsules, and tablets, as understood in the art.

[0256] Each compound described herein or its pharmaceutically acceptable salt can be formulated in various ways known in the art. For example, the first and second agents of the combination therapy can be formulated together or separately. Other embodiments of the combination therapy are described herein.

[0257] Individually or separately formulated drugs can be packaged together as a kit. Non-limiting examples include, but are not limited to, a kit containing two pills, one pill and one powder, one suppository and one vial of liquid, two topical creams, etc. The kit can include optional components useful for administering unit doses to a subject, such as vials for reconstituting powder forms, syringes for injection, custom intravenous delivery systems, inhalers, etc. In addition, unit dose kits can include instructions for preparing and administering the compositions. The kit can be manufactured as a single-use unit dose for a single subject, multiple uses for a particular subject (where the dose is constant or the potency of the individual compounds or their pharmaceutically acceptable salts changes over the course of therapy); or the kit can contain multiple doses suitable for administration to multiple subjects ("bulk packaging"). The kit components can be assembled into a cardboard box, blister pack, bottle, tube, etc.

[0258] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxylpropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and anti-adherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0259] The two or more compounds may be commingled in a tablet, capsule, or other vehicle, or may be compartmentalized. In one example, a first compound is contained within the interior of a tablet and a second compound is present on the exterior, such that a substantial portion of the second compound is released before the first compound is released.

[0260] Formulations for oral use may also be provided as chewable tablets, or as 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 as 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 the above-mentioned ingredients under the conditions of tablets and capsules, for example, using a mixer, fluidized bed apparatus, or spray-drying apparatus.

[0261] Dissolution- or diffusion-controlled release can be achieved by coating a tablet, capsule, pellet, or granule formulation of the compound appropriately, 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 described above, or shellac, beeswax, glycowax, hydrogenated castor oil, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxyl methacrylate, 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, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0262] Liquid forms for oral administration into which the compounds of the present invention or pharmaceutically acceptable salts thereof and compositions can be incorporated include solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, and elixirs and similar pharmaceutical vehicles.

[0263] Generally, when administered to humans, the oral dosage of either the compound of the present invention or a pharmaceutically acceptable salt thereof will depend on the properties of the compound and can be readily determined by one of ordinary skill in the art. Dosages can be, for example, about 0.001 mg to about 2000 mg / day, about 1 mg to about 1000 mg / day, about 5 mg to about 500 mg / day, about 100 mg to about 1500 mg / day, about 500 mg to about 1500 mg / day, about 500 mg to about 2000 mg / day, or any range therein. In some embodiments, the daily dose range for oral administration can be, for example, about 0.001 mg to about 2000 mg / kg of human body weight, in single or divided doses. However, in some instances, it may be necessary to use dosages exceeding these limits.

[0264] In some embodiments, the pharmaceutical composition may further comprise an additional compound with antiproliferative activity. Depending on the mode of administration, the compound or its pharmaceutically acceptable salt will be formulated into a suitable composition that allows easy delivery. Each compound or its pharmaceutically acceptable salt of the combination therapy can be formulated in various ways known in the art. For example, the first and second agents of the combination therapy can be formulated together or separately. Preferably, the first and second agents are formulated together for simultaneous or nearly simultaneous administration of the agents.

[0265] It will be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapy, i.e., the compounds and pharmaceutical compositions can be formulated with or administered simultaneously with, before, or after one or more other desired therapeutic agents or medical treatments. The precise combination of therapies (therapeutics or treatments) to employ in a combination regimen will take into account the compatibility of the desired therapeutic agents or treatments and the desired therapeutic effect to be achieved. It will also be recognized that the therapies employed may produce the desired effect for the same disorder, or they may produce different effects (e.g., counteract any adverse effects).

[0266] Each drug in the combination therapy described herein may be administered independently, 1 to 4 times daily for 1 day to 1 year, or even for the life of the subject. Regular long-term administration may be required.

[0267] How to use The compounds and conjugates of the present disclosure can be useful in a variety of methods. For example, the present disclosure provides methods for modulating a target protein by contacting the target protein with a compound or presenter protein / compound complex described herein. The method can include inhibiting the target protein by contacting the target protein with a compound or presenter protein / compound complex described herein, or activating the target protein by contacting the target protein with a compound or presenter protein / compound complex described herein. Modulation (e.g., inhibition or activation) can make the compounds and / or conjugates useful for treating various diseases or disorders. Thus, the compounds and conjugates can be used in methods for treating a disease or disorder in a subject in need thereof by administering a therapeutically effective amount of a compound described herein to the subject. In some embodiments, the subject has previously been treated with a prior therapy. In some embodiments, the subject has developed resistance to treatment with the prior therapy.

[0268] The present disclosure also relates to the synthesis of the various complexes disclosed. For example, the present disclosure provides methods for forming the ternary complexes described herein by contacting a target protein with a presenter protein / compound complex described herein.

[0269] In some embodiments of the above method, upon contacting the target protein, the target protein forms a covalent bond with the compound or the presenter protein / compound complex. In some embodiments, upon contacting 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 the complex. In some embodiments, upon contacting 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 the complex.

[0270] In one embodiment, the present disclosure provides a method of crosslinking 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.

[0271] The disclosure further provides methods of forming a presenter protein / compound complex described herein by contacting the presenter protein with a compound described herein under conditions sufficient to allow the formation of the complex. In some embodiments, the complex is formed by non-covalent interactions.

[0272] In another embodiment, the present disclosure provides a method of forming a ternary complex as described herein, comprising the steps of: a) contacting a presenter protein with a compound described herein under conditions sufficient to allow the formation of a presenter protein / compound complex; and b) contacting the presenter protein / compound complex with the target protein under conditions that allow for the formation of a ternary complex; The method includes:

[0273] In some embodiments, the presenter protein / compound complex binds to the target protein with at least 5-fold greater affinity than the presenter protein or compound alone, hi some embodiments, the presenter protein or compound does not substantially bind to the target protein in the absence of the formation of the presenter protein / compound complex.

[0274] The compounds of the present invention can be used in methodologies involving click chemistry. Those skilled in the art will be familiar with how to adapt the compounds disclosed herein 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 can also be adapted for use in antibody-drug conjugates and degrader applications. It is also contemplated that the aziridine moieties described herein can be incorporated into known modulators (e.g., RAS inhibitors). Exemplary scaffolds that are amenable to such modifications include known RAS scaffolds, as well as compounds disclosed in the art, e.g., WO2022152233, WO2022148422, WO2022148421, WO2022135346, WO2022133731, WO2022133038, WO2022133345, WO2022132200, WO2022152233, WO2022152233, WO2022148422, WO2022148421, WO2022135346, WO2022133731, WO2022133038, WO2022133345, WO202213220 ... O2022119748, WO2022109487, WO2022109485, WO2022105859, WO2022105857, WO2022098625, WO202 2098625, WO2022093856, WO2022087335, WO2022083569, WO2022078470, WO2022078414, WO2022072 783, WO2022066805, WO2022066646, WO2022048545, WO2022047093, WO2022042630, WO2022031678 , WO2022028492, WO2022015375, WO2022002102, WO2021190467, WO2021185233, WO2021180181, WO2 021175199, 2021173923, WO2021169990, WO2021169963, WO2021168193, WO2021158071, WO2021155 716, WO2021152149, WO2021150613, WO2021147967, WO2021147965, WO2021143693, WO2021142252,WO2021141628, WO2021139748, WO2021139678, WO2021129824, WO2021129820, WO2021127404, WO2021126816, WO2021126799, WO202112 4222, WO2021121371, WO2021121367, WO2021121330, WO2021108643, WO2020050890, WO2020047192, WO2020035031, WO2020028706, WO20 19241157, WO2019232419, WO2019217691, WO2019217307, WO2019215203, WO2019213526, WO2019213516, WO2019155399, WO2019150305, WO2019110751, WO2019099524, WO2019051291, WO2018218070, WO2018217651, WO2018218071, WO2018218069, WO2018206539, WO2018143 315, WO2018140600, WO2018140599, WO2018140598, WO2018140514, WO2018140513, WO2018140512, WO2018119183, WO2018112420, WO20 18068017, WO2018064510, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO2017058807, WO2017058805, WO2017058728, Examples include those disclosed in WO2017058902, WO2017058792, WO2017058768, WO2017058915, WO2017015562, WO2016168540, WO2016164675, WO2016049568, WO2016049524, WO2015054572, WO2014152588, WO2014143659, WO2013155223, and PCT / US2022 / 027773, each of which is incorporated by reference in its entirety.

[0275] The compounds of the present invention can be used to treat subjects, e.g., mammals (e.g., mice, rats, dogs, and humans), having a disease or disorder. The disease or disorder can be, for example, cancer, diabetes, cardiovascular disease, neurological disorder, viral disease, infectious disease, autoimmune disease, arthritis, allergic disorder, inflammation, hormone-related disease, conditions associated with organ transplantation (e.g., transplant rejection), immunodeficiency disorder, bone disorder, or proliferative disorder.

[0276] kit The invention also features kits that include (a) a pharmaceutical composition that includes an agent described herein (e.g., a compound or conjugate of the invention), and (b) a package insert with instructions for practicing any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition that includes an agent described herein (e.g., a compound or conjugate 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 practicing any of the methods described herein.

[0277] Because one aspect of the present invention contemplates treating a disease or its associated symptoms 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 include two separate pharmaceutical compositions: a compound of the present invention and one or more additional therapies. The kit may include containers for housing the separate compositions, such as divided bottles or divided foil packets. Further examples of containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions for using the separate components. The kit form is particularly advantageous when it is preferable to administer the separate components in different (e.g., oral and parenteral) dosage forms and at different dosage intervals, or when dosage adjustments of the individual components of the combination are desired by the prescribing healthcare professional.

[0278] Enumeration of Embodiments Some specific embodiments are listed below: The listed following embodiments should not be construed as limiting the scope of the present disclosure, but are presented as some examples of the utility of the present disclosure.

[0279] 1. A compound having the structure of Formula I: [ka] [Here, M + is a cation; Z is [ka] and; 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 1is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 and R 4are each independently hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ) and; or R and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C3-C6 heteroalkynyl ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-C 10 R and R form a cycloalkynyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. 4 are each independently selected from 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 each R is 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; where: R and R 4 at least one of which 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-C6 10 Cycloalkyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; Each R 1a , R 2a , R 2c , R 2d and R 2eare 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 C-C 10 aryl, or optionally substituted 5-10 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; where: Each hydrogen is independently, optionally, isotopically enriched with deuterium. or a pharmaceutically acceptable salt thereof.

[0280] 2. The compound has the structure of Formula Ia: [ka] or a pharmaceutically acceptable salt thereof.

[0281] 3. The compound has the structure of Formula Ib: [ka] or a pharmaceutically acceptable salt thereof.

[0282] 4. The compound has the structure of Formula Ic: [ka] or a pharmaceutically acceptable salt thereof.

[0283] 5. The compound has the structure of formula Id: [ka] or a pharmaceutically acceptable salt thereof.

[0284] 6. R 3 optionally substituted C1-C6 alkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C6-C 10 6. The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R is aryl, or optionally substituted 5-10 membered heteroaryl.

[0285] 7. R 3The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein is optionally substituted C1-C6 alkyl.

[0286] 8. R 3 The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein is methyl, ethyl, or benzyl.

[0287] 9. M + Li + or a pharmaceutically acceptable salt thereof.

[0288] 10. R 3 but, [ka] or a pharmaceutically acceptable salt thereof.

[0289] 11. Z, [ka] or a pharmaceutically acceptable salt thereof.

[0290] 12. A compound having the structure of Formula II: [ka] [Here, A 1 is a monovalent organic moiety; Q is [ka] and; 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 1 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ) and; or R and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 1is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 4 and optionally substituted C3-C 10Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C3-C6 heteroalkynyl ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-C 10 R and R form a cycloalkynyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. 4 are each independently selected from 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C10 Cycloalkenyl, optionally substituted C-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 each R is 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; where: R and R 4 at least one of which is not hydrogen; Each R 1a , R 2a , R 2c , R 2d and R 2e are 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; 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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; where: Each hydrogen is independently, optionally, isotopically enriched with deuterium. or a pharmaceutically acceptable salt thereof.

[0291] 13. The compound has the structure of Formula IIa: [ka] or a pharmaceutically acceptable salt thereof.

[0292] 14. The compound has the structure of Formula IIb: [ka] or a pharmaceutically acceptable salt thereof.

[0293] 15. The compound has the structure of Formula IIc: [ka] or a pharmaceutically acceptable salt thereof.

[0294] 16. The compound has the structure of formula IId: [ka] or a pharmaceutically acceptable salt thereof.

[0295] 17. Q is, [ka] or a pharmaceutically acceptable salt thereof.

[0296] 18. 1. A compound / target protein conjugate having the structure of Formula IIIa or Formula IIIb: [ka] [Here, A 1 is a monovalent organic moiety; Q is [ka] and; P 1 is A 2 and P 2 is hydrogen; or P 1 is hydroxyl and P 2 is A 2 and; 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 1 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5-10 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 1 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a ) and; or R and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 is hydrogen, halo, 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-C6 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C1-C6 heteroalkenyl, optionally substituted C1-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkynyl, optionally substituted C3-C6 heteroalkyl, optionally substituted C3-C6 heteroalkynyl ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3;R 2 is hydrogen, optionally substituted C-C alkyl, optionally substituted C-C acyl, -C(O)R 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl or optionally substituted 5-10 membered heteroaryl; or R 1 and R 2 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-C 10 R and R form an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. 4 are each independently selected from 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-C6 10Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; or R 2 and R 4 and optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 each R is 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-C6 heteroalkyl, optionally substituted C3 ... 10 Cycloalkyl, optionally substituted C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, optionally substituted 5- to 10-membered heteroaryl, or -Si(R 1a )3; where: R and R 4 at least one of which is not hydrogen; Each R 1a , R 2a , R 2c , R 2d and R 2e are 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 C-C 10 aryl, or optionally substituted 5-10 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 C-C 10 aryl, or optionally substituted 5-10 membered heteroaryl; 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 C-C 10 Cycloalkenyl, optionally substituted C-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 C-C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; where: Each hydrogen is independently, optionally, isotopically enriched with deuterium. or a pharmaceutically acceptable salt thereof.

[0297] 19. The compound / target protein complex has the structure of formula IIIa-1: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0298] 20. The compound / target protein complex has the structure of Formula IIIa-2: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0299] 21. The compound / target protein complex has the structure of formula IIIa-3: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0300] 22. The compound / target protein complex has the structure of formula IIIa-4: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0301] 23. The compound / target protein complex has the structure of formula IIIb-1: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0302] 24. The compound / target protein complex has the structure of formula IIIb-2: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0303] 25. The compound / target protein complex has the structure of formula IIIc-1: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0304] 26. The compound / target protein complex has the structure of formula IIIc-2: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0305] 27. The compound / target protein complex has the structure of formula IIIc-3: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0306] 28. The compound / target protein complex has the structure of formula IIIc-4: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0307] 29. The compound / target protein complex has the structure of formula IIId-1: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0308] 30. The compound / target protein complex has the structure of formula IIId-2: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0309] 31. The compound / target protein complex has the structure of formula IIIe-1: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0310] 32. The compound / target protein complex has the structure of formula IIIe-2: [ka] [Here, A 3 is the remainder of the target protein] 20. The compound / target protein complex of embodiment 18, having:

[0311] 33. R is an optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 A compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or a compound / target protein complex according to any one of embodiments 18 to 33, wherein the compound is aryl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl.

[0312] 34. R is an optionally substituted C3-C 10 34. The compound or compound / target protein complex of embodiment 33, or a pharmaceutically acceptable salt thereof, wherein:

[0313] 35. The compound or compound / target protein conjugate of embodiment 34, or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted cyclopropyl.

[0314] 36. R, [ka] 36. The compound or compound / target protein complex of embodiment 35, wherein:

[0315] 37. R, [ka] 37. The compound or compound / target protein complex of embodiment 36, wherein:

[0316] 38. The compound or compound / target protein complex of embodiment 33, or a pharmaceutically acceptable salt thereof, wherein R is an optionally substituted C2-C6 alkenyl or an optionally substituted C2-C6 alkynyl.

[0317] 39. R, [ka] 39. The compound or compound / target protein complex of embodiment 38, wherein:

[0318] 40. The compound of any one of embodiments 1-17 or a pharmaceutically acceptable salt thereof, or the compound / target protein complex of any one of embodiments 18-33, wherein R is an electron donating group that stabilizes the carbocation.

[0319] 41. R 1 41. The compound or compound / target protein complex of any one of embodiments 1 to 40, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0320] 42. R 2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 42. The compound or compound / target protein complex of any one of embodiments 1 to 41, wherein R is cycloalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

[0321] 43. R 2 optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 cycloalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

[0322] 44. R 2 is optionally substituted C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0323] 45. R 2 optionally substituted C3-C 10 44. The compound or compound / target protein complex of embodiment 43, or a pharmaceutically acceptable salt thereof, wherein:

[0324] 46. ​​R 2 is an optionally substituted 3- to 10-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

[0325] 47. R 2 but, [ka] 42. The compound or compound / target protein complex of any one of embodiments 1 to 41, wherein:

[0326] 48. R 2 but, [ka] 48. The compound or compound / target protein complex of embodiment 47, wherein:

[0327] 49. R 2 is methyl, or a pharmaceutically acceptable salt thereof.

[0328] 50. R 4 50. The compound or compound / target protein complex of any one of embodiments 1-49, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0329] 51. A 1 51. The compound or compound / target protein complex of any one of embodiments 12 to 50, or a pharmaceutically acceptable salt thereof, wherein is a protein.

[0330] 52. A 1 51. The compound or compound / target protein complex of any one of embodiments 12 to 50, or a pharmaceutically acceptable salt thereof, wherein is a nucleic acid.

[0331] 53. A 1 51. The compound or compound / target protein complex of any one of embodiments 12 to 50, or a pharmaceutically acceptable salt thereof, wherein

[0332] 54. A 1 51. The compound or compound / target protein complex of any one of embodiments 12-50,...

Claims

1. Structure of Formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, M ＋ is a cation; Z is 【Chemistry 2】 and R is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R １ is hydrogen, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; and R ４ is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and or R and R １ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; R ４ is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and or R and R ２ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 and R ４ are each independently hydrogen, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) and or R and R ４ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; or R １ and R ４ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -C １０ R is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; or R １ and R ２ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -C １０ R and R form an optionally substituted cycloalkynyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. ４ each independently represents hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and or R ２ and R ４ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 each R is independently hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and where: R and R ４ is not hydrogen; R ３ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; Each R １ａ , R ２ａ , R ２ｃ , R ２ｄ and R ２ｅ independently represents an optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; R ２ｂ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; R ５ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; where: each hydrogen independently, optionally isotopically enriched with deuterium; The compound, or a pharmaceutically acceptable salt thereof.

2. R ３ is optionally substituted C １ -C ６ alkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C ６ -C １０ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is aryl or an optionally substituted 5-10 membered heteroaryl.

3. R ３ is optionally substituted C １ -C ６ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

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

5. M ＋ Li ＋ 5. The compound according to any one of claims 1 to 4, wherein:

6. R ３ but, 【Transformation 3】 6. The compound according to any one of claims 1 to 5, wherein:

7. Z is, 【Chemistry 4】 7. The compound according to any one of claims 1 to 6, wherein:

8. Structure of Formula II: 【Transformation 5】 or a pharmaceutically acceptable salt thereof, A １ is a monovalent organic moiety; Q is, 【Transformation 6】 and R is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R １ is hydrogen, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; and R ４ is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and or R and R １ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; R ４ is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and or R and R ２ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) and or R and R ４ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 is hydrogen, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; or R １ and R ４ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -C １０ R is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; or R １ and R ２ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -C １０ R and R form an optionally substituted cycloalkynyl, an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. ４ each independently represents hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and or R ２ and R ４ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 each R is independently hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and where: R and R ４ is not hydrogen; Each R １ａ , R ２ａ , R ２ｃ , R ２ｄ and R ２ｅ independently represents an optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; R ２ｂ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; R ５ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; where: each hydrogen independently, optionally isotopically enriched with deuterium; The compound, or a pharmaceutically acceptable salt thereof.

9. Q is, 【Transformation 7】 9. The compound of claim 8, wherein:

10. Structure of Formula IIIa or Formula IIIb: 【Transformation 8】 or a pharmaceutically acceptable salt thereof, A １ is a monovalent organic moiety; Q is, 【Chemistry 9】 and P １ is A ２ and P ２ is hydrogen; or P １ is hydroxyl, and P ２ is A ２ and A ２ is the target protein; R is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R １ is hydrogen, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; and R ４ is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and or R and R １ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5- to 10-membered heteroaryl; R ４ is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and or R and R ２ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) and or R and R ４ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 is hydrogen, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; or R １ and R ４ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -C １０ R is hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Acyl, —C(O) ２ R ２ａ , -C(O)N(R ２ｂ ) ２ , -S(O) ２ R ２ｃ , -S(O) ２ N (R ２ｄ ) ２ , -S(O) ２ OR ２ｅ , optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; or R １ and R ２ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -C １０ R and R form an optionally substituted 3- to 10-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heterocycloalkenyl, or an optionally substituted 8- to 10-membered heterocycloalkynyl. ４ each independently represents hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and or R ２ and R ４ and optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 each R is independently hydrogen, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C １ -C ６ Heteroalkenyl, optionally substituted C １ -C ６ Heteroalkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl, or —Si(R １ａ ) ３ and where: R and R ４ is not hydrogen; Each R １ａ , R ２ａ , R ２ｃ , R ２ｄ and R ２ｅ independently represents an optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; R ２ｂ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; R ５ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Cycloalkenyl, optionally substituted C ８ -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 C ６ -C １０ aryl, or optionally substituted 5-10 membered heteroaryl; where: each hydrogen independently, optionally isotopically enriched with deuterium; A compound / target protein complex, or a pharmaceutically acceptable salt thereof.

11. R is optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ６ -C １０ Aryl, optionally substituted C ２ -C ６ alkenyl, or optionally substituted C ２ -C ６ The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or the compound / target protein complex according to claim 10, which is alkynyl.

12. R is optionally substituted C ３ -C １０ 12. The compound or compound / target protein complex of claim 11, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

13. 13. The compound or compound / target protein complex of claim 12, or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted cyclopropyl.

14. R is optionally substituted C ２ -C ６ alkenyl, or optionally substituted C ２ -C ６ 12. The compound or compound / target protein complex of claim 11, or a pharmaceutically acceptable salt thereof, which is alkynyl.

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

16. R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ 16. The compound or compound / target protein complex according to any one of claims 1 to 15, which is cycloalkyl, or an optionally substituted 3- to 10-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

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

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

19. 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 classical protein-protein interaction domains and motifs.

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

21. A method for regulating a target protein, the method comprising contacting the target protein with a compound described in any one of claims 8 to 18, or with the presentation body protein / compound complex of claim 20.

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

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

24. 19. A method of crosslinking a compound of any one of claims 8 to 18 to a second moiety, comprising contacting said moiety with said compound under conditions sufficient to form a covalent bond between said compound of any one of claims 8 to 18 and said second moiety.

25. A method for forming a presenter protein / compound complex according to claim 20, comprising contacting the presenter protein with a compound according to any one of claims 8 to 18 under conditions sufficient to allow the formation of the complex.

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

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

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