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COMPOUNDS, COMPLEXES, AND METHODS FOR THEIR PREPARATION AND OF THEIR USE

20250269037 ยท 2025-08-28

    Inventors

    Cpc classification

    International classification

    Abstract

    The invention features compounds containing an aziridine moiety and methods of synthesizing the same. The compounds may be bound to a monovalent organic moiety and may be used to bind to a target (e.g., a target protein), for example, by cross-linking 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 tri-complexes). Methods of forming the complexes and methods of using the compounds and complexes to modulate biological processes are also disclosed.

    Claims

    1. A compound having the structure of Formula I: ##STR00265## or a pharmaceutically acceptable salt thereof; wherein M.sup.+ is a cation; ##STR00266## R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; R.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or R and R.sup.1 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or R and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 and R.sup.4 are each, independently, hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a); or R and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or R.sup.1 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or R.sup.1 and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R and R.sup.4 is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or R.sup.2 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R.sup.1 and R is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; wherein at least one of R and R.sup.4 is not hydrogen; R.sup.3 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; each R.sup.1a, R.sup.2a, R.sup.2c, R.sup.2d, and R.sup.2e is, independently, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; R.sup.2b is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.5 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

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

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

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

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

    6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is: ##STR00267##

    7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Z is ##STR00268##

    8. A compound having the structure of Formula II: ##STR00269## or a pharmaceutically acceptable salt thereof, wherein A.sup.1 is a monovalent organic moiety; Q is ##STR00270## R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; R.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or R and R.sup.1 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or R and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 and R.sup.4 are each, independently, hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a); or R and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or R.sup.1 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or R.sup.1 and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R and R.sup.4 is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or R.sup.2 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R.sup.1 and R is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; wherein at least one of R and R.sup.4 is not hydrogen; each R.sup.1a, R.sup.2a, R.sup.2c, R.sup.2d, and R.sup.2e is, independently, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; R.sup.2b is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.5 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Q is ##STR00271##

    10. A compound/target protein complex, or a pharmaceutically acceptable salt thereof, wherein the compound/target protein complex has the structure of Formula IIIa or Formula IIIb: ##STR00272## wherein A.sup.1 is a monovalent organic moiety; Q is ##STR00273## P.sup.1 is A.sup.2, and P.sup.2 is hydrogen; or P.sup.1 is hydroxyl, and P.sup.2 is A.sup.2; A.sup.2 is the target protein; R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; R.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl or Si(R.sup.1a).sub.3; or R and R.sup.1 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or R and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 and R.sup.4 are each, independently, hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a); or R and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or R.sup.1 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or R.sup.1 and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and each of R and R.sup.4 is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl or Si(R.sup.1a).sub.3; or R.sup.2 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R.sup.1 and R is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; wherein at least one of R and R.sup.4 is not hydrogen; each R.sup.1a, R.sup.2a, R.sup.2c, R.sup.2d, and R.sup.2e is, independently, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; R.sup.2b is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.5 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

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

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

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

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

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

    16. The compound or compound/target protein complex of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl.

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

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

    19. The compound/target protein complex of any one of claims 10 to 18 wherein the target protein is a GTPase, GTPase activating protein, 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 a compound of any one of claims 8, 9, and 11 to 18, or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

    Description

    DETAILED DESCRIPTION

    Compounds

    [0254] The disclosure provides compounds capable of forming complexes and/or crosslinking to a target (e.g., a target protein). Also disclosed are synthetic intermediates used in the preparation of such compounds and complexes formed from reaction with the compounds.

    Synthetic Intermediates

    [0255] Compounds of the present disclosure may contain an aziridine moiety. The compounds of the invention may contain an aziridine and a group capable of reaction with a second moiety allowing for the aziridine to be incorporated into another moiety. The compound may be, for example, capable of reaction with a nucleophile (e.g., an ester). Accordingly, the compounds may have the structure of Formula I:

    ##STR00043##

    or a pharmaceutically acceptable salt thereof; wherein [0256] Z is

    ##STR00044## [0257] M.sup.+ is a cation; [0258] R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0259] R.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0260] R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0261] R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl or Si(R.sup.1a).sub.3; or [0262] R and R.sup.1 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0263] R and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 and R.sup.4 are each, independently, hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a); or [0264] R and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0265] R.sup.1 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0266] R.sup.1 and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R and R.sup.4 is, independently, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0267] R.sup.2 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R.sup.1 and R is, independently, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0268] R.sup.3 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; [0269] each R.sup.1, R.sup.23, R.sup.2c, R.sup.2d, and R.sup.2e is, independently, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; [0270] R.sup.2b is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0271] R.sup.5 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, [0272] and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0273] In some embodiments, at least one of R and R.sup.4 is not hydrogen.

    [0274] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, has the structure of Formula Ia:

    ##STR00045##

    [0275] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, has the structure of Formula Ib:

    ##STR00046##

    [0276] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, has the structure of Formula Ic:

    ##STR00047##

    [0277] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, has the structure of Formula Id:

    ##STR00048##

    [0278] In some embodiments, R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.3 is methyl, ethyl, or benzyl.

    [0279] In some embodiments, M.sup.+ is Li.sup.+.

    [0280] In some embodiments, R.sup.3 is:

    ##STR00049##

    [0281] In some embodiments, Z is

    ##STR00050##

    [0282] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt, or alternative pharmaceutically acceptable salt, thereof, or a stereoisomer thereof:

    TABLE-US-00001 TABLE 1 Ex # Structure 1 [00051]embedded image 2 [00052]embedded image 3 [00053]embedded image 4 [00054]embedded image 5 [00055]embedded image 6 [00056]embedded image 7 [00057]embedded image 8 [00058]embedded image 9 [00059]embedded image 10 [00060]embedded image 11 [00061]embedded image 12 [00062]embedded image 13 [00063]embedded image 14 [00064]embedded image 15 [00065]embedded image 16 [00066]embedded image 17 [00067]embedded image 18 [00068]embedded image 19 [00069]embedded image 20 [00070]embedded image 21 [00071]embedded image 22 [00072]embedded image 23 [00073]embedded image 24 [00074]embedded image 25 [00075]embedded image 26 [00076]embedded image 27 [00077]embedded image 28 [00078]embedded image 29 [00079]embedded image 30 [00080]embedded image

    Aziridine-Containing Compounds

    [0283] The disclosure also features compounds containing an aziridine moiety bound to a monovalent organic moiety. Persons of skill in the art are familiar with organic moieties. The monovalent organic moiety may be or may comprise, 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 degrader, a macrocycle, or a protein, such as a mutated protein. The organic moiety may be bound to an aziridine moiety as disclosed herein in a variety of ways, and persons of skill in the art are familiar with methodologies of installing an aziridine-containing synthetic intermediate described herein in a monovalent organic moiety. Non-limiting examples include the schemes below:

    ##STR00081##

    [0284] As shown in Scheme A, compounds of this type may be prepared by the reaction of an appropriate amine substituted monovalent organic moiety (1) with a carboxylate substituted aziridine (2) in the presence of standard amide coupling reagents to afford the final compound (3).

    ##STR00082##

    [0285] As shown in Scheme B, compounds of this type may be prepared by the reaction of an appropriate amine substituted monovalent organic moiety (1) with an aziridine containing an activated ester (2) in the presence of a basic amine to afford the final compound (3).

    [0286] In some embodiments, a compound containing an aziridine moiety bound to a monovalent organic moiety may have the structure of Formula II:

    ##STR00083##

    or a pharmaceutically acceptable salt thereof, [0287] wherein A.sup.1 is a monovalent organic moiety; [0288] Q is

    ##STR00084## [0289] R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0290] R.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0291] R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0292] R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl or Si(R.sup.1a).sub.3; [0293] or R and R.sup.1 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0294] R and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 and R.sup.4 are each, independently, hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a); or [0295] R and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0296] R.sup.1 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0297] R.sup.1 and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R and R.sup.4 is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0298] R.sup.2 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R.sup.1 and R is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0299] each R.sup.1a, R.sup.2a, R.sup.2c, R.sup.2d and R.sup.2e is, independently, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; [0300] R.sup.2b is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0301] R.sup.5 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, [0302] and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0303] In some embodiments, at least one of R and R.sup.4 is not hydrogen.

    [0304] In some embodiments, the compound of Formula II, or a pharmaceutically acceptable salt thereof, has the structure of Formula IIa:

    ##STR00085##

    [0305] In some embodiments, the compound of Formula II, or a pharmaceutically acceptable salt thereof, has the structure of Formula IIb:

    ##STR00086##

    [0306] In some embodiments, the compound of Formula II, or a pharmaceutically acceptable salt thereof, has the structure of Formula IIc:

    ##STR00087##

    [0307] In some embodiments, the compound of Formula II, or a pharmaceutically acceptable salt thereof, has the structure of Formula IId:

    ##STR00088##

    [0308] In some embodiments, Q is

    ##STR00089##

    [0309] In some embodiments, an organic moiety may be bound to an aziridine in alternative ways, such as to R, R.sup.1, R.sup.2 or R.sup.4.

    [0310] In some embodiments, A.sup.1 is or comprises a peptide. In some embodiments, A.sup.1 is or comprises a protein. In some embodiments, A.sup.1 is or comprises a nucleic acid. In some embodiments, A.sup.1 is a small molecule. In some embodiments, A.sup.1 is or comprises a macrocyclic small molecule.

    [0311] In some embodiments, one or more compounds of WO 2023/141300 may be excluded from any embodiment herein. In some embodiments, one or more compounds of WO 2022/271658 may be excluded from any embodiment herein. In some embodiments, one or more compounds of WO 2023/208005 may be excluded from any embodiment herein.

    [0312] In some embodiments, the compound is not a compound disclosed in WO 2021/091967. In some embodiments, the compound is not a compound of Table 2.

    TABLE-US-00002 TABLE 2 Ex# Structure C1 [00090]embedded image C2 [00091]embedded image C3 [00092]embedded image C4 [00093]embedded image C5 [00094]embedded image C6 [00095]embedded image C7 [00096]embedded image C8 [00097]embedded image C9 [00098]embedded image C10 [00099]embedded image C11 [00100]embedded image C12 [00101]embedded image C13 [00102]embedded image C14 [00103]embedded image C15 [00104]embedded image C16 [00105]embedded image C17 [00106]embedded image C18 [00107]embedded image C19 [00108]embedded image C20 [00109]embedded image C21 [00110]embedded image C22 [00111]embedded image C23 [00112]embedded image C24 [00113]embedded image C25 [00114]embedded image C26 [00115]embedded image C27 [00116]embedded image C28 [00117]embedded image C29 [00118]embedded image C30 [00119]embedded image C31 [00120]embedded image C32 [00121]embedded image C33 [00122]embedded image C34 [00123]embedded image C35 [00124]embedded image C36 [00125]embedded image C37 [00126]embedded image C38 [00127]embedded image C39 [00128]embedded image C40 [00129]embedded image C41 [00130]embedded image C42 [00131]embedded image C43 [00132]embedded image C44 [00133]embedded image C45 [00134]embedded image C46 [00135]embedded image C47 [00136]embedded image C48 [00137]embedded image C49 [00138]embedded image C50 [00139]embedded image C51 [00140]embedded image C52 [00141]embedded image C53 [00142]embedded image C54 [00143]embedded image C55 [00144]embedded image C56 [00145]embedded image C57 [00146]embedded image C58 [00147]embedded image C59 [00148]embedded image C60 [00149]embedded image C61 [00150]embedded image C62 [00151]embedded image C63 [00152]embedded image C64 [00153]embedded image C65 [00154]embedded image C66 [00155]embedded image C67 [00156]embedded image C68 [00157]embedded image C69 [00158]embedded image C70 [00159]embedded image C71 [00160]embedded image C72 [00161]embedded image C73 [00162]embedded image C74 [00163]embedded image C75 [00164]embedded image C76 [00165]embedded image C77 [00166]embedded image C78 [00167]embedded image C79 [00168]embedded image C80 [00169]embedded image C81 [00170]embedded image C82 [00171]embedded image C83 [00172]embedded image

    Presenter Protein Binding Moiety

    [0313] In some embodiments of the compounds described above, A.sup.1 is a presenter protein binding moiety. This moiety may include a group of ring atoms (e.g., 5 to 20 ring atoms, 5 to 10 ring atoms, 10 to 20 ring atoms) and the moieties attached thereto (e.g., atoms within 20 atoms of a ring atom such as, atoms within 15 atoms of a ring atom, atoms within 10 atoms of a ring atom, atoms within 5 atoms of a ring atom) that participate in binding to a presenter protein such that a provided compound specifically binds to said presenter protein, for example, with a K.sub.D of less than 10 M (e.g., less than 5 M, less than 1 M, 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) or inhibits the peptidyl-prolyl isomerase activity of the presenter protein, for example, with an IC.sub.50 of less than 1 M (e.g., less than 0.5 M, less than 0.1 M, less than 0.05 M, less than 0.01 M). In some embodiments, the presenter protein binding moiety does not encompass the entirety of atoms in a provided compound that interact with the presenter protein. In some embodiments, one or more atoms of the presenter protein binding moiety may be within the target protein interaction moiety (e.g., eukaryotic target protein interacting moiety such as a mammalian target protein interacting moiety or a fungal target protein interacting moiety or prokaryotic target protein interacting moiety such as 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.

    [0314] In some embodiments, a presenter protein binding moiety includes a N-acyl proline moiety, an N-acyl-pipecolic acid moiety, an N-acyl 3-morpholino-carboxylic acid moiety, and/or an N-acyl piperazic acid moiety (e.g., with acylation on either nitrogen atom. In certain embodiments, a presenter protein binding moiety includes an N-acyl-pipecolic acid moiety. In some embodiments, a presenter protein binding moiety includes an N-acyl proline moiety. In certain embodiments, a presenter protein binding moiety includes an N-acyl 3-morpholino-carboxylic acid moiety. In some embodiments, a presenter protein binding moiety includes a N-acyl piperazic acid moiety.

    [0315] In some embodiments, at least one atom of a presenter protein binding moiety participates in binding with one or more (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) 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 at of a presenter protein binding moiety participates in binding with at least one (e.g., two, three, or four) of Arg 41, Gln 54, Glu 55, and/or Ala 82 of FKBP12.

    [0316] In some embodiments, the presenter protein binding moiety has the structure of Formula IV:

    ##STR00173## [0317] wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; A is N(H or CH.sub.3)C(O)(CH.sub.2)where the amino nitrogen is bound to the carbon atom of CH(R.sup.10), optionally substituted C.sub.2-C.sub.4 alkylene, optionally substituted C.sub.1-C.sub.4 heteroalkylene, or optionally substituted C.sub.2-C.sub.4 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; [0318] X.sup.1 is optionally substituted C.sub.1-C.sub.2 alkylene, NR, O, or S(O).sub.n; [0319] X.sup.2 is O or NH; [0320] X.sup.3 is N or CH; [0321] n is 0, 1, or 2; [0322] R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.2-C.sub.4 alkenyl, optionally substituted C.sub.2-C.sub.4 alkynyl, C(O)R, C(O)OR, C(O)N(R).sub.2, S(O)R, S(O).sub.2R, or S(O).sub.2N(R).sub.2; each R is, independently, H or optionally substituted C.sub.1-C.sub.4 alkyl; [0323] Y.sup.1 is C, CH, or N; [0324] Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.7 are, independently, C or N; [0325] Y.sup.5 is CH, CH.sub.2 or N; [0326] Y.sup.6 is C(O), CH, CH.sub.2, or N; [0327] R.sup.1 is cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 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 [0328] R.sup.1 and R.sup.2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; [0329] R.sup.2 is absent, hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 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.sup.3 is absent, or [0330] R.sup.2 and R.sup.3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; [0331] R.sup.4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; [0332] R.sup.5 is hydrogen, C.sub.1-C.sub.4 alkyl optionally substituted with halogen, cyano, hydroxy, or C.sub.1-C.sub.4 alkoxy, cyclopropyl, or cyclobutyl; [0333] R.sup.6 is hydrogen or methyl; R.sup.7 is hydrogen, halogen, or optionally substituted C.sub.1-C.sub.3 alkyl, or R.sup.6 and R.sup.7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R.sup.8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C.sub.1-C.sub.3 alkoxyl, optionally substituted C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 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.sup.7 and R.sup.8 combine with the carbon atom to which they are attached to form CCR.sup.7R.sup.8; CN(OH), CN(OC.sub.1-C.sub.3 alkyl), CO, CS, CNH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; [0334] R.sup.7a and R.sup.8a are, independently, hydrogen, halo, optionally substituted C.sub.1-C.sub.3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; [0335] R.sup.7 is hydrogen, halogen, or optionally substituted C.sub.1-C.sub.3 alkyl; R.sup.8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C.sub.1-C.sub.3 alkoxyl, optionally substituted C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 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.sup.7 and R.sup.8 combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; [0336] R.sup.9 is hydrogen, F, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or [0337] R.sup.9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R.sup.9 is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl; [0338] R.sup.10 is hydrogen, halo, hydroxy, C.sub.1-C.sub.3 alkoxy, or C.sub.1-C.sub.3 alkyl; R.sup.10a is hydrogen or halo; [0339] R.sup.11 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0340] R.sup.34 is hydrogen or C.sub.1-C.sub.3 alkyl. Each hydrogen of a compound of Formula IV is optionally isotopically enriched in deuterium.

    [0341] In some embodiments, the presenter protein binding moiety has the structure of Formula V:

    ##STR00174## [0342] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; [0343] X.sup.1 is CH.sub.2 or O; [0344] m is 1 or 2; [0345] n is 0 or 1; [0346] R.sup.1 is hydrogen or optionally substituted 3- to 10-membered heterocycloalkyl; [0347] R.sup.2 is optionally substituted C.sub.1-C.sub.6 alkyl; and [0348] R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl or optionally substituted 3- to 6-membered cycloalkyl.

    [0349] In some embodiments, the presenter protein binding moiety has the structure of Formula VI:

    ##STR00175## [0350] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; [0351] X.sup.1, X.sup.2, and X.sup.3 are each independently selected from CH.sub.2, CHF, CF.sub.2, CO, or O; [0352] m is 1 or 2; [0353] n is 0 or 1; [0354] R.sup.1 is hydrogen, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; [0355] R.sup.2 is optionally substituted C.sub.1-C.sub.6 alkyl; and [0356] R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, [0357] and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0358] In some embodiments, the presenter protein binding moiety has the structure of any one of Formula VII, VIII, and IX:

    ##STR00176## [0359] wherein o, and p are independently 0, 1, or 2; [0360] q is an integer between 0 and 7; [0361] r is an integer between 0 and 4; [0362] X.sup.4 and X.sup.5 are each, independently, absent, CH.sub.2, O, S, SO, SO.sub.2, or NR11; [0363] each R.sup.6 and R.sup.7 are independently hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl, or R.sup.6 and R.sup.7 combine with the carbon atom to which they are bound to form CO; [0364] each R.sup.8 is, independently, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl, or two R.sup.8 combine to form an optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; [0365] R.sup.9 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl; [0366] R.sup.10 is optionally substituted C.sub.1-C.sub.6 alkyl; [0367] each R.sup.11 is, independently, hydroxyl, cyano, optionally substituted amino, halogen, thiol, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl; and [0368] R.sup.12 and R.sup.13 are each, independently, hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted aryl, C.sub.3-C.sub.7 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.7 carbocyclyl C.sub.1-C.sub.6 alkyl.

    [0369] In some embodiments, a presenter protein binding moiety has the structure of:

    ##STR00177## ##STR00178## ##STR00179## ##STR00180##

    [0370] In certain embodiments, the presenter protein binding moiety has the structure of:

    ##STR00181## ##STR00182##

    Activity-Based Probes

    [0371] Certain aziridine-containing probes are known in the art and may be used in conjunction with the methods of the present disclosure. These compounds may be useful in forming any of the complexes described herein. Exemplary aziridine-containing activity-based probes are shown below. Such probes may be modified using methods disclosed herein and known in the art to incorporate the aziridine moieties disclosed herein, such as replacing the original aziridine.

    ##STR00183## ##STR00184## ##STR00185## ##STR00186## ##STR00187##

    Compound Characteristics

    Pharmacokinetic Parameters

    [0372] Preliminary exposure characteristics of the compounds can be evaluated using, e.g., an in vivo Rat Early Pharmacokinetic (EPK) study design to show bioavailability. For example, Male Sprague-Dawley rats can be dosed via oral (PO) gavage in a particular formulation. Blood samples can then be collected from the animals at 6 timepoints out to 4 hours post-dose. Pharmacokinetic analysis can then be performed on the LC-MS/MS measured concentrations for each timepoint of each compound.

    Cell Permeability

    [0373] In some embodiments, the compound is cell-penetrant. To determine permeability of a compound any method known in the art may be employed such as a Biosensor assay as described herein.

    Proteins

    Presenter Proteins

    [0374] Presenter proteins can bind a small molecule to form a complex, which can bind to and modulate 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 mammalian presenter protein (e.g., a human presenter protein). In some embodiments, the presenter protein is a fungal presenter protein. In certain embodiments, the presenter protein is a bacterial presenter protein. In some embodiments, the presenter protein is a plant presenter protein. In some embodiments, the presenter protein is a relatively abundant protein (e.g., the presenter protein is sufficiently abundant that participation in a tri-complex does not materially negatively impact the biological role of the presenter protein in a cell and/or viability or other attributes of the cell). In some embodiments, the presenter protein is more abundant than the target protein. In certain embodiments, the presenter protein is a protein that has chaperone activity within a cell. In some embodiments, the presenter protein has multiple natural interaction partners within a cell. In certain embodiments, the presenter protein is one which is known to bind a small molecule to form a binary complex that is known to or suspected of binding to and modulating the biological activity of a target protein. Immunophilins are a class of presenter proteins which are known to have these functions and include FKBPs and cyclophilins.

    [0375] In some embodiments, a reference presenter protein exhibits peptidyl prolyl isomerase activity; in some embodiments, a presenter protein shows comparable activity to the reference presenter 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 that have prolyl isomerase activity and function as protein folding chaperones for proteins containing proline residues. Genes that encode proteins in this family include AIP, AIPL1, FKBP1A, FKBP1B, FKBP2, FKBP3, FKBP4, FKBP5, FKBP6, FKBP7, FKBP8, FKBP9, FKBP9L, FKBP10, FKBP11, FKBP14, FKBP15, and LOC541473.

    [0376] The cyclophilin family is a family of proteins that bind to cyclosporine. Genes that encode 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.

    [0377] In some embodiments, a presenter protein is a chaperone protein such as GRP78/BiP, GRP94, GRP170, calnexin, calreticulin, HSP47, ERp29, Protein disulfide isomerase (PDI), and ERp57.

    [0378] In some embodiments, a presenter protein is an allelic variant or splice variant of a FKBP or cyclophilin disclosed herein.

    [0379] In some embodiments, a presenter protein is a polypeptide whose amino acid sequence i) shows significant identity with that of a reference presenter protein; ii) includes a portion that shows significant identity with a corresponding portion of a reference presenter protein; and/or iii) includes at least one characteristic sequence found in presenter protein. In many embodiments, identity is considered significant for the purposes of defining a presenter protein if it is above 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher. In some embodiments, the portion showing significant identity has a length of 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 amino acids or more.

    [0380] Representative presenter proteins are encoded by the genes or homologs thereof listed in Table 3; in some embodiments, a reference presenter protein is encoded by a gene set forth in Table 3. Also, those of ordinary skill in the art, referring to Table 3, can readily identify sequences that are characteristic of presenter proteins generally, and/or of particular subsets of presenter proteins.

    TABLE-US-00003 TABLE 3 Genes that Encode Selected Presenter Proteins Uniprot Accession Gene Name Number AIP O00170 AIPL1 Q9NZN9 FKBP1A P62942 FKBP1B P68106 FKBP2 P26885 FKBP3 Q00688 FKBP4 Q02790 FKBP5 Q13451 FKBP6 O75344 FKBP7 Q9Y680 FKBP8 Q14318 FKBP9 O95302 FKBP9L Q75LS8 FKBP10 Q96AY3 FKBP11 Q9NYL4 FKBP14 Q9NWM8 FKBP15 Q5T1M5 LOC541473 PPIA Q567Q0 PPIB P23284 PPIC P45877 PPID Q08752 PPIE Q9UNP9 PPIG Q13427 PPIH O43447 PPIL1 Q9Y3C6 PPIL2 Q13356 PPIL3 Q9H2H8 PPIL4 Q8WUA2 PPIL5 Q32Q17 PPIL6 Q8IXY8 PPWD1 Q96BP3

    Target Proteins

    [0381] A target protein (e.g., a eukaryotic target protein such as a mammalian target protein or a fungal target protein or a prokaryotic target protein such as a bacterial target protein) is a protein which mediates a disease condition or a symptom of a disease condition. As such, a desirable therapeutic effect can be achieved by modulating (inhibiting or increasing) its activity. Target proteins useful in the complexes and methods of the invention include those which do not naturally associate with a presenter protein, e.g., those which have an affinity for a presenter protein in the absence of a binary complex with a compound of the invention of greater than 1 M, preferably greater than 5 M, and more preferably greater than 10 M. Alternatively, target proteins which do not naturally associate with a presenter protein are those which have an affinity for a compound of the invention in the absence of a binary complex greater than 1 M, preferably greater than 5 M, and more preferably greater than 10 M. In another alternative, target proteins which do not naturally associate with a presenter protein are those which have an affinity for a binary complex of cyclosporine, rapamycin, or FK506 and a presenter protein (e.g., FKBP) of greater than 1 M, preferably greater than 5 M, and more preferably greater than 10 M. In yet another alternative, target proteins which do not naturally associate with a presenter protein are those which are other than calcineurin or mTOR. The selection of suitable target proteins for the complexes and methods of the invention may depend on the presenter protein. For example, target proteins that have low affinity for a cyclophilin may have high affinity for an FKBP and would not be used together with the latter.

    [0382] Target proteins can be naturally occurring, e.g., wild type. Alternatively, a target protein can vary from the wild type protein but still retain biological function, e.g., as an allelic variant, a splice mutant or a biologically active fragment.

    [0383] In some embodiments, a target protein is a transmembrane protein. In some embodiments, a target protein has a coiled coil structure. In certain embodiments, a target protein is one protein of a dimeric complex.

    [0384] In some embodiments, a target protein of the invention includes one or more surface sites (e.g., a flat surface site) characterized in that, in the absence of forming a presenter protein/compound complex, small molecules typically demonstrate low or undetectable binding to the site(s). In some embodiments, a target protein includes one or more surface sites (e.g., a flat surface site) to which, in the absence of forming a presenter protein/compound complex, a particular small molecule (e.g., the compound) shows low or undetectable binding (e.g., binding at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100 fold or more lower than that observed with a presenter protein/compound complex involving the same compound). In some embodiments, a target protein has a surface characterized by one or more sites (and, in some embodiments, an entire surface) that lack(s) any a traditional binding pocket, for example, a cavity or pocket on the protein structure with physiochemical and/or geometric properties comparable to proteins whose activity has been modulated by one or more small molecules. In certain embodiments, a target protein has a traditional binding pocket and a site for a protein-protein interaction. In some embodiments, a target protein is an undruggable target, for example, a target protein is not a member of a protein family which is known to be targeted by drugs and/or does not possess a binding site that is expected (e.g., according to art-accepted understanding, as discussed herein) to be suitable for binding to a small molecule.

    [0385] In some embodiments, the target protein is a GTPase such as DIRAS1, DIRAS2, DIRAS3, ERAS, GEM, HRAS, KRAS, MRAS, NKIRAS1, NKIRAS2, NRAS, RALA, RALB, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, RASD1, RASD2, RASL10A, RASL10B, RASL11A, RASL11B, RASL12, REM1, REM2, RERG, RERGL, RRAD, RRAS, RRAS2, RHOA, RHOB, RHOBTB1, RHOBTB2, RHOBTB3, RHOC, RHOD, RHOF, RHOG, RHOH, RHOJ, RHOQ, RHOU, RHOV, RND1, RND2, RND3, RAC1, RAC2, RAC3, CDC42, RAB1A, RAB1B, RAB2, RAB3A, RAB3B, RAB3C, RAB3D, RAB4A, RAB4B, RABSA, RAB5B, RAB5C, RAB6A, RAB6B, RAB6C, RAB7A, RAB7B, RAB7L1, RAB8A, RAB8B, RAB9, RAB9B, RABL2A, RABL2B, RABL4, RAB10, RAB11A, RAB11B, RAB12, RAB13, RAB14, RAB15, RAB17, RAB18, RAB19, RAB20, RAB21, RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28, RAB2B, RAB30, RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37, RAB38, RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, RAB41, RAB42, RAB43, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, ARF1, ARF3, ARF4, ARF5, ARF6, ARL1, ARL2, ARL3, ARL4, ARL5, ARL5C, ARL6, ARL7, ARL8, ARL9, ARL10A, ARL10B, ARL10C, ARL11, ARL13A, ARL13B, ARL14, ARL15, ARL16, ARL17, TRIM23, ARL4D, ARFRP1, ARL13B, RAN, RHEB, RHEBL1, RRAD, GEM, REM, REM2, RIT1, RIT2, RHOT1, or RHOT2. In some embodiments, the target protein is a GTPas activating protein such as NF1, IQGAP1, PLEXIN-B1, RASAL1, RASAL2, ARHGAP5, ARHGAP8, ARHGAP12, ARHGAP22, ARHGAP25, BCR, DLC1, DLC2, DLC3, GRAF, RALBP1, RAP1GAP, SIPA1, TSC2, AGAP2, ASAP1, or ASAP3. In some embodiments, the target protein is a Guanine nucleotide-exchange factor such as CNRASGEF, RASGEF1A, RASGRF2, RASGRP1, RASGRP4, SOS1, RALGDS, RGL1, RGL2, RGR, ARHGEF10, ASEF/ARHGEF4, ASEF2, DBS, ECT2, GEF-H.sub.1, LARG, NET1, OBSCURIN, P-REX1, P-REX2, PDZ-RHOGEF, TEM4, TIAM1, TRIO, VAV1, VAV2, VAV3, DOCK1, DOCK2, DOCK3, DOCK4, DOCK8, DOCK10, C.sub.3G, BIG2/ARFGEF2, EFA6, FBX8, or GEP100. In certain embodiments, the target protein is a protein with a protein-protein interaction domain such as ARM; BAR; BEACH; BH; BIR; BRCT; BROMO; BTB; C.sub.1; C.sub.2; CARD; CC; CALM; CH; CHROMO; CUE; DEATH; DED; DEP; DH; EF-hand; EH; ENTH; EVH1; F-box; FERM; FF; FH2; FHA; FYVE; GAT; GEL; GLUE; GRAM; GRIP; GYF; HEAT; HECT; IQ; LRR; MBT; MH1; MH2; MIU; NZF; PAS; PB1; PDZ; PH; POLO-Box; PTB; PUF; PWWP; PX; RGS; RING; SAM; SC; SH2; SH3; SOCS; SPRY; START; SWIRM; TIR; TPR; TRAF; SNARE; TUBBY; TUDOR; UBA; UEV; UIM; VHL; VHS; WD40; WW; SH2; SH3; TRAF; Bromodomain; or TPR. In some embodiments, the target protein is a heat shock protein such as Hsp20, Hsp27, Hsp70, Hsp84, alpha B crystalline, TRAP-1, hsf1, or Hsp90. In certain embodiments, the target protein is an ion channel such as Cav2.2, Cav3.2, IKACh, Kv1.5, TRPA1, NAv1.7, Nav1.8, Nav1.9, P2X3, or P2X4. In some embodiments, the target protein is a coiled-coil protein such as geminin, SPAG4, VAV1, MAD1, ROCK1, RNF31, NEDP1, HCCM, EEA1, Vimentin, ATF4, Nemo, SNAP25, Syntaxin 1a, FYCO1, or CEP250. In certain embodiments, the target protein is a kinase such as ABL, ALK, AXL, BTK, EGFR, FMS, FAK, FGFR1, 2, 3, 4, FLT3, HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, IGF1R, INSR, JAK1, JAK2, JAK3, KIT, MET, PDGFRA, PDGFRB, 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, CDK7, CDK8, CDK9, CDK10, ERK1, ERK2, ERK3, ERK4, GSK3A, GSK3B, JNK1, JNK2, JNK3, AurA, ARuB, PLK1, PLK2, PLK3, PLK4, IKK, KIN1, cRaf, PKN3, c-Src, Fak, PyK2, or AMPK. In some embodiments, the target protein is a phosphatase such as WIP1, SHP2, SHP1, PRL-3, PTP1B, or STEP. In certain embodiments the target protein is a ubiquitin ligase such as BMI-1, MDM2, NEDD4-1, Beta-TRCP, SKP2, E6AP, or APC/C. In some embodiments, the target protein is a chromatin modifier/remodeler such as a chromatin modifier/remodeler encoded by the gene BRG1, BRM, ATRX, PRDM3, ASH1L, CBP, KAT6A, KAT6B, MLL, NSD1, SETD2, EP300, KAT2A, or CREBBP. In some embodiments, the target protein is a transcription factor such as a transcription factor encoded by the gene EHF, ELF1, ELF3, ELF4, ELF5, ELK1, ELK3, ELK4, ERF, ERG, ETS1, ETV1, ETV2, ETV3, ETV4, ETV5, ETV6, FEV, FLI1, GAVPA, SPDEF, SP11, SPIC, SPIB, E2F1, E2F2, E2F3, E2F4, E2F7, E2F8, ARNTL, BHLHA15, BHLHB2, BHLBHB3, BHLHE22, BHLHE23, BHLHE41, CLOCK, FIGLA, HAS5, HES7, HEY1, HEY2, ID4, MAX, MESP1, MLX, MLXIPL, MNT, MSC, MYF6, NEUROD2, NEUROG2, NHLH1, OLIG1, OLIG2, OLIG3, SREBF2, TCF3, TCF4, TFAP4, TFE3, TFEB, TFEC, USF1, ARF4, ATF7, BATF3, CEBPB, CEBPD, CEBPG, CREB3, CREB3L1, DBP, HLF, JDP2, MAFF, MAFG, MAFK, NRL, NFE2, NFIL3, TEF, XBP1, PROX1, TEAD1, TEAD3, TEAD4, ONECUT3, ALX3, ALX4, ARX, BARHL2, BARX, BSX, CART1, CDX1, CDX2, DLX1, DLX2, DLX3, DLX4, DLX5, DLX6, DMBX1, DPRX, DRGX, DUXA, EMX1, EMX2, EN1, EN2, ESX1, EVX1, EVX2, GBX1, GBX2, GSC, GSC2, GSX1, GSX2, HESX1, HMX1, HMX2, HMX3, HNF1A, HNF1B, HOMEZ, HOXA1, HOXA10, HOXA13, HOXA2, HOXAB13, HOXB2, HOXB3, HOXB5, HOXC10, HOXC11, HOXC12, HOXC13, HOXD11, HOXD12, HOXD13, HOXD8, IRX2, IRX5, ISL2, ISX, LBX2, LHX2, LHX6, LHX9, LMX1A, LMX1B, MEIS1, MEIS2, MEIS3, MEOX1, MEOX2, MIXL1, MNX1, MSX1, MSX2, NKX2-3, NKX2-8, NKX3-1, NKX3-2, NKX6-1, NKX6-2, NOTO, ONECUT1, ONECUT2, OTX1, OTX2, PDX1, PHOX2A, PHOX2B, PITX1, PITX3, PKNOX1, PROP1, PRRX1, PRRX2, RAX, RAXL1, RHOXF1, SHOX, SHOX2, TGIF1, TGIF2, TGIF2LX, UNCX, VAX1, VAX2, VENTX, VSX1, VSX2, CUX1, CUX2, POU F1, POU2F1, POU2F2, POU2F3, POU3F1, POU3F2, POU3F3, POU3F4, POU4F1, POU4F2, POU4F3, POU5F1P1, POU6F2, RFX2, RFX3, RFX4, RFX5, TFAP2A, TFAP2B, TFAP2C, GRHL1, TFCP2, NFIA, NFIB, NFIX, GCM1, GCM2, HSF1, HSF2, HSF4, HSFY2, EBF1, IRF3, IRF4, IRF5, IRF7, IRF8, IRF9, MEF2A, MEF2B, MEF2D, SRF, NRF1, CPEB1, GMEB2, MYBL1, MYBL2, SMAD3, CENPB, PAX1, PAX2, PAX9, PAX3, PAX4, PAX5, PAX6, PAX7, BCL6B, EGR1, EGR2, EGR3, EGR4, GLIS1, GLIS2, GLI2, GLIS3, HIC2, HINFP1, KLF13, KLF14, KLF16, MTF1, PRDM1, PRDM4, SCRT1, SCRT2, SNAI2, SP1, SP3, SP4, SP8, YY1, YY2, ZBED1, ZBTB7A, ZBTB7B, ZBTB7C, ZIC1, ZIC3, ZIC4, ZNF143, ZNF232, ZNF238, ZNF282, ZNF306, ZNF410, ZNF435, ZBTB49, ZNF524, ZNF713, ZNF740, ZNF75A, ZNF784, ZSCAN4, CTCF, LEF1, SOX10, SOX14, SOX15, SOX18, SOX2, SOX21, SOX4, SOX7, SOX8, SOX9, SRY, TCF7L1, FOXO3, FOXB1, FOXC1, FOXC2, FOXD2, FOXD3, FOXG1, FOXI1, FOXJ2, FOXJ3, FOXK1, FOXL1, FOXO1, FOXO4, FOXO6, FOXP3, EOMES, MGA, NFAT5, NFATC1, NFKB1, NFKB2, TP63, RUNX2, RUNX3, T, TBR1, TBX1, TBX15, TBX19, TBX2, TBX20, TBX21, TBX4, TBX5, AR, ESR1, ESRRA, ESRRB, ESRRG, HNF4A, NR2C.sub.2, NR2E1, NR2F1, NR2F6, NR3C.sub.1, NR3C.sub.2, NR4A2, RARA, RARB, RARG, RORA, RXRA, RXRB, RXRG, THRA, THRB, VDR, GATA3, GATA4, or GATA5; or C-myc, Max, Stat3, androgen receptor, C-Jun, C-Fox, N-Myc, L-Myc, MITF, Hif-1alpha, Hif-2alpha, 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, RORt, IL17RA, eIF4E, TLR7R, PCSK9, IgE R, CD40, CD40L, Shn-3, TNFR1, TNFR2, IL31RA, OSMR, IL12beta1,2, Tau, FASN, KCTD 6, KCTD 9, Raptor, Rictor, RALGAPA, RALGAPB, Annexin family members, BCOR, NCOR, beta catenin, AAC 11, PLD1, PLD2, Frizzled7, RaLP, MLL-1, Myb, Ezh2, RhoGD12, EGFR, CTLA4R, GCGC (coact), Adiponectin R2, GPR 81, IMPDH2, IL-4R, IL-13R, IL-1R, IL2-R, IL-6R, IL-22R, TNF-R, TLR4, Nrlp3, or OTR.

    Methods of Synthesis

    [0386] Methods of synthesizing cyclopropyl aziridines that are disclosed herein are known in the art. The methods may include those shown in the following scheme.

    ##STR00188##

    [0387] (2R,3R)-beta-phenyl aziridines have been synthesized using the Davis auxiliary (para-toluenesulfinamide) (Davis et al., J. Org. Chem. 1994, 59 (12), 3243-3245; Davis et al., J. Org. Chem. 1999, 64 (20), 7559-7567). See letter A, above.

    [0388] (2S,3S)-beta-cyclopropyl aziridines (letter B, above) can be synthesized using the Ellman's auxiliary (tert-butylsulfinamide) (Sols et al., Org. Biomol. Chem. 2011, 9 (14), 5034).

    [0389] Beta-cyclopropyl aziridines can also be prepared by reaction of the diphenylmethyl imine with the diazo ester 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 and a mixture of enantiomers.

    [0390] Alternatively, beta-cyclopropyl aziridines can be made on a large scale using the following scheme:

    ##STR00189##

    [0391] The (2R,3R)-beta-cyclopropyl aziridine can be synthesized by the reaction of the (R)-para-toluenesulfinamide with benzyl 2-bromoacetate and LiHMDS. Removal of the chiral auxiliary is achieved using either TFA or methyl Grignard. Methylation of the aziridine nitrogen is performed by either Chan-Lam coupling with methyl boronic acid or alkylation with methyl iodide.

    Complexes

    Presenter Protein/Compound Complexes

    [0392] In naturally occurring protein-protein interactions, the binding event is driven largely by hydrophobic residues on flat surface sites of the two proteins, in contrast to many small molecule-protein interactions which are driven by interactions between the small molecule in a cavity or pocket on the protein. The hydrophobic residues on the flat surface site form hydrophobic hot spots on the two interacting proteins wherein most of the binding interactions between the two proteins are van der Waals interactions. Small molecules may be used as portable hotspots for proteins which are lacking one (e.g., presenter proteins) through the formation of complexes (e.g., a presenter protein/compound complex) to participate in pseudo protein-protein interactions (e.g., forming a tri-complex with a target protein).

    [0393] Many mammalian proteins are able to bind to any of a plurality of different partners; in some cases, such alternative binding interactions contribute to biological activity of the proteins. Many of these proteins adapt the inherent variability of the hot spot protein regions to present the same residues in different structural contexts. More specifically, the protein-protein interactions can be mediated by a class of natural products produced by a select group of fungal and bacterial species. These molecules exhibit both a common structural organization and resultant functionality that provides the ability to modulate protein-protein interaction. These molecules contain a presenter protein binding moiety that is highly conserved and a target protein interacting moiety that exhibits a high degree of variability among the different natural products. The presenter protein binding moiety confers specificity for the presenter protein and allows the molecule to bind to the presenter protein to form a binary complex; the mammalian target protein interacting moiety confers specificity for the target protein and allows the binary complex to bind to the target protein, typically modulating (e.g., positively or negatively modulating) its activity.

    [0394] These natural products are presented by presenter proteins, such as FKBPs and cyclophilins and act as diffusible, cell-penetrant, orally bio-available adaptors for protein-protein interactions. Examples include well known and clinically relevant molecules such as Rapamycin (Sirolimus), FK506 (Tacrolimus), and Cyclosporin. In brief, these molecules bind endogenous intracellular presenter proteins, the FKBPs e.g., rapamycin and FK506 or cyclophilins e.g., diluents, and the resulting binary complexes of presenter protein-bound molecules selectively bind and inhibit the activity of intracellular target proteins. Formation of a tri-complex between the presenter protein, the molecule, and the target protein is driven by both protein-molecule and protein-protein interactions and both are required for inhibition of the target protein. In the example of the FKBP-rapamycin complex, the intracellular target is the serine-threonine kinase mTOR, whereas for FKBP-FK506 complex, the intracellular target is the phosphatase calcineurin. Of particular interest in the preceding two examples, FKBP12 is utilized as a partner presentation protein by both the rapamycin and FK506 presentation ligands. Moreover, the sub-structure components of rapamycin and FK506 responsible for binding to FKBP12 are closely related structurally, i.e., the so-called Conserved Region, but it is the dramatic structural differences between rapamycin and FK506 in the non FKBP12-binding regions, i.e., the Variable Region, that results in the specific targeting of two distinct intracellular proteins, mTOR and calcineurin, respectively. In this fashion, the Variable Regions of rapamycin and FK506 are serving as contributors to the binding energy necessary for enabling presenter protein-target protein interaction.

    [0395] In some embodiments, a presenter protein/compound complexes of the invention bind to a target protein with 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 affinity than the complex binds to each of mTOR and/or calcineurin.

    [0396] In some embodiments, a presenter protein/compound complexes of the invention bind to a target protein with 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 affinity than the affinity of the compound to a target protein when the compound is not bound in a complex with a presenter protein.

    [0397] In certain embodiments, a presenter protein/compound complexes of the invention bind to a target protein with 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 affinity than the affinity of the presenter protein to a target protein when the presenter protein is not bound in a complex with a compound.

    [0398] In some embodiments, a presenter protein/compound complexes of the invention inhibit a naturally occurring interaction between a target protein and a ligand, such as a protein or a small molecule that specifically binds to the target protein.

    [0399] In certain embodiments, when the presenter protein is a prolyl isomerase, the prolyl isomerase activity is inhibited by formation of the presenter protein/compound complex. In some embodiments of the presenter protein/compound complexes of the invention, the compound specifically binds to said presenter protein with a K.sub.D of less than 10 M (e.g., less than 5 M, less than 1 M, 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) or inhibits the peptidyl-prolyl isomerase activity of the presenter protein, for example, with an IC.sub.50 of less than 1 M (e.g., less than 0.5 M, less than 0.1 M, less than 0.05 M, less than 0.01 M).

    Compound/Target Protein Complexes

    [0400] The compounds of the present disclosure may be useful for forming complexes with a target protein. The complexes can be formed by way of non-covalent interactions (e.g., van der Waals interactions or pi-interactions). Alternatively, or in addition, such complexes may be formed by way of cross-linking the target by formation of a covalent bond between the compound and the target protein. The compounds described herein may contain an electrophilic aziridine group capable of reaction with a nucleophilic residue of the target protein (e.g., an aspartic acid, glutamic acid, cysteine, glutamine, asparagine, lysine, or histidine residue).

    [0401] The inclusion of a carbocation stabilizing electron donating group at a position beta to a carbonyl substituent may aid in promoting cross-linking with a target protein. For example, cyclopropyl substituents aid in allowing the aziridine to react with a nucleophilic residue (e.g., an aspartic acid residue). Without being bound by theory, the inventors postulate that in situ protonation of the weakly basic aziridine nitrogen enhances reactivity of the aziridine ring. Stabilization of a nascent carbocation (.sup.+) p-orbital at the aziridine beta-carbon by the pseudo aromatic cyclopropyl (.sub.c-c bonds) moiety further facilitates a reaction with a low reactivity and highly solvated aspartate anion.

    ##STR00190##

    [0402] Beyond a beta-cyclopropyl group, additional moieties may be beneficial at stabilizing carbocations, either through hyperconjugation or resonance, including, but not limited to aryl, vinyl, ynyl, and cubyl groups.

    [0403] In some embodiments, a compound/target protein complex of the disclosure has the structure of Formula III:

    ##STR00191## [0404] wherein A.sup.1 is a monovalent organic moiety; [0405] Q is

    ##STR00192## [0406] P.sup.1 is A.sup.2, and P.sup.2 is hydrogen; or P.sup.1 is hydroxyl, and P.sup.2 is A.sup.2; [0407] A.sup.2 is the target protein; [0408] R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0409] R.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0410] R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0411] R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl or Si(R.sup.1a).sub.3; [0412] or R and R.sup.1 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0413] R and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 and R.sup.4 are each, independently, hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a); or [0414] R and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0415] R.sup.1 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0416] R.sup.1 and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R and R.sup.4 is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0417] R.sup.2 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R.sup.1 and R is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0418] each R.sup.1a, R.sup.2a, R.sup.2c, R.sup.2d, and R.sup.2e is, independently, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; [0419] R.sup.2b is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0420] R.sup.5 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, [0421] and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0422] In some embodiments, at least one of R and R.sup.4 is not hydrogen.

    [0423] In some embodiments, the compound/target protein complex has the structure of Formula IIIa-1:

    ##STR00193##

    wherein A.sup.3 is the rest of the target protein.

    [0424] In some embodiments, the compound/target protein complex has the structure of Formula IIIa-2:

    ##STR00194##

    wherein A.sup.3 is the rest of the target protein.

    [0425] In some embodiments, the compound/target protein complex has the structure of Formula IIIa-3:

    ##STR00195##

    wherein A.sup.3 is the rest of the target protein.

    [0426] In some embodiments, the compound/target protein complex has the structure of Formula IIIa-4:

    ##STR00196##

    wherein A.sup.3 is the rest of the target protein.

    [0427] In some embodiments, the compound/target protein complex has the structure of/target protein complex of claim 16, wherein the compound/target protein complex has the structure of Formula IIIb-1:

    ##STR00197##

    wherein A.sup.3 is the rest of the target protein.

    [0428] In some embodiments, the compound/target protein complex has the structure of Formula IIIb-2:

    ##STR00198##

    wherein A.sup.3 is the rest of the target protein.

    [0429] In some embodiments, the compound/target protein complex has the structure of Formula IIIc-1:

    ##STR00199##

    wherein A.sup.3 is the rest of the target protein.

    [0430] In some embodiments, the compound/target protein complex has the structure of Formula IIIc-2:

    ##STR00200##

    wherein A.sup.3 is the rest of the target protein.

    [0431] In some embodiments, the compound/target protein complex has the structure of Formula IIIc-3:

    ##STR00201##

    wherein A.sup.3 is the rest of the target protein.

    [0432] In some embodiments, the compound/target protein complex has the structure of Formula IIIc-4:

    ##STR00202##

    wherein A.sup.3 is the rest of the target protein.

    [0433] In some embodiments, the compound/target protein complex has the structure of Formula IIId-1:

    ##STR00203##

    wherein A.sup.3 is the rest of the target protein.

    [0434] In some embodiments, the compound/target protein complex has the structure of Formula IIId-2:

    ##STR00204##

    wherein A.sup.3 is the rest of the target protein.

    [0435] In some embodiments, the compound/target protein complex has the structure of Formula IIIe-1:

    ##STR00205##

    wherein A.sup.3 is the rest of the target protein.

    [0436] In some embodiments, the compound/target protein complex has the structure of Formula IIIe-1:

    ##STR00206##

    wherein A.sup.3 is the rest of the target protein.

    [0437] In some embodiments, R is optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.6 alkenyl, or optionally substituted C.sub.2-C.sub.6 alkynyl. In some embodiments, R is optionally substituted C.sub.3-C.sub.10 cycloalkyl. In some embodiments, R is optionally substituted cyclopropyl.

    [0438] In some embodiments, R is

    ##STR00207##

    In some embodiments, R is

    ##STR00208##

    In some embodiments, R is optionally substituted C.sub.2-C.sub.6 alkenyl, or optionally substituted C.sub.2-C.sub.6 alkynyl. In some embodiments, R is

    ##STR00209##

    In some embodiments, R is a carbocation-stabilizing electron-donating group.

    Tri-Complexes

    [0439] The vast majority of small molecule drugs act by binding a functionally important site on a target protein, thereby modulating (e.g., positively or negatively modulating) the activity of that protein. For example, the cholesterol-lowering drugs statins bind the enzyme active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrates. The fact that many such drug/target interacting pairs are known may have misled some into believing that a small molecule modulator could be discovered for most, if not all, proteins provided a reasonable amount of time, effort, and resources. This is far from the case. Current estimates hold that only about 10% of all human proteins are targetable by small molecules. The other 90% are currently considered refractory or intractable toward small molecule drug discovery. Such targets are commonly referred to as undruggable. These undruggable targets include a vast and largely untapped reservoir of medically important human proteins. Thus, there exists a great deal of interest in discovering new molecular modalities capable of modulating the function of such undruggable targets.

    [0440] The present invention encompasses the recognition that small molecules are typically limited in their targeting ability because their interactions with the target are driven by adhesive forces, the strength of which is roughly proportional to contact surface area. Because of their small size, the only way for a small molecule to build up enough intermolecular contact surface area to effectively interact with a target protein is to be literally engulfed by that protein. Indeed, a large body of both experimental and computational data supports the view that only those proteins having a hydrophobic pocket on their surface are capable of binding small molecules. In those cases, binding is enabled by engulfment. Not a single example exists of a small molecule binding with high-affinity to a protein outside of a hydrophobic pocket.

    [0441] Nature has evolved a strategy that allows a small molecule to interact with target proteins at sites other than hydrophobic pockets. This strategy is exemplified by the naturally occurring immunosuppressive drugs cyclosporine A, rapamycin, and FK506. The activity of these drugs involves the formation of a high-affinity complex of the small molecule with a small presenting protein. The composite surface of the small molecule and the presenting protein then engages the target. Thus, for example, the binary complex formed between cyclosporine A and cyclophilin A targets calcineurin with high affinity and specificity, but neither cyclosporine A nor cyclophilin A alone binds calcineurin with measurable affinity.

    [0442] Many important therapeutic targets exert their function by complexation with other proteins. The protein/protein interaction surfaces in many of these systems contain an inner core of hydrophobic side chains surrounded by a wide ring of polar residues. The hydrophobic residues contribute nearly all of the energetically favorable contacts, and hence this cluster has been designated as a hotspot for engagement in protein-protein interactions. Importantly, in the aforementioned complexes of naturally occurring small molecules with small presenting proteins, the small molecule provides a cluster of hydrophobic functionality akin to a hotspot, and the protein provides the ring of mostly polar residues. In other words, presented small molecule systems mimic the surface architecture employed widely in natural protein/protein interaction systems.

    [0443] Compounds (e.g., macrocyclic compounds) of the invention are capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) to form a presenter protein/compound complex as described above which binds to a target protein to form a tri-complex. The formation of these tri-complexes allows for modulation of proteins that do not have traditional binding pockets and/or are considered undruggable. The presenter protein/compound complexes are able to modulate biological processes through cooperative binding between the compound and the presenter protein. Both the compound and presenter protein have low affinity for the target protein alone, but the presenter protein/compound complex has high affinity for the target protein. Cooperative binding can be determined by measurement of the buried surface area of the target protein that includes atoms from the compound and/or presenter protein and/or by measurement of the free binding energy contribution of the compound and/or presenter protein. Binding is considered cooperative if at least one atom from each of the compound and presenter protein participates in binding with the target protein.

    [0444] The binding of a presenter protein/compound complex and a target protein is achieved through formation of a combined binding site including residues from both the presenter protein and compound that allow for increased affinity that would not be possible with either the presenter protein or 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 tri-complex includes one or more atoms that participate in binding to the compound and/or at least 20% (e.g., at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%) of the total buried surface area of the target protein in the tri-complex includes one or more atoms that participate in binding to 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 tri-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 tri-complex.

    [0445] In some embodiments, a presenter protein/compound complex binds at a flat surface site on a target protein. In some embodiments, a compound (e.g., macrocyclic compound) in a presenter protein/compound complex binds at a hydrophobic surface site on a target protein, e.g., a site that includes at least 50% hydrophobic residues. In some embodiments, at least 70% of the binding interactions between one or more of the atoms of a compound and one or more atoms of a target protein are van der Waals and/or -effect interactions. In certain embodiments, a presenter protein/compound complex binds to a target protein at a site of a naturally occurring protein-protein interaction between a target protein and a protein that specifically binds the target protein. In some embodiments, a presenter protein/compound complex does not bind at an active site of a target protein. In some embodiments, a presenter protein/compound complex binds at an active site of a target protein.

    [0446] A characteristic of compounds of the invention that form tri-complexes with a presenter protein and a target protein is a lack of major structural reorganization in the presenter protein/compound complex compared to the tri-complex. This lack of major structural reorganization results in a low entropic cost to reorganize into a configuration favorable for the formation of the tri-complex once the presenter protein/compound complex has been formed. For example, threshold quantification of RMSD can be measured using the align command in PyMOL version 1.7rc1 (Schrdinger LLC). Alternatively, RMSD can be calculated using the ExecutiveRMS parameter from the algorithm LigAlign (J. Mol. Graphics and Modelling 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) is substantially unchanged in the tri-complex compared to the compound when in the presenter protein/compound complex before binding to the target protein. For example, the root mean squared deviation (RMSD) of the two aligned structures is less than 1.

    Pharmaceutical Compositions and Methods of Use

    [0447] One embodiment of the present invention provides pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, as well as methods of using the compounds of the invention to prepare such compositions.

    [0448] 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.

    [0449] In some embodiments, a compound is present in a pharmaceutical composition in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

    [0450] A pharmaceutically acceptable excipient, as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Excipients include, but are not limited to: butylated optionally substituted hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxylpropyl cellulose, optionally substituted hydroxylpropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, 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 of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients. See, e.g., 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, a composition includes at least two different pharmaceutically acceptable excipients.

    [0451] Compounds described herein, whether expressly stated or not, may be provided or utilized in salt form, e.g., a pharmaceutically acceptable salt form, unless expressly stated to the contrary. The term pharmaceutically acceptable salt, as use herein, refers to those salts of the compounds described herein that are, 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 and the like, and are 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 in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.

    [0452] The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention, be prepared from inorganic or organic bases. 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, such as hydrochloric, sulfuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art.

    [0453] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-optionally substituted hydroxyl-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.

    [0454] As used herein, the term subject refers to any member of the animal kingdom. In some embodiments, subject refers to humans, at any stage of development. In some embodiments, subject refers to a human patient. In some embodiments, subject refers to non-human animals. In some embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In some embodiments, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish, or worms. In some embodiments, a subject may be a transgenic animal, genetically-engineered animal, or a clone.

    [0455] As used herein, the term dosage form refers to a physically discrete unit of a compound (e.g., a compound of the present invention) for administration to a subject. Each unit contains a predetermined quantity of compound. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms. As used herein, the term dosing regimen refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

    [0456] A therapeutic regimen refers to a dosing regimen whose administration across a relevant population is correlated with a desired or beneficial therapeutic outcome.

    [0457] The term treatment (also treat or treating), in its broadest sense, refers to any administration of a substance (e.g., a compound of the present invention) that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, or reduces incidence of one or more symptoms, features, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment may be administered to a subject who does not exhibit signs of the relevant disease, disorder or condition or of a subject who exhibits only early signs of the disease, disorder, or condition. Alternatively, or additionally, in some embodiments, treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, or condition.

    [0458] The term therapeutically effective amount means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence or severity of, or delays onset of, one or more symptoms of the disease, disorder, or condition. Those of ordinary skill in the art will appreciate that the term therapeutically effective amount does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment. It is specifically understood that particular subjects may, in fact, be refractory to a therapeutically effective amount. In some embodiments, reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those of ordinary skill in the art will appreciate that, in some embodiments, a therapeutically effective amount may be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated or administered in a plurality of doses, for example, as part of a dosing regimen.

    [0459] For use as treatment of subjects, the compounds of the invention, or a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof, are formulated in ways consonant with these parameters. A summary of such techniques may be found in Remington: The Science and Practice of Pharmacy, 21.sup.st Edition, 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.

    [0460] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of a compound of the present invention, or pharmaceutically acceptable salt thereof, by weight or volume. In some embodiments, compounds, or a pharmaceutically acceptable salt thereof, described herein may be present in amounts totaling 1-95% by weight of the total weight of a composition, such as a pharmaceutical composition.

    [0461] The composition may be provided in a dosage form that is suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, reproductive or oral mucosa. Thus, the pharmaceutical composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, 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.

    [0462] As used herein, the term administration refers to the administration of a composition (e.g., a compound, or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal or vitreal.

    [0463] Formulations may be prepared in a manner suitable for systemic administration or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. A formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, preservatives and the like. Compounds, or a pharmaceutically acceptable salt thereof, can be administered also in liposomal compositions or as microemulsions.

    [0464] For injection, formulations can be prepared in conventional forms as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol and the like. Such compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, and so forth.

    [0465] Various sustained release systems for drugs have also been devised. See, for example, U.S. Pat. No. 5,624,677.

    [0466] Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration. Oral administration is also suitable for compounds of the invention, or a pharmaceutically acceptable salt thereof. Suitable forms include syrups, capsules, and tablets, as is understood in the art.

    [0467] Each compound, or a pharmaceutically acceptable salt thereof, as described herein, may be formulated in a variety of ways that are known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Other modalities of combination therapy are described herein.

    [0468] The individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include optional components that aid in the administration of the unit dose to subjects, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions. The kit may be manufactured as a single use unit dose for one subject, multiple uses for a particular subject (at a constant dose or in which the individual compounds, or a pharmaceutically acceptable salt thereof, may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple subjects (bulk packaging). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

    [0469] 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, sugar, mannitol, microcrystalline cellulose, starches 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, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, optionally substituted hydroxylpropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

    [0470] Two or more compounds may be mixed together in a tablet, capsule, or other vehicle, or may be partitioned. In one example, the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that a substantial portion of the second compound is released prior to the release of the first compound.

    [0471] Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein 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 wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

    [0472] Dissolution or diffusion-controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound, or a pharmaceutically acceptable salt thereof, into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-optionally substituted hydroxylmethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbon.

    [0473] The liquid forms in which the compounds, or a pharmaceutically acceptable salt thereof, and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

    [0474] Generally, when administered to a human, the oral dosage of any of the compounds of the invention, or a pharmaceutically acceptable salt thereof, will depend on the nature of the compound, and can readily be determined by one skilled in the art. A dosage may be, for example, about 0.001 mg to about 2000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 100 mg to about 1500 mg per day, about 500 mg to about 1500 mg per day, about 500 mg to about 2000 mg per day, or any range derivable therein. In some embodiments, the daily dose range for oral administration, for example, may lie within the range of from about 0.001 mg to about 2000 mg per kg body weight of a human, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.

    [0475] In some embodiments, the pharmaceutical composition may further comprise an additional compound having antiproliferative activity. Depending on the mode of administration, compounds, or a pharmaceutically acceptable salt thereof, will be formulated into suitable compositions to permit facile delivery. Each compound, or a pharmaceutically acceptable salt thereof, of a combination therapy may be formulated in a variety of ways that are known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Desirably, the first and second agents are formulated together for the simultaneous or near simultaneous administration of the agents.

    [0476] It will be appreciated that the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).

    [0477] Administration of each drug in a combination therapy, as described herein, can, independently, be one to four times daily for one day to one year, and may even be for the life of the subject. Chronic, long-term administration may be indicated.

    Methods of Use

    [0478] The compounds and complexes of the present disclosure may be useful in various methods. For example, the present disclosure provides a method of modulating a target protein by contacting the target protein with a compound or presenter protein/compound complex described herein. The method may include inhibiting a target protein by contacting the target protein with a compound or presenter protein/compound complex described herein or activating a target protein by contacting the target protein with a compound or presenter protein/compound complex described herein. The modulating (e.g., inhibiting or activating) may render the compounds and/or complexes useful for the treatment of various diseases or disorders. Accordingly, the compounds and complexes may be used in a method of treating a disease or disorder in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound described herein. In some embodiments, the subject has previously been treated with a prior therapy. In some embodiments, the subject has developed resistance to treatment with a prior therapy.

    [0479] The present disclosure also relates to the synthesis of the various complexes disclosed. For example, the disclosure provides a method of forming a tri-complex described herein by contacting a target protein with a presenter protein/compound complex described herein.

    [0480] In some embodiments of the foregoing methods, upon contacting the target protein, the target protein forms a covalent bond to 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 to 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 to the compound or the complex.

    [0481] In an embodiment, the 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.

    [0482] The disclosure further provides a method of forming a presenter protein/compound complex described herein by contacting a presenter protein with a compound described herein under conditions sufficient to permit the formation of a complex. In some embodiments, the complex is formed by way of noncovalent interactions.

    [0483] In another embodiment, the disclosure provides a method of forming a tri-complex described herein, including the following steps: [0484] a) contacting a presenter protein with the compound described herein under conditions sufficient to permit the formation of presenter protein/compound complex; and [0485] b) contacting the presenter protein/compound complex with a target protein under conditions that permit the formation of a tri-complex.

    [0486] 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 the compound alone. In some embodiments, the presenter protein or the compound do not substantially bind to the target protein in the absence of forming the presenter protein/compound complex.

    [0487] Compounds of the present invention may be used in methodologies including click chemistry. Persons having skill in the art would be familiar with how to adapt compounds disclosed herein for click chemistry applications. See, e.g., 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. Compounds of the present invention are also adaptable for uses in antibody-drug conjugates as well as degrader applications. Incorporation of the aziridine moieties described herein into known modulators (e.g., RAS inhibitors) are also contemplated. Exemplary scaffolds that are amenable to such modification include known RAS scaffolds and compounds disclosed in the art, such as WO 2022152233, WO 2022148422, WO 2022148421, WO 2022135346, WO 2022133731, WO 2022133038, WO 2022133345, WO 2022132200, WO 2022119748, WO 2022109487, WO 2022109485, WO 2022105859, WO 2022105857, WO 2022098625, WO 2022098625, WO 2022093856, WO 2022087335, WO 2022083569, WO 2022078470, WO 2022078414, WO 2022072783, WO 2022066805, WO 2022066646, WO 2022048545, WO 2022047093, WO 2022042630, WO 2022031678, WO 2022028492, WO 2022015375, WO 2022002102, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO 2021139678, WO 2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO 2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO 2021108643, WO 2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO 2018217651, WO 2018218071, WO 2018218069, WO 2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO 2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO 2018068017, WO 2018064510, WO 2017201161, WO 2017172979, WO 2017100546, WO 2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659, WO 2013155223, and PCT/US2022/027773, each of which is incorporated by reference in its entirety.

    [0488] Compounds of the present invention may be used in the treatment of subjects having a disease or disorder, such as mammals (e.g., mice, rats, dogs, and humans). The disease or disorder may be, for example, cancer, diabetes, cardiovascular disease, neurological disorder, viral disease, infectious disease, autoimmune disease, arthritis, an allergic disorder, inflammation, a hormone-related disease, a condition associated with organ transplantation (e.g., transplant rejection), an immunodeficiency disorder, a bone disorder, or a proliferative disorder.

    Kits

    [0489] The invention also features kits including (a) a pharmaceutical composition including an agent (e.g., a compound or complex of the invention) described herein, and (b) a package insert with instructions to perform any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent (e.g., a compound or complex of the invention) described herein, (b) one or more additional therapies (e.g., non-drug treatment or therapeutic agent), and (c) a package insert with instructions to perform any of the methods described herein.

    [0490] As one aspect of the present invention contemplates the treatment of the disease or symptoms associated therewith with a combination of pharmaceutically active compounds that may be administered separately, the invention further relates to combining separate pharmaceutical compositions in kit form. The kit may comprise two separate pharmaceutical compositions: a compound of the present invention, and one or more additional therapies. The kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may comprise directions for the use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.

    ENUMERATED EMBODIMENTS

    [0491] Some specific embodiments are listed below. The below enumerated embodiments should not be construed to limit the scope of the disclosure, rather, the below are presented as some examples of the utility of the disclosure.

    [0492] 1. A compound having the structure of Formula I:

    ##STR00210##

    or a pharmaceutically acceptable salt thereof; wherein [0493] M.sup.+ is a cation;

    ##STR00211## [0494] R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0495] R.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0496] R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0497] R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0498] R and R.sup.1 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0499] R and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 and R.sup.4 are each, independently, hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a); or [0500] R and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0501] R.sup.1 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0502] R.sup.1 and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R and R.sup.4 is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0503] R.sup.2 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R.sup.1 and R is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0504] wherein at least one of R and R.sup.4 is not hydrogen; [0505] R.sup.3 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; [0506] each R.sup.1a, R.sup.2a, R.sup.2c, R.sup.2d, and R.sup.2e is, independently, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; [0507] R.sup.2b is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0508] R.sup.5 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, [0509] and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0510] 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ia:

    ##STR00212##

    [0511] 3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ib:

    ##STR00213##

    [0512] 4. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ic:

    ##STR00214##

    [0513] 5. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Id:

    ##STR00215##

    [0514] 6. The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl.

    [0515] 7. The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl.

    [0516] 8. The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is methyl, ethyl, or benzyl.

    [0517] 9. The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein M.sup.+ is Li.sup.+.

    [0518] 10. The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R.sup.3 is:

    ##STR00216##

    [0519] 11. The compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Z is

    ##STR00217##

    [0520] 12. A compound having the structure of Formula II:

    ##STR00218##

    or a pharmaceutically acceptable salt thereof, [0521] wherein A.sup.1 is a monovalent organic moiety; [0522] Q is

    ##STR00219## [0523] R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0524] R.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0525] R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0526] R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0527] or R and R.sup.1 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0528] R and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 and R.sup.4 are each, independently, hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a); or [0529] R and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0530] R.sup.1 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl; R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0531] R.sup.1 and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R and R.sup.4 is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0532] R.sup.2 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R.sup.1 and R is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0533] wherein at least one of R and R.sup.4 is not hydrogen; [0534] each R.sup.1a, R.sup.2a, R.sup.2c, R.sup.2d, and R.sup.2e is, independently, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; [0535] R.sup.2b is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0536] R.sup.5 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, [0537] and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0538] 13. The compound of embodiment 12, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IIa:

    ##STR00220##

    [0539] 14. The compound of embodiment 12, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IIb:

    ##STR00221##

    [0540] 15. The compound of embodiment 12, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IIc:

    ##STR00222##

    [0541] 16. The compound of embodiment 12, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula IId:

    ##STR00223##

    [0542] 17. The compound of any one of embodiments 12 to 16, or a pharmaceutically acceptable salt thereof, wherein Q is

    ##STR00224##

    [0543] 18. A compound/target protein complex, or a pharmaceutically acceptable salt thereof, wherein the compound/target protein complex has the structure of Formula IIIa or Formula IIIb:

    ##STR00225## [0544] wherein A.sup.1 is a monovalent organic moiety; [0545] Q is

    ##STR00226## [0546] P.sup.1 is A.sup.2, and P.sup.2 is hydrogen; or P.sup.1 is hydroxyl, and P.sup.2 is A.sup.2; [0547] A.sup.2 is the target protein; [0548] R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0549] R.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0550] R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0551] R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl or Si(R.sup.1a).sub.3; or [0552] R and R.sup.1 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, and R.sup.4 is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; or [0553] R and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 and R.sup.4 are each, independently, hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a); or [0554] R and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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.sup.1 is hydrogen, halo, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0555] R.sup.1 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; and R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 acyl, C(O).sub.2R.sup.2a, C(O)N(R.sup.2b).sub.2, S(O).sub.2R.sup.2c, S(O).sub.2N(R.sup.2d).sub.2, S(O).sub.2OR.sup.2e, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or [0556] R.sup.1 and R.sup.2 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 cycloalkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 5- to 10-membered heterocycloalkenyl, or optionally substituted 8- to 10-membered heterocycloalkynyl, and each of R and R.sup.4 is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl or Si(R.sup.1a).sub.3; or [0557] R.sup.2 and R.sup.4 combine to form an optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.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 each of R.sup.1 and R is, independently, hydrogen, cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.1-C.sub.6 heteroalkenyl, optionally substituted C.sub.1-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, optionally substituted 5- to 10-membered heteroaryl, or Si(R.sup.1a).sub.3; [0558] wherein at least one of R and R.sup.4 is not hydrogen; [0559] each R.sup.1, R.sup.23, R.sup.2c, R.sup.2d, and R.sup.2e is, independently, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; [0560] R.sup.2b is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl; and [0561] R.sup.5 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkenyl, optionally substituted C.sub.8-C.sub.10 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.sub.6-C.sub.10 aryl, or optionally substituted 5- to 10-membered heteroaryl, [0562] and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0563] 19. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIa-1:

    ##STR00227##

    wherein A.sup.3 is the rest of the target protein.

    [0564] 20. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIa-2:

    ##STR00228##

    wherein A.sup.3 is the rest of the target protein.

    [0565] 21. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIa-3:

    ##STR00229##

    wherein A.sup.3 is the rest of the target protein.

    [0566] 22. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIa-4:

    ##STR00230##

    wherein A.sup.3 is the rest of the target protein.

    [0567] 23. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIb-1:

    ##STR00231##

    wherein A.sup.3 is the rest of the target protein.

    [0568] 24. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIb-2:

    ##STR00232##

    wherein A.sup.3 is the rest of the target protein.

    [0569] 25. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIc-1:

    ##STR00233##

    wherein A.sup.3 is the rest of the target protein.

    [0570] 26. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIc-2:

    ##STR00234##

    wherein A.sup.3 is the rest of the target protein.

    [0571] 27. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIc-3:

    ##STR00235##

    wherein A.sup.3 is the rest of the target protein.

    [0572] 28. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIc-4:

    ##STR00236##

    wherein A.sup.3 is the rest of the target protein.

    [0573] 29. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIId-1:

    ##STR00237##

    wherein A.sup.3 is the rest of the target protein.

    [0574] 30. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIId-2:

    ##STR00238##

    wherein A.sup.3 is the rest of the target protein.

    [0575] 31. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIe-1:

    ##STR00239##

    wherein A.sup.3 is the rest of the target protein.

    [0576] 32. The compound/target protein complex of embodiment 18, wherein the compound/target protein complex has the structure of Formula IIIe-2:

    ##STR00240##

    wherein A.sup.3 is the rest of the target protein.

    [0577] 33. The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or the compound/target protein complex of any one of embodiments 18 to 33, wherein R is optionally substituted C.sub.3-C.sub.10 cycloalkyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.2-C.sub.6 alkenyl, or optionally substituted C.sub.2-C.sub.6 alkynyl.

    [0578] 34. The compound or compound/target protein complex of embodiment 33, or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted C.sub.3-C.sub.10 cycloalkyl

    [0579] 35. The compound or compound/target protein complex of embodiment 34, or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted cyclopropyl.

    [0580] 36. The compound or compound/target protein complex of embodiment 35, or a pharmaceutically acceptable salt thereof, wherein R is

    ##STR00241##

    [0581] 37. The compound or compound/target protein complex of embodiment 36, or a pharmaceutically acceptable salt thereof, wherein R is

    ##STR00242##

    [0582] 38. The compound or compound/target protein complex of embodiment 33, or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted C.sub.2-C.sub.6 alkenyl, or optionally substituted C.sub.2-C.sub.6 alkynyl.

    [0583] 39. The compound or compound/target protein complex of embodiment 38, or a pharmaceutically acceptable salt thereof, wherein R is

    ##STR00243##

    [0584] 40. The compound of any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or the compound/target protein complex of any one of embodiments 18 to 33, wherein R is a carbocation-stabilizing electron-donating group.

    [0585] 41. The compound or compound/target protein complex of any one of embodiments 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is hydrogen.

    [0586] 42. The compound or compound/target protein complex of any one of embodiments 1 to 41, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl.

    [0587] 43. The compound or compound/target protein complex of embodiment 42, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.3-C.sub.10 cycloalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl.

    [0588] 44. The compound or compound/target protein complex of embodiment 43, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is optionally substituted C.sub.1-C.sub.6 alkyl.

    [0589] 45. The compound or compound/target protein complex of embodiment 43, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is optionally substituted C.sub.3-C.sub.10 cycloalkyl.

    [0590] 46. The compound or compound/target protein complex of embodiment 43, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is optionally substituted 3- to 10-membered heterocycloalkyl.

    [0591] 47. The compound or compound/target protein complex of any one of embodiments 1 to 41, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is:

    ##STR00244##

    [0592] 48. The compound or compound/target protein complex of embodiment 47, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is:

    ##STR00245##

    [0593] 49. The compound or compound/target protein complex of embodiment 48, or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is methyl.

    [0594] 50. The compound or compound/target protein complex of any one of embodiments 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is hydrogen.

    [0595] 51. The compound or compound/target protein complex of any one of embodiments 12 to 50, or a pharmaceutically acceptable salt thereof, wherein A.sup.1 is a protein.

    [0596] 52. The compound or compound/target protein complex of any one of embodiments 12 to 50, or a pharmaceutically acceptable salt thereof, wherein A.sup.1 is a nucleic acid.

    [0597] 53. The compound or compound/target protein complex of any one of embodiments 12 to 50, or a pharmaceutically acceptable salt thereof, wherein A.sup.1 is a small molecule.

    [0598] 54. The compound or compound/target protein complex of any one of embodiments 12 to 50, or a pharmaceutically acceptable salt thereof, wherein A.sup.1 is a macrocyclic small molecule.

    [0599] 55. The compound or compound/target protein complex of any one of embodiments 12 to 50, or a pharmaceutically acceptable salt thereof, wherein A.sup.1 has the structure of Formula IV:

    ##STR00246## [0600] wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds; [0601] A is N(H or CH.sub.3)C(O)(CH.sub.2)where the amino nitrogen is bound to the carbon atom of CH(R.sup.10), optionally substituted C.sub.2-C.sub.4 alkylene, optionally substituted C.sub.1-C.sub.4 heteroalkylene, or optionally substituted C.sub.2-C.sub.4 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; [0602] X.sup.1 is optionally substituted C.sub.1-C.sub.2 alkylene, NR, O, or S(O).sub.n; [0603] X.sup.2 is O or NH; [0604] X.sup.3 is N or CH; [0605] n is 0, 1, or 2; [0606] R is hydrogen, cyano, optionally substituted C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.2-C.sub.4 alkenyl, optionally substituted C.sub.2-C.sub.4 alkynyl, C(O)R, C(O)OR, C(O)N(R).sub.2, S(O)R, S(O).sub.2R, or S(O).sub.2N(R).sub.2; [0607] each R is, independently, H or optionally substituted C.sub.1-C.sub.4 alkyl; [0608] Y.sup.1 is C, CH, or N; [0609] Y.sup.2, Y.sup.3, Y.sup.4, and Y.sup.7 are, independently, C or N; [0610] Y.sup.5 is CH, CH.sub.2 or N; [0611] Y.sup.6 is C(O), CH, CH.sub.2, or N; [0612] R.sup.1 is cyano, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 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 [0613] R.sup.1 and R.sup.2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; [0614] R.sup.2 is absent, hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 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.sup.3 is absent, or R.sup.2 and R.sup.3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; [0615] R.sup.4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; [0616] R.sup.5 is hydrogen, C.sub.1-C.sub.4 alkyl optionally substituted with halogen, cyano, hydroxy, or C.sub.1-C.sub.4 alkoxy, cyclopropyl, or cyclobutyl; [0617] R.sup.6 is hydrogen or methyl; R.sup.7 is hydrogen, halogen, or optionally substituted C.sub.1-C.sub.3 alkyl, or R.sup.6 and R.sup.7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; [0618] R.sup.8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C.sub.1-C.sub.3 alkoxyl, optionally substituted C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 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.sup.7 and R.sup.8 combine with the carbon atom to which they are attached to form CCR.sup.7R.sup.8; CN(OH), CN(OC.sub.1-C.sub.3 alkyl), CO, CS, CNH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; [0619] R.sup.7a and R.sup.8a are, independently, hydrogen, halo, optionally substituted C.sub.1-C.sub.3 alkyl, or combine with the carbon to which they are attached to form a carbonyl; [0620] R.sup.7 is hydrogen, halogen, or optionally substituted C.sub.1-C.sub.3 alkyl; R.sup.8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C.sub.1-C.sub.3 alkoxyl, optionally substituted C.sub.1-C.sub.3 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 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 [0621] R.sup.7 and R.sup.8 combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; [0622] R.sup.9 is hydrogen, F, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or [0623] R.sup.9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R.sup.9 is hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl; [0624] R.sup.10 is hydrogen, halo, hydroxy, C.sub.1-C.sub.3 alkoxy, or C.sub.1-C.sub.3 alkyl; [0625] R.sup.10a is hydrogen or halo; [0626] R.sup.11 is hydrogen or C.sub.1-C.sub.3 alkyl; and [0627] R.sup.34 is hydrogen or C.sub.1-C.sub.3 alkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0628] 56. The compound or compound/target protein complex of any one of embodiments 12 to 50, or a pharmaceutically acceptable salt thereof, wherein A.sup.1 has the structure of Formula V:

    ##STR00247## [0629] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; [0630] X.sup.1 is CH.sub.2 or O; [0631] m is 1 or 2; [0632] n is 0 or 1; [0633] R.sup.1 is hydrogen or optionally substituted 3- to 10-membered heterocycloalkyl; [0634] R.sup.2 is optionally substituted C.sub.1-C.sub.6 alkyl; and [0635] R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl or optionally substituted 3- to 6-membered cycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0636] 57. The compound or compound/target protein complex of any one of embodiments 12 to 50, or a pharmaceutically acceptable salt thereof, wherein A.sup.1 has the structure of Formula VI:

    ##STR00248## [0637] wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; [0638] X.sup.1, X.sup.2, and X.sup.3 are each independently selected from CH.sub.2, CHF, CF.sub.2, CO, or 0; [0639] m is 1 or 2; [0640] n is 0 or 1; [0641] R.sup.1 is hydrogen, optionally substituted C.sub.1-C.sub.6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; [0642] R.sup.2 is optionally substituted C.sub.1-C.sub.6 alkyl; and [0643] R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl, and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0644] 58. The compound or compound/target protein complex of any one of embodiments 12 to 50, wherein A.sup.1 has the structure of any one of Formula VII, VIII, and IX:

    ##STR00249## [0645] wherein o, and p are independently 0, 1, or 2; [0646] q is an integer between 0 and 7; [0647] r is an integer between 0 and 4; [0648] X.sup.4 and X.sup.5 are each, independently, absent, CH.sub.2, O, S, SO, SO.sub.2, or NR.sup.11; [0649] each R.sup.6 and R.sup.7 are independently hydrogen, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl, or R.sup.6 and R.sup.7 combine with the carbon atom to which they are bound to form CO; [0650] each R.sup.8 is, independently, hydroxyl, optionally substituted amino, halogen, thiol, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6heteroalkynyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl, or two R.sup.8 combine to form an optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, or optionally substituted C.sub.2-C.sub.9 heteroaryl; [0651] R.sup.9 is optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl; [0652] R.sup.10 is optionally substituted C.sub.1-C.sub.6 alkyl; [0653] each R.sup.11 is, independently, hydroxyl, cyano, optionally substituted amino, halogen, thiol, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted C.sub.1-C.sub.6 heteroalkyl, optionally substituted C.sub.2-C.sub.6 heteroalkenyl, optionally substituted C.sub.2-C.sub.6 heteroalkynyl, optionally substituted C.sub.3-C.sub.10 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heteroaryl, optionally substituted C.sub.2-C.sub.9 heteroaryl C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.9 heterocyclyl, or optionally substituted C.sub.2-C.sub.9 heterocyclyl C.sub.1-C.sub.6 alkyl; and [0654] R.sup.12 and R.sup.13 are each, independently, hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, optionally substituted C.sub.2-C.sub.6 alkynyl, optionally substituted aryl, C.sub.3-C.sub.7 carbocyclyl, optionally substituted C.sub.6-C.sub.10 aryl C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.3-C.sub.7 carbocyclyl C.sub.1-C.sub.6 alkyl, [0655] and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.

    [0656] 59. A tri-complex comprising a presenter protein, a compound of any one of embodiments 12 to 58, and a target protein.

    [0657] 60. The compound/target protein complex of any one of embodiments 18 to 58, or the tri-complex of embodiment 59, wherein the target protein is a GTPase, GTPase activating protein, 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.

    [0658] 61. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is a GTPase selected from the group consisting of DIRAS1, DIRAS2, DIRAS3, ERAS, GEM, HRAS, KRAS, MRAS, NKIRAS1, NKIRAS2, NRAS, RALA, RALB, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, RASD1, RASD2, RASL10A, RASL10B, RASL11A, RASL11B, RASL12, REM1, REM2, RERG, RERGL, RRAD, RRAS, RRAS2, RHOA, RHOB, RHOBTB1, RHOBTB2, RHOBTB3, RHOC, RHOD, RHOF, RHOG, RHOH, RHOJ, RHOQ, RHOU, RHOV, RND1, RND2, RND3, RAC1, RAC2, RAC3, CDC42, RAB1A, RAB1B, RAB2, RAB3A, RAB3B, RAB3C, RAB3D, RAB4A, RAB4B, RABSA, RAB5B, RAB5C, RAB6A, RAB6B, RAB6C, RAB7A, RAB7B, RAB7L1, RAB8A, RAB8B, RAB9, RAB9B, RABL2A, RABL2B, RABL4, RAB10, RAB11A, RAB11B, RAB12, RAB13, RAB14, RAB15, RAB17, RAB18, RAB19, RAB20, RAB21, RAB22A, RAB23, RAB24, RAB25, RAB26, RAB27A, RAB27B, RAB28, RAB2B, RAB30, RAB31, RAB32, RAB33A, RAB33B, RAB34, RAB35, RAB36, RAB37, RAB38, RAB39, RAB39B, RAB40A, RAB40AL, RAB40B, RAB40C, RAB41, RAB42, RAB43, RAP1A, RAP1B, RAP2A, RAP2B, RAP2C, ARF1, ARF3, ARF4, ARF5, ARF6, ARL1, ARL2, ARL3, ARL4, ARL5, ARL5C, ARL6, ARL7, ARL8, ARL9, ARL10A, ARL10B, ARL10C, ARL11, ARL13A, ARL13B, ARL14, ARL15, ARL16, ARL17, TRIM23, ARL4D, ARFRP1, ARL13B, RAN, RHEB, RHEBL1, RRAD, GEM, REM, REM2, RIT1, RIT2, RHOT1, and RHOT2.

    [0659] 62. The compound/target protein complex or tri-complex of embodiment 61, wherein the target protein is a member of the RAS family.

    [0660] 63. The compound/target protein complex or tri-complex of embodiment 62, wherein the target protein is HRAS, KRAS, or NRAS.

    [0661] 64. The compound/target protein complex or tri-complex of embodiment 63, wherein the target protein is KRAS.

    [0662] 65. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is a GTPase activating factor selected from the group consisting of NF1, IQGAP1, PLEXIN-B1, RASAL1, RASAL2, ARHGAP5, ARHGAP8, ARHGAP12, ARHGAP22, ARHGAP25, BCR, DLC1, DLC2, DLC3, GRAF, RALBP1, RAP1GAP, SIPA1, TSC2, AGAP2, ASAP1, and ASAP3.

    [0663] 66. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is a Guanine nucleotide-exchange factor selected from the group consisting of CNRASGEF, RASGEF1A, RASGRF2, RASGRP1, RASGRP4, SOS1, RALGDS, RGL1, RGL2, RGR, ARHGEF10, ASEF/ARHGEF4, ASEF2, DBS, ECT2, GEF-H1, LARG, NET1, OBSCURIN, P-REX1, P-REX2, PDZ-RHOGEF, TEM4, TIAM1, TRIO, VAV1, VAV2, VAV3, DOCK1, DOCK2, DOCK3, DOCK4, DOCK8, DOCK10, C3G, BIG2/ARFGEF2, EFA6, FBX8, and GEP100.

    [0664] 67. The compound/target protein complex of any one of embodiments 18 to 58, or the tri-complex of embodiment 59, wherein the target protein is a protein with a protein-protein interaction domain selected from the group consisting of ARM, BAR, BEACH, BH, BIR, BRCT, BROMO, BTB, C.sub.1, C.sub.2, CARD, CC, CALM, CH, CHROMO, CUE, DEATH, DED, DEP, DH, EF-hand, EH, ENTH, EVH1, F-box, FERM, FF, FH2, FHA, FYVE, GAT, GEL, GLUE, GRAM, GRIP, GYF, HEAT, HECT, IQ, LRR, MBT, MH1, MH2, MIU, NZF, PAS, PB1, PDZ, PH, POLO-Box, PTB, PUF, PWWP, PX, RGS, RING, SAM, SC, SH2, SH3, SOCS, SPRY, START, SWIRM, TIR, TPR, TRAF, SNARE, TUBBY, TUDOR, UBA, UEV, UIM, VHL, VHS, WD40, WW, SH2, SH3, TRAF, Bromodomain, and TPR.

    [0665] 68. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is a heat shock protein selected from the group consisting of Hsp20, Hsp27, Hsp70, Hsp84, alpha B crystalline, TRAP-1, hsf1, and Hsp90.

    [0666] 69. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is an ion channel selected from the group consisting of Cav2.2, Cav3.2, IKACh, Kv1.5, TRPA1, NAv1.7, Nav1.8, Nav1.9, P2X3, or P2X4.

    [0667] 70. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is a coiled-coil protein selected from the group consisting of geminin, SPAG4, VAV1, MAD1, ROCK1, RNF31, NEDP1, HCCM, EEA1, Vimentin, ATF4, Nemo, SNAP25, Syntaxin 1 a, FYCO1, and CEP250.

    [0668] 71. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is a kinase selected from the group consisting of ABL, ALK, AXL, BTK, EGFR, FMS, FAK, FGFR1, 2, 3, 4, FLT3, HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, IGF1R, INSR, JAK1, JAK2, JAK3, KIT, MET, PDGFRA, PDGFRB, 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, 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.

    [0669] 72. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is a phosphatase selected from the group consisting of WIP1, SHP2, SHP1, PRL-3, PTP1B, and STEP.

    [0670] 73. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is a ubiquitin ligase selected from the group consisting of BMI-1, MDM2, NEDD4-1, Beta-TRCP, SKP2, E6AP, and APC/C.

    [0671] 74. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is a chromatin modifier/remodeler encoded by a gene selected from the group consisting of BRG1, BRM, ATRX, PRDM3, ASH1L, CBP, KAT6A, KAT6B, MLL, NSD1, SETD2, EP300, KAT2A, and CREBBP.

    [0672] 75. The compound/target protein complex or tri-complex of embodiment 60, wherein the target protein is a transcription factor encoded by a gene selected from the group consisting of EHF, ELF1, ELF3, ELF4, ELF5, ELK1, ELK3, ELK4, ERF, ERG, ETS1, ETV1, ETV2, ETV3, ETV4, ETV5, ETV6, FEV, FLI1, GAVPA, SPDEF, SP11, SPIC, SPIB, E2F1, E2F2, E2F3, E2F4, E2F7, E2F8, ARNTL, BHLHA15, BHLHB2, BHLBHB3, BHLHE22, BHLHE23, BHLHE41, CLOCK, FIGLA, HAS5, HES7, HEY1, HEY2, ID4, MAX, MESP1, MLX, MLXIPL, MNT, MSC, MYF6, NEUROD2, NEUROG2, NHLH1, OLIG1, OLIG2, OLIG3, SREBF2, TCF3, TCF4, TFAP4, TFE3, TFEB, TFEC, USF1, ARF4, ATF7, BATF3, CEBPB, CEBPD, CEBPG, CREB3, CREB3L1, DBP, HLF, JDP2, MAFF, MAFG, MAFK, NRL, NFE2, NFIL3, TEF, XBP1, PROX1, TEAD1, TEAD3, TEAD4, ONECUT3, ALX3, ALX4, ARX, BARHL2, BARX, BSX, CART1, CDX1, CDX2, DLX1, DLX2, DLX3, DLX4, DLX5, DLX6, DMBX1, DPRX, DRGX, DUXA, EMX1, EMX2, EN1, EN2, ESX1, EVX1, EVX2, GBX1, GBX2, GSC, GSC2, GSX1, GSX2, HESX1, HMX1, HMX2, HMX3, HNF1A, HNF1B, HOMEZ, HOXA1, HOXA10, HOXA13, HOXA2, HOXAB13, HOXB2, HOXB3, HOXB5, HOXC10, HOXC11, HOXC12, HOXC13, HOXD11, HOXD12, HOXD13, HOXD8, IRX2, IRX5, ISL2, ISX, LBX2, LHX2, LHX6, LHX9, LMX1A, LMX1B, MEIS1, MEIS2, MEIS3, MEOX1, MEOX2, MIXL1, MNX1, MSX1, MSX2, NKX2-3, NKX2-8, NKX3-1, NKX3-2, NKX6-1, NKX6-2, NOTO, ONECUT1, ONECUT2, OTX1, OTX2, PDX1, PHOX2A, PHOX2B, PITX1, PITX3, PKNOX1, PROP1, PRRX1, PRRX2, RAX, RAXL1, RHOXF1, SHOX, SHOX2, TGIF1, TGIF2, TGIF2LX, UNCX, VAX1, VAX2, VENTX, VSX1, VSX2, CUX1, CUX2, POU1F1, POU2F1, POU2F2, POU2F3, POU3F1, POU3F2, POU3F3, POU3F4, POU4F1, POU4F2, POU4F3, POU5F1P1, POU6F2, RFX2, RFX3, RFX4, RFX5, TFAP2A, TFAP2B, TFAP2C, GRHL1, TFCP2, NFIA, NFIB, NFIX, GCM1, GCM2, HSF1, HSF2, HSF4, HSFY2, EBF1, IRF3, IRF4, IRF5, IRF7, IRF8, IRF9, MEF2A, MEF2B, MEF2D, SRF, NRF1, CPEB1, GMEB2, MYBL1, MYBL2, SMAD3, CENPB, PAX1, PAX2, PAX9, PAX3, PAX4, PAX5, PAX6, PAX7, BCL6B, EGR1, EGR2, EGR3, EGR4, GLIS1, GLIS2, GLI2, GLIS3, HIC2, HINFP1, KLF13, KLF14, KLF16, MTF1, PRDM1, PRDM4, SCRT1, SCRT2, SNAI2, SP1, SP3, SP4, SP8, YY1, YY2, ZBED1, ZBTB7A, ZBTB7B, ZBTB7C, ZIC1, ZIC3, ZIC4, ZNF143, ZNF232, ZNF238, ZNF282, ZNF306, ZNF410, ZNF435, ZBTB49, ZNF524, ZNF713, ZNF740, ZNF75A, ZNF784, ZSCAN4, CTCF, LEF1, SOX10, SOX14, SOX15, SOX18, SOX2, SOX21, SOX4, SOX7, SOX8, SOX9, SRY, TCF7L1, FOXO3, FOXB1, FOXC1, FOXC2, FOXD2, FOXD3, FOXG1, FOXI1, FOXJ2, FOXJ3, FOXK1, FOXL1, FOXO1, FOXO4, FOXO6, FOXP3, EOMES, MGA, NFAT5, NFATC1, NFKB1, NFKB2, TP63, RUNX2, RUNX3, T, TBR1, TBX1, TBX15, TBX19, TBX2, TBX20, TBX21, TBX4, TBX5, AR, ESR1, ESRRA, ESRRB, ESRRG, HNF4A, NR2C.sub.2, NR2E1, NR2F1, NR2F6, NR3C.sub.1, NR3C.sub.2, 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-1alpha, Hif-2alpha, Bcl6, E2F1, NF-kappaB, Stat5, and ER(coact).

    [0673] 76. The compound/target protein complex of any one of embodiments 18 to 58, or the tri-complex of embodiment 59, wherein the target protein is selected from the group consisting of TrkA, P2Y14, mPEGS, ASK1, ALK, Bcl-2, BCL-XL, mSIN1, RORt, IL17RA, elF4E, TLR7R, PCSK9, IgE R, CD40, CD40L, Shn-3, TNFR1, TNFR2, IL31RA, OSMR, IL12beta1,2, Tau, FASN, KCTD 6, KCTD 9, Raptor, Rictor, RALGAPA, RALGAPB, Annexin family members, BCOR, NCOR, beta catenin, AAC 11, PLD1, PLD2, Frizzled7, RaLP, MLL-1, Myb, Ezh2, RhoGD12, EGFR, CTLA4R, GCGC (coact), Adiponectin R2, GPR 81, IMPDH2, IL-4R, IL-13R, IL-1R, IL2-R, IL-6R, IL-22R, TNF-R, TLR4, Nrlp3, and OTR.

    [0674] 77. A presenter protein/compound complex comprising a presenter protein and a compound of any one of embodiments 12 to 17 and 33 to 58.

    [0675] 78. The tri-complex of any one of embodiments 59 to 76, or the presenter protein/compound complex of embodiment 77, wherein the presenter protein is a prolyl isomerase.

    [0676] 79. The tri-complex of any one of embodiments 59 to 76, or the presenter protein/compound complex of embodiment 77, wherein the presenter protein is a member of the FKBP family, a member of the cyclophilin family, or PIN1.

    [0677] 80. The tri-complex or the presenter protein/compound complex of embodiment 79, wherein the presenter protein is a member of the FKBP family selected from the group consisting of FKBP12, FKBP12.6, FKBP13, FKBP19, FKBP22, FKBP23, FKBP25, FKBP36, FKBP38, FKBP51, FKBP52, FKBP60, FKBP65, and FKBP133.

    [0678] 81. The tri-complex or the presenter protein/compound complex of embodiment 80, wherein the member of the FKBP family is FKBP12, FKBP12.6, FKBP25, or FKBP52.

    [0679] 82. The tri-complex or the presenter protein/compound complex of embodiment 79, wherein the presenter protein is a member of the cyclophilin family selected from the group consisting of PP1A, CYPB, CYPC, CYP40, CYPE, CYPD, NKTR, SRCyp, CYPH, CWC27, CYPL1, CYP60, CYPJ, PPIL4, PPIL6, RANBP2, PPWD1, PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, and PPIAL4G.

    [0680] 83. The tri-complex or the presenter protein/compound complex of embodiment 82, wherein the member of the cyclophilin family is PPIAL4A, PPIAL4B, PPIAL4C, PPIAL4D, or PPIAL4G.

    [0681] 84. A method of modulating a target protein, the method comprising contacting the target protein with the compound of any one of embodiments 12 to 58 or the presenter protein/compound complex of any one of embodiments 77 to 83.

    [0682] 85. A method of inhibiting a target protein, the method comprising contacting the target protein with the compound of any one of embodiments 12 to 58 or the presenter protein/compound complex of any one of embodiments 77 to 83.

    [0683] 86. A method of activating a target protein, the method comprising contacting the target protein with the compound of any one of embodiments 12 to 58 or the presenter protein/compound complex of any one of embodiments 77 to 83.

    [0684] 87. A method of forming a tri-complex of any one of embodiments 59 to 83, the method comprising contacting a target protein with a presenter protein/compound complex of any one of embodiments 77 to 83.

    [0685] 88. The method of any one of embodiments 84 to 87, wherein upon contacting the target protein, the target protein forms a covalent bond to the compound or the presenter protein/compound complex.

    [0686] 89. The method of embodiment 88, wherein 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 to the compound or the complex.

    [0687] 90. The method of embodiment 89, wherein upon contacting the target protein, an aspartic acid, glutamic acid, cysteine, glutamine, or asparagine residue of the target protein forms a covalent bond to the compound or the complex

    [0688] 91. A method of crosslinking a compound of any one of embodiments 12 to 58 to a second moiety, the method comprising contacting the moiety with the compound under conditions sufficient to form a covalent bond between the compound of any one of embodiments 12 to 58 and the second moiety.

    [0689] 92. The method of embodiment 91, wherein the second moiety is a target protein.

    [0690] 93. A method of forming the presenter protein/compound complex of any one of embodiments 77 to 83, the method comprising contacting a presenter protein with the compound of any one of embodiments 12 to 58 under conditions sufficient to permit the formation of a complex.

    [0691] 94. The method of embodiment 93, wherein the complex is formed by way of noncovalent interactions.

    [0692] 95. A method of forming the tri-complex of any one of embodiments 59 to 83, the method comprising: [0693] a) contacting a presenter protein with the compound of any one of embodiments 12 to 58 under conditions sufficient to permit the formation of presenter protein/compound complex; and [0694] b) contacting the presenter protein/compound complex with a target protein under conditions that permit the formation of a tri-complex.

    [0695] 96. The method of embodiment 95, wherein the presenter protein/compound complex binds to the target protein with at least 5-fold greater affinity than the presenter protein or the compound of any one of embodiments 12 to 58 alone.

    [0696] 97. The method of embodiment 95 or 96, wherein the presenter protein or the compound of any one of embodiments 12 to 58 do not substantially bind to the target protein in the absence of forming the presenter protein/compound complex.

    [0697] 98. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of embodiments 12 to 58.

    [0698] 99. The method of embodiment 98, wherein the subject has previously been treated with a prior therapy.

    [0699] 100. The method of embodiment 98 or 99, wherein the subject has developed resistance to treatment with a prior therapy.

    EXAMPLES

    [0700] The disclosure is further illustrated by the following examples and synthesis examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure or scope of the appended claims.

    Example 1. Synthesis of Compounds

    ##STR00250##

    Step 1: Synthesis of (R,E)-N-(cyclopropylmethylene)-4-methylbenzenesulfonamide

    [0701] To a solution of cyclopropanecarbaldehyde (6 g, 85.60 mmol) in THF (120 mL) was added (R)-4-methylbenzenesulfonamide (13.29 g, 85.60 mmol) and Ti(OEt).sub.4 (39.05 g, 171.21 mmol) at room temperature under N.sub.2. The mixture was stirred at 75 C. for 2 h. The reaction mixture was poured into brine/H.sub.2O (1:1, 600 mL) at 0-15 C. The mixture was filtered through a pad of Celite, and the pad was washed with EtOAc (6200 mL). The combined filtrates were extracted with EtOAc (2200 mL). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography. (0.fwdarw.10% EtOAc/pet. ether) to afford the product (14.6 g, 82% yield) as a solid.

    Step 2: Synthesis of ethyl (2R,3R)-3-cyclopropyl-1-((R)-p-tolylsulfinyl)aziridine-2-carboxylate

    [0702] To a solution of ethyl 2-bromoacetate (23.52 g, 140.86 mmol) in THF (700 mL) was added LiHMDS (1 M, 140.86 mL) at 70 C. over 10 min under N.sub.2. The mixture was stirred at 70 C. for 20 min. A solution of (R,E)-N-(cyclopropylmethylene)-4-methylbenzenesulfonamide (14.6 g, 70.43 mmol) in THE (150 mL) was added into the reaction solution at 70 C. over 10 min. The mixture was stirred at 70 C. for 1 h 20 min under N.sub.2. The reaction mixture was poured into cold H.sub.2O (1.2 L) and stirred at room temperature for 5 min. The aqueous layer was extracted with EtOAc (3300 mL), and the combined organic layers were washed with brine (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography. (0.fwdarw.10% EtOAc/pet. ether) to afford the product (11 g, 53% yield) as an oil. LCMS (ESI) m/z [M+H] calcd for C.sub.15H.sub.20NO.sub.3S: 294.11; found: 294.1.

    Step 3: Synthesis of ethyl (2R,3R)-3-cyclopropylaziridine-2-carboxylate

    [0703] Ethyl (2R,3R)-3-cyclopropyl-1-[(R)-p-tolylsulfinyl]aziridine-2-carboxylate (6 g, 20.45 mmol) was dissolved in anhydrous THF (300 mL). MeMgBr (3 M, 13.63 mL) was added dropwise at 65 C. over 40 min under N.sub.2. The reaction mixture was stirred for 5 min. Sat. aq. NH.sub.4Cl (90 mL) was added dropwise at 65 C. The cooling bath was removed, and the reaction mixture was warmed to room temperature. EtOAc (300 mL) was added, and the organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0.fwdarw.50% EtOAC/pet. ether) to afford the product as an oil.

    Step 4: Synthesis of ethyl (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate

    [0704] To a solution of ethyl (2R,3R)-3-cyclopropylaziridine-2-carboxylate (400 mg, 2.58 mmol) in DCE (8 mL) was added methylboronic acid (462.85 mg, 7.73 mmol), 2,2-bipyridine (402.54 mg, 2.58 mmol), Cu(OAc).sub.2 (468.14 mg, 2.58 mmol), and Na.sub.2CO.sub.3 (819.54 mg, 7.73 mmol). The reaction mixture was stirred at 45 C. for 40 h. The mixture was poured into aq. NH.sub.4Cl (15 mL) and extracted with DCM (315 mL) and the combined organic phases were washed with brine (20 mL), dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0.fwdarw.50% EtOAc/pet. ether) to afford the product (230 mg, 53% yield) as an oil. LCMS (ESI) m/z [M+H] calcd for C.sub.9H.sub.16NO.sub.2: 170.1; found: 170.1.

    Step 5: Synthesis of lithium (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate

    [0705] To a solution of ethyl (2R,3R)-3-cyclopropyl-1-methylaziridine-2-carboxylate (230 mg, 1.36 mmol) in THF (2 mL) was added a solution of LiOH.Math.H.sub.2O (114.07 mg, 2.72 mmol) in H.sub.2O (1 mL). The reaction mixture was stirred at room temperature for 1 h. The pH was adjusted to about 8 with 0.5N HCl at 0 C., and the solution was lyophilized directly to give the product (230 mg, crude) as a solid.

    ##STR00251##

    Step 1: Synthesis of benzyl (2R,3R)-3-cyclopropyl-1-((R)-p-tolylsulfinyl)aziridine-2-carboxylate

    [0706] To a solution of (R)N-(cyclopropylmethylidene)-4-methylbenzenesulfonamide (100 g, 482.4 mmol) and benzyl 2-bromoacetate (143.66 g, 627.1 mmol) in THF (1 L) at 60 C. was added LiHMDS (627.1 mL, 627.1 mmol) dropwise over 30 min. The resulting mixture was stirred at 40 C. for 1.5 h and then cold H.sub.2O (1.5 L) was added. The aqueous layer was extracted with EtOAc (21 L), and the combined organic layers were washed with H.sub.2O (22 L) and brine (2 L), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% EtOAc/pet. ether) to afford the desired product (137 g, 80% yield) as an oil.

    Step 2: Synthesis of benzyl (2R,3R)-3-cyclopropylaziridine-2-carboxylate

    [0707] To a solution of benzyl (2R,3R)-3-cyclopropyl-1-((R)-p-tolylsulfinyl)aziridine-2-carboxylate (60 g, 168.80 mmol) in acetone (786 mL), H.sub.2O (131 mL) and MeOH (102 mL) at 0 C. was added TFA (96.24 g, 844.0 mmol). The resulting mixture was stirred at 0 C. for 60 min and then the reaction mixture was added to NH.sub.3.Math.H.sub.2O (500 mL of 28% NH.sub.3.Math.H.sub.2O in 1 L of H.sub.2O) at 0 C. The resulting mixture was extracted with EtOAc (3700 mL), and the combined organic layers were washed with H.sub.2O (3400 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (9% EtOAc/pet. ether) to afford the desired product. LCMS (ESI) m/z [M+H] calcd for C.sub.13H.sub.15NO.sub.2 218.12; found: 218.3.

    ##STR00252##

    Step 1: Synthesis of ethyl (2R,3R)-3-cyclopropyl-1-ethylaziridine-2-carboxylate

    [0708] To a solution of ethyl (2R,3R)-3-cyclopropylaziridine-2-carboxylate (0.5 g, 3.22 mmol) in DMF (5 mL) at room temperature was added Etl (1.80 mL, 22.55 mmol) and K.sub.2CO.sub.3 (1.78 g, 12.89 mmol). The reaction mixture was stirred for 16 h and was quenched with H.sub.2O (50 mL) at 0 C. The resulting mixture was extracted with EtOAc (315 mL). The combined organic layers were washed with brine (15 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0.fwdarw.25% EtOAc/pet. ether) to afford the product (0.35 g, 59% yield) as an oil.

    Step 2: Synthesis of lithium (2R,3R)-3-cyclopropyl-1-ethylaziridine-2-carboxylate

    [0709] To a solution of ethyl (2R,3R)-3-cyclopropylaziridine-2-carboxylate (0.12 g, 654.85 mol) in THF (1.2 mL) at 0 C. was added a solution of LiOH.Math.H.sub.2O (54.96 mg, 1.31 mmol) in H.sub.2O (0.4 mL). The reaction mixture was warmed to room temperature and stirred for 4 h. The mixture was adjusted to pH=7-8 and lyophilized to afford the product (0.18 g, crude) as a white solid.

    ##STR00253##

    Step 1: Synthesis of ethyl (2R,3R)-3-cyclopropyl-1-(2-fluoroethyl)aziridine-2-carboxylate

    [0710] To a solution of ethyl (2R,3R)-3-cyclopropylaziridine-2-carboxylate (300 mg, 1.93 mmol) in DMF (3 mL) at room temperature was added 1-fluoro-2-iodoethane (1.68 g, 9.67 mmol) and K.sub.2CO.sub.3 (1.60 g, 11.60 mmol). The reaction mixture was stirred a 50 C. for 15 h. The reaction mixture was then cooled to room temperature and quenched with H.sub.2O (30 mL). The resulting mixture was extracted with EtOAc (315 mL), and the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (33% EtOAc/pet. ether) to afford the product (120 mg, 31% yield) as an oil. LCMS (ESI) m/z [M+H] calcd for C.sub.10H.sub.16FNO.sub.2: 202.12; found: 202.2.

    Step 2: Synthesis of lithium (2R,3R)-3-cyclopropyl-1-(2-fluoroethyl)aziridine-2-carboxylate

    [0711] To a solution of ethyl (2R,3R)-3-cyclopropyl-1-(2-fluoroethyl)aziridine-2-carboxylate (100 mg, 496.93 mol) in THF (1 mL) and H.sub.2O (0.3) at room temperature was added LiOH.Math.H.sub.2O (41.71 mg, 993.85 mol). The reaction mixture was stirred for 1 h. The mixture was quenched with H.sub.2O (3 mL) and the resulting mixture was lyophilized to afford the product (90 mg, crude) as a solid.

    ##STR00254##

    Step 1: Synthesis of ethyl (2R,3R)-3-cyclopropyl-1-(2,2-difluoroethyl)aziridine-2-carboxylate

    [0712] To a solution of ethyl (2R,3R)-3-cyclopropylaziridine-2-carboxylate (120 mg, 773.23 mol) in DMF (2 mL) at room temperature was added 2,2-difluoroethyl trifluoromethanesulfonate (281.45 mg, 1.31 mmol) and K.sub.2CO.sub.3 (534.32 mg, 3.87 mmol). The reaction mixture was stirred for 15 h and was then quenched with sat. NH.sub.4Cl (5 mL). The resulting mixture was extracted with EtOAc (33 mL), and the combined organic layers were washed with brine (5 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0.fwdarw.25% EtOAc/pet. ether) to afford the product (80 mg, 47% yield) as an oil.

    Step 2: Synthesis of lithium (2R,3R)-3-cyclopropyl-1-(2,2-difluoroethyl)aziridine-2-carboxylate

    [0713] To a solution of ethyl (2R,3R)-3-cyclopropyl-1-(2,2-difluoroethyl)aziridine-2-carboxylate (130 mg, 592.99 mol) in THF (1.3 mL) at room temperature was added a solution of LiOH.Math.H.sub.2O (49.77 mg, 1.19 mmol) in H.sub.2O (0.6 mL). The reaction mixture was stirred for 1 h. The mixture was quenched with H.sub.2O (4 mL) and the resulting mixture was lyophilized to afford the product (100 mg, crude) as a solid.

    ##STR00255##

    Step 1: ethyl (2R,3R)-1,3-dicyclopropylaziridine-2-carboxylate

    [0714] To a solution of ethyl (2R,3R)-3-cyclopropylaziridine-2-carboxylate (50 mg, 322.18 mol) in DCE (1 mL) was added cyclopropylboronic acid (83.02 mg, 966.53 mol), 2,2-bipyridine (50.32 mg, 322.18 mol), Cu(OAc).sub.2 (58.52 mg, 322.18 mol), and Na.sub.2CO.sub.3 (102.44 mg, 966.53 mol). The reaction mixture was stirred at room temperature for 16 h. The mixture was poured into brine (5 mL) and extracted with DCM (33 mL). The combined organic phases were washed with brine, dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (33% EtOAc/pet. ether) to give the product (35 mg, 56% yield) as an oil.

    Step 2: lithium (2R,3R)-1,3-dicyclopropylaziridine-2-carboxylate

    [0715] To a solution of ethyl (2R,3R)-1,3-dicyclopropylaziridine-2-carboxylate (80 mg, 409.72 mol) in THF (1 mL) was added a solution of LiOH.Math.H.sub.2O (34.39 mg, 819.43 mol) in H.sub.2O (0.5 mL). The reaction mixture was stirred at room temperature for 1 h and was then quenched with H.sub.2O (4 mL). The solution was lyophilized directly to give the product (100 mg, crude) as a solid.

    ##STR00256##

    Step 1: Synthesis of ethyl (2R,3R)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-cyclopropylaziridine-2-carboxylate

    [0716] To a solution of ethyl (2R,3R)-3-cyclopropylaziridine-2-carboxylate (320 mg, 2.06 mmol) in DMF (3 mL) at room temperature was added (2-bromoethoxy)(tert-butyl)dimethylsilane (2.46 g, 10.30 mmol) and K.sub.2CO.sub.3 (1.14 g, 8.24 mmol). The reaction mixture was heated to 75 C. and stirred for 24 h. The reaction mixture was then cooled to room temperature and quenched with H.sub.2O (50 mL). The resulting mixture was extracted with EtOAc (330 mL), and the combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0.fwdarw.100% EtOAc/pet. ether) to afford the product (410 mg, 64% yield) as an oil. LCMS (ESI) m/z [M+H] calcd for C.sub.16H.sub.31NO.sub.3Si: 314.22; found: 314.1.

    Step 2: Synthesis of lithium (2R,3R)-3-cyclopropyl-1-(2-hydroxyethyl)aziridine-2-carboxylate

    [0717] To a solution of ethyl (2R,3R)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-cyclopropylaziridine-2-carboxylate (410 mg, 1.31 mmol) in THF (4 mL) at 0 C. was added a solution of LiOH.Math.H.sub.2O (219.50 mg, 5.23 mmol) in H.sub.2O (2 mL). The reaction mixture was stirred for 24 h. The mixture was quenched with H.sub.2O (5 mL) and the resulting mixture was lyophilized to afford the product (330 mg, crude) as a solid. LCMS (ESI) m/z [M+H] calcd for C.sub.8H.sub.13NO.sub.3: 172.09; found: 172.1.

    ##STR00257##

    Step 1: Synthesis of ethyl 2,3-dibromo-3-cyclopropylpropanoate

    [0718] To a solution of Br.sub.2 (5.0 mL, 97.38 mmol) in DCM (30 mL) was added to a solution of ethyl (E)-3-cyclopropylacrylate (13 g, 92.74 mmol) in DCM (100 mL). The mixture was stirred at room temperature for 5 min. The reaction mixture was then added to H.sub.2O (100 mL) and the aqueous layer was extracted with DCM (350 mL). The combined organic layers were washed with brine (80 mL), dried with Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0.fwdarw.9% EtOAc/pet. ether) to afford the desired product (8 g, 29% yield) as an oil.

    Step 2: Synthesis of ethyl 3-cyclopropyl-1-(oxetan-3-yl)aziridine-2-carboxylate

    [0719] To a solution of oxetan-3-amine (65.79 g, 900.0 mmol) in EtOH (45 mL) at 0 C. was added a solution of ethyl 2,3-dibromo-3-cyclopropylpropanoate (9 g, 30.0 mmol) in EtOH (45 mL). The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0.fwdarw.50% EtOAc/pet. ether) to afford the desired product (3.9 g, 62% yield) as a solid. LCMS (ESI) m/z [M+H] calcd for C.sub.11H.sub.17NO.sub.3: 212.13; found: 212.1.

    Step 3: Synthesis of ethyl (2S,3S)-3-cyclopropyl-1-(oxetan-3-yl)aziridine-2-carboxylate and ethyl

    [0720] (2R,3R)-3-cyclopropyl-1-(oxetan-3-yl)aziridine-2-carboxylate Ethyl 3-cyclopropyl-1-(oxetan-3-yl)aziridine-2-carboxylate (1.5 g) was purified by prep-SFC (Daicel CHIRALPAK IC (250 mm30 mm, 10 m); 25% EtOH/CO.sub.2) then the solution was concentrated under reduced pressure to afford ethyl (2S,3S)-3-cyclopropyl-1-(oxetan-3-yl)aziridine-2-carboxylate (600 mg, 40% yield) and ethyl (2R,3R)-3-cyclopropyl-1-(oxetan-3-yl)aziridine-2-carboxylate (600 mg, 40% yield) as oils. LCMS (ESI) m/z [M+H] calcd for C.sub.11H.sub.17NO.sub.3: 212.13; found: 212.1.

    Step 4: Synthesis of lithium (2S,3S)-3-cyclopropyl-1-(oxetan-3-yl)aziridine-2-carboxylate

    [0721] To a solution of ethyl (2S,3S)-3-cyclopropyl-1-(oxetan-3-yl)aziridine-2-carboxylate (250 mg, 1.18 mmol) in THF (2.5 mL) at 0 C. was added a solution of LiOH.Math.H.sub.2O (99.31 mg, 2.37 mmol) in H.sub.2O (1.25 mL). The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with H.sub.2O (4 mL) and lyophilized directly to afford the desired product (200 mg, 89% yield) as a solid.

    Step 5: Synthesis of lithium (2R,3R)-3-cyclopropyl-1-(oxetan-3-yl)aziridine-2-carboxylate

    [0722] To a solution of ethyl (2S,3S)-3-cyclopropyl-1-(oxetan-3-yl)aziridine-2-carboxylate (250 mg, 1.18 mmol) in THF (2.5 mL) at 0 C. was added a solution of LiOH.Math.H.sub.2O (99.32 mg, 2.37 mmol) in H.sub.2O (1.25 mL). The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was diluted with H.sub.2O (4 mL) and lyophilized directly to afford the desired product (200 mg, 89% yield) as a solid.

    ##STR00258##

    Step 1: Synthesis of ethyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropanoate

    [0723] A solution of ethyl (E)-3-cyclopropylacrylate (10.4 mL, 71 mmol) in tert-BuOH (270 mL) and H.sub.2O (270 mL) was stirred at 0 C. After 5 min MsNH.sub.2 (6.8 g, 71 mmol) and (DHQD).sub.2PHAL (100 g, 130 mmol) were added and the reaction mixture was warmed to room temperature. After stirring overnight, sat. Na.sub.2SO.sub.3 was added and the mixture was stirred for 30 min. The mixture was acidified to pH 6 with KH.sub.2PO.sub.4. Purification by silica gel column chromatography (33% EtOAc/pet. ether) afforded desired product (5.5 g, 44% yield).

    Step 2: Synthesis of ethyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-(((4-nitrophenyl)sulfonyl)oxy)propanoate

    [0724] A solution of ethyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropanoate (5.40 g, 31.0 mmol) and Et.sub.3N (13.0 mL, 93.0 mmol) in DCM (20 mL) was stirred at 0 C. and a solution of 4-nitrobenzenesulfonyl chloride (6.53 g, 29.5 mmol) in DCM (10 mL) was added. The reaction mixture was stirred for 1.5 h and was then extracted with DCM (3200 mL). The combined organic layers were washed with brine (100 mL), dried with Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (33% EtOAc/pet. ether) afforded desired product (6.9 g, 62% yield).

    Step 3: Synthesis of ethyl (2R,3R)-2-azido-3-cyclopropyl-3-hydroxypropanoate

    [0725] A mixture of ethyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-(((4-nitrophenyl)sulfonyl)oxy)propanoate (6.90 g, 19.2 mmol) and NaN.sub.3 (6.24 g, 96.0 mmol) in DMF (70.0 mL) was heated to 50 C. The reaction mixture was stirred for 5 h and then extracted with EtOAc (3200 mL). The combined organic layers were washed with brine (100 mL), dried with Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20% EtOAc/pet. ether) afforded desired product (2.8 g, 73% yield).

    Step 4: Synthesis of ethyl (2R,3S)-3-cyclopropylaziridine-2-carboxylate

    [0726] A mixture of triphenylphosphine (1.84 g, 7.02 mmol) in DMF (5 mL) was stirred at 0 C. After 5 min ethyl (2R,3R)-2-azido-3-cyclopropyl-3-hydroxypropanoate (1.40 g, 7.03 mmol) was added and the reaction was warmed to room temperature. The reaction mixture was heated to 80 C. and stirred for 1 h. The mixture was then cooled to room temperature and extracted with EtOAc (350 mL). The combined organic layers were washed with brine (50 mL), dried with Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20% EtOAc/pet. ether) afforded the desired product (230 mg, 46% yield). LCMS (ESI) m/z: [M+H] calcd for C.sub.8H.sub.13NO.sub.2: 156.10; found 156.2.

    Step 5: Synthesis of lithium (2R,3S)-3-cyclopropylaziridine-2-carboxylate

    [0727] To a mixture of ethyl (2R,3S)-3-cyclopropylaziridine-2-carboxylate (230 mg, 1.5 mmol) in MeOH (3.0 mL) was added LiOH.Math.H.sub.2O (125 mg, 3.0 mmol). The reaction was stirred for 3 h and then filtered. The filtrate was concentrated under reduced pressure which afforded the desired product (150 mg, crude). LCMS (ESI) m/z: [M+H] calcd for C.sub.6H.sub.9NO.sub.2: 128.07; found 128.2.

    ##STR00259##

    Step 1: Synthesis of ethyl (2S,3R)-3-cyclopropylaziridine-2-carboxylate

    [0728] A mixture of PPh.sub.3 (1.4 g, 5.4 mmol) in DMF (15.0 mL) was stirred at 0 C. After 30 min, ethyl (2S,3S)-2-azido-3-cyclopropyl-3-hydroxypropanoate (980 mg, 4.92 mmol) was added. The reaction mixture was heated to 80 C. After 2 h the reaction was quenched by the addition of H.sub.2O (20 mL) and was extracted with EtOAc (330 mL). Purification by silica gel column chromatography (17% EtOAc/pet. ether) afforded desired product (500 mg, 65% yield).

    Step 2: Synthesis of lithium (2S,3R)-3-cyclopropylaziridine-2-carboxylate

    [0729] To a solution of ethyl (2S,3R)-3-cyclopropylaziridine-2-carboxylate (450 mg, 2.9 mmol) in THE (6.0 mL) and H.sub.2O (2.0 mL) was added LiOH (90 mg, 3.8 mmol). The reaction was stirred for 2 h and then filtered. The filtrate was concentrated under reduced pressure which afforded the desired product (300 mg, crude).

    ##STR00260##

    Step 1: Synthesis of (S,E)-N-benzylidene-2-methylpropane-2-sulfinamide

    [0730] A solution of (S)-2-methylpropane-2-sulfinamide (2.50 g, 20.6 mmol), titanium ethoxide (9.41 g, 41.25 mmol) and benzaldehyde (2.19 g, 20.7 mmol) was heated at 70 C. for 1 h, cooled, and diluted with H.sub.2O (250 mL). The aqueous layer was extracted with EtOAc (380 mL), and the combined organic layers were washed with brine (2100 mL), dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the desired product (4.3 g, crude) which was used without further purification. LCMS (ESI) m/z: [M+H] calcd for C.sub.11H.sub.15NOS: 210.10; found 210.2.

    Step 2: Synthesis of ethyl (2S,3S)-1-((S)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylate

    [0731] To a solution of ethyl bromoacetate (798 mg, 4.78 mmol) in THF (15 mL) at 78 C. was added LiHMDS (1 M in THF, 4.78 mL, 4.78 mmol). After 1 h, (S,E)-N-benzylidene-2-methylpropane-2-sulfinamide (500 mg, 2.39 mmol) in THF (5 mL) was added in portions over 20 min. The reaction mixture was stirred at 78 C. for 2 h and then quenched by the addition of sat. NH.sub.4Cl. The aqueous layer was extracted with EtOAc (340 mL), and the combined organic layers were washed with brine (230 mL), dried with Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. Purification by reverse phase chromatography (30.fwdarw.60% MeCN/H.sub.2O, 0.1% HCO.sub.2H) afforded the desired product (480 mg, 61% yield). LCMS (ESI) m/z: [M+H] calcd for C.sub.15H.sub.21NO.sub.3S: 296.13; found 296.2.

    Step 3: Synthesis lithium (2S,3S)-1-((S)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylate

    [0732] To a solution of ethyl (2S,3S)-1-((S)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylate (600 mg, 2.03 mmol) in THF (4.0 mL) at 0 C. was added a solution of LiOH (97.2 mg, 4.06 mmol) in H.sub.2O (4.0 mL). The resulting mixture was stirred for 2 h at 0 C. and then acidified to pH 5 with 1 M HCl. The aqueous layer was extracted with EtOAc (340 mL), and the combined organic layers were washed with brine (220 mL), dried with Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford the desired compound (450 mg, crude) which was used without further purification. LCMS (ESI) m/z: [M+H] calcd for C.sub.13H.sub.17NO.sub.3S: 268.10; found 268.1.

    ##STR00261##

    Step 1: Synthesis (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide

    [0733] A solution (R)-2-methylpropane-2-sulfinamide (2.50 g, 20.6 mmol), titanium tetraethoxide (9.41 g, 41.3 mmol) and benzaldehyde (2.19 g, 20.6 mmol) was heated 70 C. for 1 h, cooled, and diluted with H.sub.2O (250 mL). The aqueous layer was extracted with EtOAc (390 mL), and the combined organic layers were washed with brine (2100 mL), dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the desired product (4.2 g, crude) which was used without further purification. LCMS (ESI) m/z: [M+H] calcd for C.sub.11H.sub.15NOS: 210.10; found 210.1.

    Step 2: Synthesis of ethyl (2R,3R)-1-((R)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylate

    [0734] To a solution of ethyl bromoacetate (6.38 g, 38.2 mmol) in THF (150 mL) at 78 C. was added LiHMDS (1 M in THF, 7.19 mL, 42.9 mmol). After 1 h, (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide (4.0 g, 19.1 mmol) in THF (50 mL) was added in portions over 20 min. The reaction mixture was stirred at 78 C. for 2 h and then quenched by the addition of sat. NH.sub.4Cl. The aqueous layer was extracted with EtOAc (380 mL), and the combined organic layers were washed with brine (260 mL), dried with Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Purification by reverse phase chromatography (30.fwdarw.60% MeCN/H.sub.2O, 0.1% HCO.sub.2H) afforded the desired product (3.9 g, 62% yield). LCMS (ESI) m/z: [M+H] calcd for C.sub.15H.sub.21NO.sub.3S: 296.13; found 296.2.

    Step 3: Synthesis lithium (2R,3R)-1-((R)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylate

    [0735] To a solution of ethyl (2R,3R)-1-((R)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylate (200 mg, 0.677 mmol) in THF (1.5 mL) at 0 C. was added a solution of LiOH (32.4 mg, 1.35 mmol) in H.sub.2O (1.3 mL). The resulting mixture was stirred for 2 h at 0 C. and then acidified to pH 5 with 1 M HCl. The aqueous layer was extracted with EtOAc (320 mL), and the combined organic layers were washed with brine (210 mL), dried with Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford the desired compound (220 mg, crude) which was used without further purification. LCMS (ESI) m/z: [M+H] calcd for C.sub.13H.sub.17NO.sub.3S: 268.10; found 268.4.

    ##STR00262##

    Step 1: Synthesis of (E)-N-(4-methoxybenzylidene)-2-methylpropane-2-sulfinamide

    [0736] A solution of (S)-2-methylpropane-2-sulfinamide (2.50 g) and anisaldehyde (2.81 g) in Ti(OEt).sub.4 (20.0 mL) was stirred at 70 C. for 1 h. The resulting mixture was cooled to room temperature, diluted with EtOAc (60 mL), and then poured into H.sub.2O. The mixture was filtered, and the filter cake was washed with EtOAc (350 mL). The resulting mixture was extracted with EtOAc (350 mL), and the combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% EtOAc/pet. ether) to afford the desired product (4 g, 81% yield). LCMS (ESI) m/z: [M+H] calcd for C.sub.12H.sub.17NO.sub.2S: 240.11; found 240.1.

    Step 2: Synthesis of ethyl (2S,3S)-1-(tert-butylsulfinyl)-3-(4-methoxyphenyl)aziridine-2-carboxylate

    [0737] To a solution of ethyl 2-bromoacetate (5.60 g, 33.5 mmol) in THF (100 mL) at 78 C. was added LiHMDS (1 M in THF, 34 mL, 33.473 mmol). After 30 min a solution of (E)-N-(4-methoxybenzylidene)-2-methylpropane-2-sulfinamide (4 g, 16.74 mmol) in THF (20 mL) was added. The resulting mixture was stirred at 78 C. for an additional 3 h. The reaction was then quenched with sat. aq. NH.sub.4Cl. The mixture was extracted with EtOAc (3100 mL), and the combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25% EtOAc/pet. Ether) to afford the desired product (2.7 g, 50% yield). LCMS (ESI) m/z: [M+H] calcd for C.sub.16H.sub.23NO.sub.4S: 326.14; found 326.1.

    Step 3: Synthesis of lithium (2S,3S)-1-((S)-tert-butylsulfinyl)-3-(4-methoxyphenyl)aziridine-2-carboxylate

    [0738] To a solution of ethyl (2S,3S)-1-(tert-butylsulfinyl)-3-(4-methoxyphenyl)aziridine-2-carboxylate (800.0 mg, 2.68 mmol) in THF (2.0 mL) at 0 C. was added a solution of LiOH.Math.H.sub.2O (309.46 mg, 7.38 mmol) in H.sub.2O (3.0 mL). The resulting mixture was warmed to room temperature and stirred for 4 h. The mixture was then acidified to pH 6 with sat. aq. NH.sub.4Cl and then extracted with EtOAc (350 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered. And concentrated under reduced pressure to afford the desired product (690 mg, 94% yield). LCMS (ESI) m/z: [MH] calcd for C.sub.14H.sub.19NO.sub.4S: 296.10; found 296.2.

    ##STR00263##

    Step 1: Synthesis of ethyl (2R,3S)-2,3-dihydroxy-3-(4-methoxyphenyl)propanoate

    [0739] To a solution of ethyl p-methoxycinnamate (5.0 g, 24.24 mmol) in tBuOH (70.0 mL) and H.sub.2O (70.0 mL) at 0 C. was added AD-mix- (33.80 g, 43.39 mmol) and methanesulfonamide (2.31 mg, 0.024 mmol). The resulting mixture was warmed to room temperature and stirred overnight. The reaction was then cooled to 0 C. and quenched with KHSO.sub.4 (aq.). The mixture was extracted with EtOAc (3100 mL), and the combined organic layers were washed with brine (290 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc/pet. ether) to afford the desired product (5.7 g, 88% yield).

    Step 2: Synthesis of ethyl (2R,3S)-3-hydroxy-3-(4-methoxyphenyl)-2-(((4-nitrophenyl)sulfonyl)oxy)propanoate

    [0740] To a solution of ethyl (2R,3S)-2,3-dihydroxy-3-(4-methoxyphenyl)propanoate (3.0 g, 12.49 mmol) and Et.sub.3N (0.174 mL, 1.249 mmol) in DCM (30.0 mL) at 0 C. was added 4-nitrobenzenesulfonyl chloride (2.76 g, 12.49 mmol). The resulting mixture was stirred for 1 h and was then diluted with H.sub.2O. The mixture was extracted with DCM (3100 mL) and the combined organic layers were washed with brine (2100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (50% EtOAc/pet. ether) to afford the desired product (3.8 g, 68% yield). LCMS (ESI) m/z: [M+Na] calcd for C.sub.18H.sub.19NO.sub.9S: 448.07; found 448.2.

    Step 3: Synthesis of ethyl (2S,3S)-2-azido-3-hydroxy-3-(4-methoxyphenyl)propanoate

    [0741] To a solution of ethyl (2R,3S)-3-hydroxy-3-(4-methoxyphenyl)-2-(((4-nitrophenyl)sulfonyl)oxy)propanoate (1.20 g, 2.82 mmol) in THF at 0 C. was added TBAF (1 M in THF, 5.64 mL, 5.64 mmol) and TMSN.sub.3 (648.79 mg, 5.64 mmol). The resulting mixture was heated at 60 C. and stirred for 16 h. The reaction was then cooled to 0 C. and quenched with sat. aq. NH.sub.4Cl. The mixture was extracted with EtOAc (3100 mL), and the combined organic layers were washed with H.sub.2O (2100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (33% EtOAc/pet. ether) to afford the desired product (540 mg, 71% yield).

    Step 4: Synthesis of ethyl (2S,3R)-3-(4-methoxyphenyl)aziridine-2-carboxylate

    [0742] To a solution of ethyl (2S,3S)-2-azido-3-hydroxy-3-(4-methoxyphenyl)propanoate (440.0 mg, 1.659 mmol) in DMF was added PPh.sub.3 (522.06 mg, 1.99 mmol). The resulting mixture was stirred at room temperature for 30 min and was then heated to 80 C. and stirred overnight. The mixture was then extracted with EtOAc (3100 mL), and the combined organic layers were washed with H.sub.2O (2100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (25% EtOAc/pet. ether) to afford the desired product (200 mg, 52% yield). LCMS (ESI) m/z: [M+H] calcd for C.sub.12H.sub.15NO.sub.3: 222.12; found 222.1.

    Step 5: Synthesis of lithium (2S,3R)-3-(4-methoxyphenyl)aziridine-2-carboxylate

    [0743] To a solution of ethyl (2S,3R)-3-(4-methoxyphenyl)aziridine-2-carboxylate (200.0 mg, 0.904 mmol) in MeOH and H.sub.2O at 0 C. was added LiOH.Math.H.sub.2O (86.6 mg, 3.62 mmol). The resulting mixture was stirred for 1 h and was then neutralized to pH 7 with HCl (aq.). The mixture was extracted with EtOAc (3100 mL), and the combined organic layers were washed with H.sub.2O (2100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford the desired product (180 mg, 98% yield). LCMS (ESI) m/z: [MH] calcd for C.sub.10H.sub.11NO.sub.3: 192.07; found 192.0.

    ##STR00264##

    Step 1: Synthesis of ethyl (2S,3R)-2,3-dihydroxy-3-(4-methoxyphenyl)propanoate

    [0744] To a solution of ethyl p-methoxycinnamate (5.0 g, 24.24 mmol) in tBuOH (70.0 mL) and H.sub.2O (70.0 mL) at 0 C. was added AD-mix-B (33.80 g, 43.39 mmol) and methanesulfonamide (2.31 mg, 0.024 mmol). The resulting mixture was warmed to room temperature and stirred overnight. The reaction was then cooled to 0 C. and quenched with KHSO.sub.4 (aq.). The mixture was extracted with EtOAc (3100 mL), and the combined organic layers were washed with brine (290 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc/pet. ether) to afford the desired product (5.7 g, 88% yield).

    Step 2: Synthesis of ethyl (2S,3R)-3-hydroxy-3-(4-methoxyphenyl)-2-(((4-nitrophenyl)sulfonyl)oxy)propanoate

    [0745] To a solution of ethyl (2S,3R)-2,3-dihydroxy-3-(4-methoxyphenyl)propanoate (5.80 g, 24.14 mmol) and Et.sub.3N (10.1 mL, 72.42 mmol) in DCM (30.0 mL) at 0 C. was added 4-nitrobenzenesulfonyl chloride (5.34 g, 24.1 mmol). The resulting mixture was stirred for 1 h and was then diluted with H.sub.2O. The mixture was extracted with DCM (3100 mL) and the combined organic layers were washed with brine (2100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (50% EtOAc/pet. ether) to afford the desired product (7.2 g, 67% yield). LCMS (ESI) m/z: [M+H] calcd for C.sub.18H.sub.19NO.sub.9S: 426.09; found 426.2.

    Step 3: Synthesis of ethyl (2R,3R)-2-azido-3-hydroxy-3-(4-methoxyphenyl)propanoate

    [0746] To a solution of ethyl (2S,3R)-3-hydroxy-3-(4-methoxyphenyl)-2-(((4-nitrophenyl)sulfonyl)oxy)propanoate (5.0 g, 11.75 mmol) in THF at 0 C. was added TBAF (1 M in THF, 23.5 mL, 23.51 mmol) and TMSN.sub.3 (2.7 g, 23.5 mmol). The resulting mixture was heated to 60 C. and stirred for 16 h. The reaction was then cooled to 0 C. and quenched with sat. aq. NH.sub.4Cl. The mixture was extracted with EtOAc (3100 mL), and the combined organic layers were washed with H.sub.2O (2100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (33% EtOAc/pet. ether) to afford the desired product (2.3 g, 70% yield).

    Step 4: Synthesis of ethyl (2R,3S)-3-(4-methoxyphenyl)aziridine-2-carboxylate

    [0747] To a solution of ethyl (2R,3R)-2-azido-3-hydroxy-3-(4-methoxyphenyl)propanoate (2.30 g, 8.67 mmol) in DMF was added PPh.sub.3 (2.73 g, 10.4 mmol). The resulting mixture was stirred at room temperature for 30 min and was then heated to 80 C. and stirred overnight. The mixture was then extracted with EtOAc (3100 mL), and the combined organic layers were washed with H.sub.2O (2100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (25% EtOAc/pet. ether) to afford the desired product (1.6 g, 79% yield). LCMS (ESI) m/z: [M+H] calcd for C.sub.12H.sub.15NO.sub.3: 222.12; found 222.1.

    Step 5: Synthesis of lithium (2R,3S)-3-(4-methoxyphenyl)aziridine-2-carboxylate

    [0748] To a solution of ethyl (2S,3R)-3-(4-methoxyphenyl)aziridine-2-carboxylate (200.0 mg, 0.904 mmol) in MeOH and H.sub.2O at 0 C. was added LiOH.Math.H.sub.2O (86.6 mg, 3.62 mmol). The resulting mixture was stirred for 1 h and was then neutralized to pH 7 with HCl (aq.). The mixture was extracted with EtOAc (3100 mL) and the combined organic layers were washed with H.sub.2O (2100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to afford the desired product (180 mg, 98% yield). LCMS (ESI) m/z: [MH] calcd for C.sub.10H.sub.11NO.sub.3: 192.07; found 192.0.

    Other Embodiments

    [0749] While the disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the disclosure that come within known or customary practice within the art to which the disclosure pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.

    [0750] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.