Inhibitors of cyclin-dependent kinase 7 (cdk7)

A method of treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

• or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable excipient;
• wherein:
• R1 is —NRaRb, —CHRaRb, or —ORa, wherein each of Ra and Rb is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or Ra and Rb are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
• each of R3 and R4 is independently hydrogen, halogen, optionally substituted C1-C6 alkyl, or optionally substituted aryl, or R3 and R4 are joined to form an optionally substituted C3-C6 carbocyclyl ring;
• R5 is independently hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
• L1 is —NRL1—, —NRL1C(═O)—, —C(═O)NRL1—, —O—, or —S—, wherein RL1 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
• Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• L2 is a bond, —C(═O)—, —NRL2—, —C(═O)NRL2—, —NRL2C(═O)—, —O—, or —S—, wherein RL2 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protection group;
• Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• and
• R2 is any of Formulae (i-1)-(i-42):
• wherein:
• L3 is a bond or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b=CRL3b—, cis-CRL3b═CRL3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NRL3a—, —NRL3aS(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—, wherein RL3a is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RL3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
• L4 is a bond or an optionally substituted, branched or unbranched C1-6 hydrocarbon chain;
• each of RE1, RE2, and RE3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH2OREE, —CH2N(REE)2, —CH2SREE, —OREE, —N(REE)2, —Si(REE)3, and —SREE, wherein each occurrence of REE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two REE groups are joined to form an optionally substituted heterocyclic ring;
• or RE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
• RE4 is a leaving group;
• RE5 is halogen;
• RE6 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
• each instance of Y is independently O, S, or NRE7, wherein RE7 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
• a is 1 or 2;
• and
• each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.

A method of inhibiting the activity of a cyclin-dependent kinase (CDK) in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of Formula (I):

• or a pharmaceutically acceptable salt, solvate hydrate tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable excipient;
• wherein:
• R1 is —NRaRb, —CHRaRb, or —ORa, wherein each of Ra and Rb is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or Ra and Rb are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
• each of R3 and R4 is independently hydrogen, halogen, optionally substituted C1-C6 alkyl, or optionally substituted aryl, or R3 and R4 are joined to form an optionally substituted C3-C6 carbocyclyl ring;
• R5 is independently hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
• L1 is —NRL1—, —NRL1C(═O)—, —C(═O)NRL1—, —O—, or —S—, wherein RL1 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
• Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• L2 is a bond, —C(═O)—, —NRL2—, —C(═O)NRL2—, —NRL2C(═O)—, —O—, or —S—, wherein RL2 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protection group;
• Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• and
• R2 is any of Formulae (i-1)-(i-42):
• wherein:
• L3 is a bond or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b=CRL3b—, cis-CRL3b═CRL3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NRL3a—, —NRL3aS(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—, wherein RL3a is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RL3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
• L4 is a bond or an optionally substituted, branched or unbranched C1-6 hydrocarbon chain;
• each of RE1, RE2, and RE3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH2OREE, —CH2N(REE)2, —CH2SREE, —OREE, —N(REE)2, —Si(REE)3, and —SREE, wherein each occurrence of REE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two REE groups are joined to form an optionally substituted heterocyclic ring;
• or RE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
• RE4 is a leaving group;
• RE5 is halogen;
• RE6 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
• each instance of Y is independently O, S, or NRE7, wherein RE7 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
• a is 1 or 2;
• and
• each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.

A method of inhibiting transcription in a biological sample or subject, the method comprising:

• administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of Formula (I):
• or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable excipient;
• wherein:
• R1 is —NRaRb, —CHRaRb, or —ORa, wherein each of Ra and Rb is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or Ra and Rb are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
• each of R3 and R4 is independently hydrogen, halogen, optionally substituted C1-C6 alkyl, or optionally substituted aryl, or R3 and R4 are joined to form an optionally substituted C3-C6 carbocyclyl ring;
• R5 is independently hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
• L1 is —NRL1—, —NRL1C(═O)—, —C(═O)NRL1—, —O—, or —S—, wherein RL1 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
• Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• L2 is a bond, —C(═O)—, —NRL2—, —C(═O)NRL2—, —NRL2C(═O)—, —O—, or —S—, wherein RL2 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protection group;
• Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• and
• R2 is any of Formulae (i-1)-(i-42):
• wherein:
• L3 is a bond or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b=CRL3b—, cis-CRL3b═CRL3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NRL3a—, —NRL3aS(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—, wherein RL3a is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RL3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
• L4 is a bond or an optionally substituted, branched or unbranched C1-6 hydrocarbon chain;
• each of RE1, RE2, and RE3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH2OREE, —CH2N(REE)2, —CH2SREE, —OREE, —N(REE)2, —Si(REE)3, and —SREE, wherein each occurrence of REE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two REE groups are joined to form an optionally substituted heterocyclic ring;
• or RE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
• RE4 is a leaving group;
• RE5 is halogen;
• RE6 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
• each instance of Y is independently O, S, or NRE7, wherein RE7 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
• a is 1 or 2;
• and
• each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.

A method of inhibiting cell growth in a biological sample or subject, the method comprising:

• administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of Formula (I):
• or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable excipient;
• wherein:
• R1 is —NRaRb, —CHRaRb or —ORa, wherein each of Ra and Rb is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or Ra and Rb are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
• each of R3 and R4 is independently hydrogen, halogen, optionally substituted C1-C6 alkyl, or optionally substituted aryl, or R3 and R4 are joined to form an optionally substituted C3-C6 carbocyclyl ring;
• R5 is independently hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
• L1 is —NRL1—, —NRL1C(═O)—, —C(═O)NRL1—, —O—, or —S—, wherein RL1 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
• Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• L2 is a bond, —C(═O)—, —NRL2—, —C(═O)NRL2—, —NRL2C(═O)—, —O—, or —S—, wherein RL2 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protection group;
• Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
• and
• R2 is any of Formulae (i-1)-(i-42):
• wherein:
• L3 is a bond or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b=CRL3b—, cis-CRL3b—, ═CRL3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NRL3a—, —NRL3aS(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—, wherein RL3a is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RL3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
• L4 is a bond or an optionally substituted, branched or unbranched C1-6 hydrocarbon chain;
• each of RE1, RE2, and RE3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH2OREE, —CH2N(REE)2, —CH2SREE, —OREE, —N(REE)2, —Si(REE)3, and —SREE, wherein each occurrence of REE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two REE groups are joined to form an optionally substituted heterocyclic ring;
• or RE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
• RE4 is a leaving group;
• RE5 is halogen;
• RE6 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
• each instance of Y is independently O, S, or NRE7, wherein RE7 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
• a is 1 or 2;
• and
• each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.