Boron-containing diacylhydrazines

A method regulating gene expression of a gene of interest in a host cell, the method comprising contacting the host cell with a compound having Formula I-A:

• wherein:
• R1 and R2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and haloalkyl;
• or
• R1 and R2 taken together with the carbon atom to which they are attached form a 4- to 8-membered cycloalkyl;
• R3 is selected from the group consisting of hydrogen, optionally substituted alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R4a is selected from the group consisting of:
• X1 is selected from the group consisting of —O— and —N(R8a)—;
• Y1 is —(CR9aR9b)m—;
• Z1 is selected from the group consisting of —O— and —N(R8b)—, or Z1 is absent;
• R6a is selected from the group consisting of hydroxy, alkyl, and alkoxy;
• or
• R6a forms a hydroxy acid adduct or an amino acid adduct;
• R7a and R7b are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
• R7a′ and R7b′ are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
• R8a and R8b are each independently selected from the group consisting of hydrogen and alkyl;
• R9a and R9b are each independently selected from the group consisting of hydrogen and alkyl;
• m is 1, 2, 3, or 4;
• X2 is selected from the group consisting of —O— and —N(R8c)—;
• Y2 is —(CR9cR9d)n—;
• Z2 is selected from the group consisting of —O— and —N(R8d)—, or Z2 is absent;
• R6b is selected from the group consisting of hydroxy, alkyl, and alkoxy;
• or
• R6b forms a hydroxy acid adduct or an amino acid adduct;
• R7c and R7d are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
• R8c and R8d are each independently selected from the group consisting of hydrogen and alkyl;
• R9c and R9d are each independently selected from the group consisting of hydrogen and alkyl;
• n is 1, 2, 3, or 4;
• X is selected from the group consisting of —O— and —N(R8e)—;
• R6c is selected from the group consisting of hydroxy, alkyl, and alkoxy;
• or
• R6c forms a hydroxy acid adduct or an amino acid adduct;
• R7e and R7f are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
• R8e is selected from the group consisting of hydrogen and alkyl;
• R6d is selected from the group consisting of hydroxy, alkyl, and alkoxy;
• or
• R6d forms a hydroxy acid adduct or an amino acid adduct;
• R6f is selected from the group consisting of hydrogen, alkyl, amino, and hydroxy;
• X5 is selected from the group consisting of —O— and —N(R8k)—;
• R7g and R7h are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
• R8k is selected from the group consisting of hydrogen and alkyl;
• X6 is selected from the group consisting of —O— and —N(R8l)—;
• X7 is selected from the group consisting of —O— and —N(R8n)—;
• R8l is selected from the group consisting of hydrogen and alkyl;
• R8m is selected from the group consisting of hydrogen and alkyl;
• R8n is selected from the group consisting of hydrogen and alkyl;
• R10i, R10j and R10k are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, optionally substituted alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, heteroalkyl, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C═N(R21)-amino;
• or
• R10i is selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, —N(H)CHO, —N(H)CN, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, heteroalkyl, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C═N(R21)-amino;
• and/or
• R10j and R10k taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo, or optionally substituted heteroaryl group;
• R11a and R11b are each independently selected from the group consisting of hydrogen and alkyl;
• R12a and R12b are selected from the group consisting of hydroxy and alkoxy;
• or
• R12a and R12b taken together form a linkage —O(CR13aR13b)pO—;
• or
• B(R12a)(R12b) forms a fluoride adduct;
• R13a and R13b are each independently selected from the group consisting of hydrogen and C1-4 alkyl;
• o is 0, 1, 2, 3, 4, or 5;
• p is 2, 3, or 4;
• R5 is R4-3, R4-4, R4-8, R4-9, or R4-10;
• or
• R5 is selected from the group consisting of:
• X3 is selected from the group consisting of —O— and —N(R8f)—;
• Y3 is —(CR9eR9f)q—;
• Z3 is selected from the group consisting of —O— and —N(R8g)—, or Z3 is absent;
• R6c is selected from the group consisting of hydroxy and alkyl;
• or
• R6e forms a hydroxy acid adduct or an amino acid adduct;
• R7i and R7j are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
• R8f and R8g are each independently selected from the group consisting of hydrogen and alkyl;
• R9e and R9f are each independently selected from the group consisting of hydrogen and alkyl;
• q is 1, 2, 3, or 4;
• X4 is selected from the group consisting of —O— and —N(R8h)—;
• Y4 is —(CR9gR9h)t—;
• Z4 is selected from the group consisting of —O— and —N(R8i)—, or Z4 is absent;
• R6g is selected from the group consisting of hydroxy and alkyl;
• or
• R6g forms a hydroxy acid adduct or an amino acid adduct;
• R7k and R7l are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
• R8h and R8i are each independently selected from the group consisting of hydrogen and alkyl;
• R9g and R9h are each independently selected from the group consisting of hydrogen and alkyl;
• r is 1, 2, 3, or 4;
• R10e is selected from the group consisting of hydrogen and —(CR11cR11d)s—B(R12c)(R12d);
• and
• R10f, R10g, and R10h are independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C═N(R21)-amino;
• or
• R10f is selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C═N(R21)-amino;
• and
• R10g and R10h taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo, or optionally substituted heteroaryl group;
• or
• R11c and R11d are each independently selected from the group consisting of hydrogen and alkyl;
• R12c and R12d are selected from the group consisting of hydroxy and alkoxy;
• or
• R12c and R12d taken together form a linkage —O(CR13cR13d)tO—;
• or
• —B(R12c)(R12d) forms a fluoride adduct;
• R13e and R13d are each independently selected from the group consisting of hydrogen and C1-4 alkyl;
• s is 0, 1, 2, 3, 4, or 5;
• t is 2, 3, or 4;
• R14a and R14b are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C═N(R21)-amino;
• R15a and R15b are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, optionally substituted alkyl, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxy, aryloxy, arylalkyloxy, alkylthio, carboxamido, sulfonamido, —COR16, —SO2R17, —N(R18)COR19, —N(R18)SO2R20 or N(R18)C═N(R21)-amino;
• R16 is selected from the group consisting of hydrogen, hydroxy, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy, and arylalkyloxy;
• R17 is selected from the group consisting of haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
• R18 is selected from the group consisting of hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, and optionally substituted heteroaryl;
• R19 is selected from the group consisting of hydrogen, haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, alkoxy, aryloxy, arylalkyloxy, and amino;
• R20 is selected from the group consisting of haloalkyl, hydroxyalkyl, arylalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, and amino;
• R21 is selected from the group consisting of hydrogen, alkyl, aryl, cyano, and nitro;
• with the provisos:
• a) when R4 is R4-5, R4-6, or R4-7 and R5 is R5-3, then one of R10a or R10c is not hydrogen;
• and
• b) when R4 is R4-5, R4-6, or R4-7 and R5 is R5-4 or R5-5, then R10a is not hydrogen, or a pharmaceutically acceptable salt or solvate thereof,
• wherein the host cell is genetically modified to comprise:
• (1) a polynucleotide encoding a gene switch comprising an ecdysone receptor ligand binding domain;
• and
• (2) a polynucleotide encoding the gene of interest.