Boron-containing diacylhydrazines

Patent metadata

Field	Value
Publication number	US-10464951-B2
Application number	US-201615354239-A
Country	US
Kind code	B2
Filing date	Nov 17, 2016
Priority date	Mar 15, 2013
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

The present disclosure provides boron-containing diacylhydrazines having Formula I:

and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 5 are defined as set forth in the specification. The present disclosure also provides the use of boron-containing diacylhydrazines is ecdysone receptor-based inducible gene expression systems. Thus, the present disclosure is useful for applications such as gene therapy, treatment of disease, large scale production of proteins and antibodies, cell-based screening assays, functional genomics, proteomics, metabolomics, and regulation of traits in transgenic organisms, where control of gene expression levels is desirable.

First claim

What is claimed is:

1. A method of treating herpes simplex virus infection, influenza virus infection, human immune deficiency virus infection, or tuberculosis in a subject, the method comprising administering to said subject a compound having Formula I-A:

wherein:
R 1 and R 2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, and haloalkyl; or
R 1 and R 2 taken together with the carbon atom to which they are attached form a 4- to 8-membered cycloalkyl;
R 3 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;
R 4a is selected from the group consisting of:

X 1 is selected from the group consisting of —O— and —N(R 8a )—;
Y 1 is —(CR 9a R 9b ) m —;
Z 1 is selected from the group consisting of —O— and —N(R 8b )—, or Z 1 is absent;
R 6a is selected from the group consisting of hydroxy, alkyl, and alkoxy; or
R 6a forms a hydroxy acid adduct or an amino acid adduct;
R 7a and R 7b are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
R 7a′ and R 7b′ are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkl, alkoxy, and alkylthio;
R 8a and R 8b are each independently selected from the group consisting of hydrogen and alkyl;
R 9a and R 9b are each independently selected from the group consisting of hydrogen and alkyl;
m is 1, 2, 3, or 4;
X 2 is selected from the group consisting of —O— and —N(R 8c )—;
Y 2 is —(CR 9c R 9d ) n —;
Z 2 is selected from the group consisting of —O— and —N(R 8d )—, or Z 2 is absent;
R 6b is selected from the group consisting of hydroxy, alkyl, and alkoxy; or
R 6b forms a hydroxy acid adduct or an amino acid adduct;
R 7c and R 7d are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
R 8c and R 8d are each independently selected from the group consisting of hydrogen and alkyl;
R 9c and R 9d 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(R 8e )—;
R 6c is selected from the group consisting of hydroxy, alkyl, and alkoxy; or
R 6c forms a hydroxy acid adduct or an amino acid adduct;
R 7e and R 7f are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
R 8e is selected from the group consisting of hydrogen and alkyl;
R 6d is selected from the group consisting of hydroxy, alkyl, and alkoxy; or
R 6d forms a hydroxy acid adduct or an amino acid adduct;
R 6f is selected from the group consisting of hydrogen, alkyl, amino, and hydroxy;
X 5 is selected from the group consisting of —O— and —N(R 8k )—;
R 7g and R 7h are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
R 8k is selected from the group consisting of hydrogen and alkyl;
X 6 is selected from the group consisting of —O— and —N(R 8l )—;
X 7 is selected from the group consisting of —O— and —N(R 8n )—;
R 8l is selected from the group consisting of hydrogen and alkyl;
R 8m is selected from the group consisting of hydrogen and alkyl;
R 8n is selected from the group consisting of hydrogen and alkyl;
R 10i , R 10j , and R 10k 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, —COR 16 , —SO 2 R 17 , —N(R 18 )COR 19 , —N(R 18 )SO 2 R 20 or N(R 18 )C═N(R 21 )-amino; or
R 10i 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, —COR 16 , —SO 2 R 17 , —N(R 18 )COR 19 , —N(R 18 )SO 2 R 20 or N(R 18 )C═N(R 21 )-amino; and/or
R 10j and R 10k taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo, or optionally substituted heteroaryl group;
R 11a and R 11b are each independently selected from the group consisting of hydrogen and alkyl;
R 12a and R 12b are selected from the group consisting of hydroxy and alkoxy; or
R 12a and R 12b taken together form a linkage —O(CR 13a R 13b ) p O—; or
—B(R 12a )(R 12b ) forms a fluoride adduct;
R 13a and R 13b are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
o is 0, 1, 2, 3, 4, or 5;
p is 2, 3, or 4;
R 5 is R 4 -3, R 4 -4, R 4 -8, R 4 -9, or R 4 -10; or
R 5 is selected from the group consisting of:

X 3 is selected from the group consisting of —O— and —N(R 8f )—;
Y 3 is —(CR 9e R 9f ) q —;
Z 3 is selected from the group consisting of —O— and —N(R 8g )—, or Z 3 is absent;
R 6e is selected from the group consisting of hydroxy and alkyl; or
R 6e forms a hydroxy acid adduct or an amino acid adduct;
R 7i and R 7j are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
R 8f and R 8g are each independently selected from the group consisting of hydrogen and alkyl;
R 9e and R 9f are each independently selected from the group consisting of hydrogen and alkyl;
q is 1, 2, 3, or 4;
X 4 is selected from the group consisting of —O— and —N(R 8h )—;
Y 4 is —(CR 9g R 9h ) r —;
Z 4 is selected from the group consisting of —O— and —N(R 8i )—, or Z 4 is absent;
R 6g is selected from the group consisting of hydroxy and alkyl; or
R 6g forms a hydroxy acid adduct or an amino acid adduct;
R 7k and R 7l are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl,

Assignees

• Intrexon Corp

Inventors

• Chellappan Sheela K
• Hormann Robert E
• Shulman Inna

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title