Boron-containing diacylhydrazine compounds

Patent metadata

Field	Value
Publication number	US-9944659-B2
Application number	US-201514855646-A
Country	US
Kind code	B2
Filing date	Sep 16, 2015
Priority date	Sep 17, 2014
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

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

and the pharmaceutically acceptable salts and solvates thereof, wherein A, 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 compound having Formula I:

or a pharmaceutically acceptable salt, solvate, or boronic anhydride thereof, wherein:
A is selected from the group consisting of hydrogen and —C(R 1 )(R 2 )(R 3 );
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen and optionally substituted alkyl;
R 4 is selected from the group consisting of:

X is selected from the group consisting of —O— and —N(R 8a )—;
X 1 is selected from the group consisting of —O— and —N(R 8b )—;
X 2 is selected from the group consisting of —O— and —N(R 8c )—;
X 3 is selected from the group consisting of —O— and —N(R 8d )—;
Y 1 is —(CR 9a R 9b ) m —;
m is 0, 1, 2, or 3;
Z 1 is selected from the group consisting of —O— and —N(R 8e )—, or Z 1 is absent;
Z 2 is selected from the group consisting of O, S, and NH;
R 6a is selected from the group consisting of hydrogen, —B(OH) 2 , and pinacolborane;
R 6b , R 6c , and R 6d are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, —N(H)(cyano)alkyl, —CHO, optionally substituted alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, 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 10 , —SO 2 R 11 , —N(R 12 )COR 13 , —N(R 12 )SO 2 R 14 or N(R 12 )C═N(R 15 )-amino; or
R 6b 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 10 , —SO 2 R 11 , —N(R 12 )COR 13 , —N(R 12 )SO 2 R 14 or N(R 12 )C═N(R 15 )-amino; and/or
R 6c and R 6d taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo, or optionally substituted heteroaryl group;
R 6f is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino, and hydroxy;
R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g , R 7h , 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 8a , R 8b , R 8c , R 8d , R 8e , R 8f , and R 8g are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, and arylcarbonyl;
R 9a and R 9b are each independently selected from the group consisting of hydrogen, alkyl, and cyano;
R 5 is selected from the group consisting of:

X 4 is selected from the group consisting of —O— and —N(R 8h )—;
X 5 is selected from the group consisting of —O— and —N(R 8i )—;
X 6 is selected from the group consisting of —O— and —N(R 8j )—;
X 7 is selected from the group consisting of —O— and —N(R 8k )—;
Y 2 is —(CR 9c R 9d ) n —;
n is 0, 1 2, or 3;
Z 3 is selected from the group consisting of —O— and —N(R 8l )—, or Z 3 is absent;
Z 4 is selected from the group consisting of O, S, and NH;
R 6e is selected from the group consisting of hydrogen, —B(OH) 2 , and pinacolborane;
R 6g , R 6h , and R 6i are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, —N(H)CHO, —N(H)CN, —N(H)(cyano)alkyl, —CHO, optionally substituted alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, arylalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, 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 10 , —SO 2 R 11 , —N(R 12 )COR 13 , —N(R 12 )SO 2 R 14 or N(R 12 )C═N(R 15 )-amino; or
R 6g 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 10 , —SO 2 R 11 , —N(R 12 )COR 13 , —N(R 12 )SO 2 R 14 or N(R 12 )C═N(R 15 )-amino; and/or
R 6h and R 6i taken together with two adjacent carbon atoms form a fused optionally substituted cycloalkyl, optionally substituted heterocyclo, or optionally substituted heteroaryl group;
R 6j is selected from the group consisting of hydrogen, alkyl, amino, and hydroxy;
R 7k , R 7l , R 7m , R 7n , R 7o , R 7p , R 7q , R 7r , R 7s , and R 7t are each independently selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, and alkylthio;
R 8h , R 8i , R 8j , R 8k , R 8l , R 8m , and R 8n are each independently selected from the group consisting of hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, alkylsulfonyl, arylsulfonyl, alkylcarbonyl, and arylcarbonyl;
R 9c and R 9d are each independently selected from the group consisting of hydrogen, alkyl, and cyano;
R 10 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;
R 11 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;
R 12 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;
R 13 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;
R 14 is selected from the group consisting of haloalkyl,

Assignees

• Intrexon Corp

Inventors

• James Ray A
• Chellappan Sheela K
• Hormann Robert E

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

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

• A61P7/06

  Antianaemics · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P33/14

  Ectoparasiticides, e.g. scabicides · CPC title