Phosphonamidates that are Bcl family antagonists for use in clinical management of conditions caused or mediated by senescent cells and for treating cancer

Patent metadata

Field	Value
Publication number	US-10738042-B2
Application number	US-201916425228-A
Country	US
Kind code	B2
Filing date	May 29, 2019
Priority date	Apr 30, 2018
Publication date	Aug 11, 2020
Grant date	Aug 11, 2020

Abstract

This disclosure provides compounds with Bcl inhibitory activity based on a new chemical scaffold, as shown in Formula (I):

Phosphonamidate compounds disclosed herein typically include a P-phenyl phosphonamidate moiety which is substituted with an N-aryl or N-heteroaryl group. The P-phenyl phosphonamidate moiety may be optionally substituted at phosphorus with thio (═S) instead of oxo (═O), and/or with a thioxy group or a second amino group instead of an oxy group. One of the heteroatoms attached to phosphorus may be cyclically linked to the N-substituted nitrogen atom that is attached to the phosphorus to provide a heterocyclic ring. By incorporating such a cyclic constraint between two phosphorus substituents of the core linking moiety, a favorable binding conformation may be promoted in the compounds. Selected compounds promote apoptosis in senescent cells, and can be developed for treating senescent-related conditions, such as osteoarthritis, ophthalmic disease, pulmonary disease, and atherosclerosis. Selected compounds promote apoptosis in cancer cells, and can be developed as chemotherapeutic agents.

First claim

The invention claimed is:

1. A compound of Formula (VIa):

wherein:
X 1 is O or S;
R 1 is selected from SR 21 , OR 21 , and NR 21 R 22 ;
R 3 is selected from hydrogen and C 1 to 6 alkyl;
R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ;
Z 4 is selected from CH and N;
Z 6 is selected from O, CHC(O)R 18a , and CH(CH 2 ) p R 18a wherein p is 0-6 and each R 18s is independently selected from —OR, —N(R) 2 , —OP(═O)(OH) 2 , and —OP(═O)(OR) 2 wherein each R is independently H or alkyl;
R 14 and R 16 are independently selected from hydrogen and halogen;
R 17 is selected from SO 2 R 52 , COR 52 , CO 2 R 52 , CONR 51 R 52 , CONR 52 SO 2 R 51 and SO 2 NR 51 R 52 ;
R 18 , R 19 , R 21 , R 22 and R 52 are independently selected from hydrogen and C 1 to 6 alkyl; and
R 51 is C 1 to 6 alkyl,
and salt forms thereof.

2. The compound of claim 1 , selected from the following table:

Com-

pound
R 1
R 3
R 4
R 14
R 16
R 17
R 18
R 19
Z 4
Z 6

1
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O

2
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOH

3
OCH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O

4
OCH 2 CH 3
H
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O

5
OCH 2 CH 3
H
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O

6
OCH 2 CH 3
CH 3
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O

7
OCH 2 CH 3
H
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOH

8
OH
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O

9
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHCH 2 OH

10
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHCH 2 OPO(OH) 2

11
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2 .

3. A compound of Formula (VIb):

wherein:
X 1 is O or S;
R 1 is selected from SR 21 , OR 21 , and NR 21 R 22 ;
R 3 is selected from hydrogen and C 1 to 6 alkyl;
Y 2 is selected from —OR 52 , —N(R 52 ) 2 , and —OP(═O)(OR 52 ) 2 ;
R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ;
Z 4 is selected from CH and N;
R 14 and R 16 are independently selected from hydrogen and halogen;
R 17 is selected from SO 2 R 52 , COR 52 , CO 2 R 52 , CONR 51 R 52 , CONR 52 SO 2 R 51 and SO 2 NR 51 R 52 ;
R 18 , R 19 , R 21 , R 22 and R 52 are independently selected from hydrogen and C 1 to 6 alkyl; and
R 51 is C 1 to 6 alkyl,
and salt form thereof.

4. The compound of claim 3 , selected from the following table:

Compound
R 1
R 3
R 4
R 14
R 16
R 17
R 18
R 19
Z 4
Y 2

12
OCH 2 CH 3
H
NO 2

Assignees

• Unity Biotechnology
• Unity Biotechnology Inc

Inventors

• Beausoleil Anne-Marie
• Hudson Ryan

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07F9/6533

  Six-membered rings · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• C07F9/650952

  having the nitrogen atoms in the positions 1 and 4 · CPC title