Phosphorodiamidates and other phosphorus derivatives of fingolimod and related S1P receptor modulators

Patent metadata

Field	Value
Publication number	US-11078221-B2
Application number	US-201816651058-A
Country	US
Kind code	B2
Filing date	Sep 28, 2018
Priority date	Sep 29, 2017
Publication date	Aug 3, 2021
Grant date	Aug 3, 2021

Abstract

Compounds of general formula (I): (Formula I)) wherein R 1 , Q, R 3 , R 4 , R 5 , R 6 , R 7 and Ar 1 are as defined herein are inhibitors of class I histone deacetylases and are of use in the treatment of lysosomal storage disorders, especially Niemann-Pick type C disease, as well as other lysosomal storage disorders, defective autophagy, accumulation of free cholesterol and mycobacterial diseases.

First claim

The invention claimed is:

1. A compound of general formula (I) including all stereoisomers thereof and all isotopic variants thereof:

wherein
R 1 is —OAr 2 or -Q′R 3′ ;
wherein Ar 2 is a C 6-10 aryl or a 5-10 membered heteroaryl group optionally substituted with one or more substituents selected from OH, halo, nitro, C 1-6 alkyl, C 1-6 haloalkyl, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 or SF 5 ;

Q and Q′ are each independently O, S or NR 2 ;
R 2 is H or C 1-6 alkyl optionally substituted by one or more halo, OH or phenyl substituents;
R 3 and R 3′ are each independently C 1-10 alkyl or C 1-10 alkyl—C(O)OR 11 , either of which is optionally substituted by one or more substituents R 12 ;
R 11 is C 1-6 alkyl, C 1-6 haloalkyl or benzyl;
R 12 is —O—R 13 , —SR 13 , Z, —Z—O—R 13 , —O—Z—R 13 , —Z—R 13 , —C(O)R 13 , —C(O)OR 13 , NR 13 R 14 ,
C(O)NR 13 R 14 , —NHC(O)R 13 , —NHC(O)OR 13 , NH(C═NH)NR 13 R 14 , —OC(O)—R 13 , —SC(O)R 13 or —S—S—R 13 ;
R 13 and R 14 are each independently H or C 1-6 alkyl;
Z is a C 6-10 aryl or a 5- to 10-membered heteroaryl group optionally substituted with one or more substituent selected from halo or OH;

or when Q or Q′ is NR 2 , R 2 and R 3 or R 2 and R 3′ together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring substituted with C(O)OR 11 , wherein R 11 is as defined above;
R 4 is OH or a group:

where R 1 , Q and R 3 are as defined above;
each of R 5 and R 6 is independently selected from hydrogen or C 1-4 alkyl; or
R 5 and R 6 together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O or S;
Ar 1 is a phenyl or a 5- or 6-membered heteroaryl group, either of which is optionally substituted with one or more substituents selected from halo, OH, C 1-4 alkyl or C 1-4 haloalkyl; and
R 7 is C 1-10 alkyl optionally substituted with phenyl or a 5- or 6-membered heteroaryl group, wherein the phenyl or heteroaryl groups are optionally substituted with one or more substituents selected from halo, NO 2 , OH, C 1-4 alkyl, C 1-4 haloalkyl, O(C 1-4 alkyl) or phenyl optionally substituted with halo, OH, C 1-4 alkyl, C 1-4 haloalkyl or O(C 1-4 alkyl) and optionally labelled with a fluorescent, visible or isotopic detectable label;
or a pharmaceutically or veterinarily acceptable salt or hydrate thereof.

2. A compound according to claim 1 wherein the asymmetric carbon atom (*) to which the NR 5 R 6 , CH 2 R 4 , —CH 2 CH 2 —Ar 1 —R 7 and the phosphate moiety:

are attached is in the S-orientation.

3. A compound according to claim 1 wherein R 1 is OAr 2 .

4. A compound according to claim 3 wherein Ar 2 is phenyl, naphthyl, or tetrahydronaphthyl, any of which is optionally substituted with one or more substituents as defined in claim 1 .

5. A compound according to claim 1 wherein R 1 is -Q′R 3′ .

6. A compound according to claim 1 wherein Q and/or Q′ (when present) is NR 2 where R 2 is H or C 1-4 alkyl optionally substituted with one or more halo, OH or phenyl substituents.

7. A compound according to claim 1 wherein R 3 and/or R 3′ (when present) is a group C 1-10 alkyl—C(O)OR 11 .

8. A compound according to claim 7 wherein R 3 and/or R 3′ (when present) is —C(R 12a R 12b )C(O)OR 11 or —C(R 12a R 12b )CH 2 C(O)OR 11 ;
wherein R 11 is as defined above;
R 12a is H or C 1-6 alkyl optionally substituted by a group R 12 as defined above; and
R 12b is C 1-4 alkyl or H.

9. A compound according to claim 8 wherein R 12a is a side chain of a naturally-occurring amino acid selected from alanine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine or glycine or a non-natural amino acid.

10. A compound according to claim 8 wherein R 12b is H, methyl or ethyl.

11. A compound according to claim 9 wherein the R 12a side chain is modified such that OH and/or SH groups are replaced with O—C 1-6 alkyl or S—C 1-6 alkyl and/or carboxylic acid groups are esterified as a C 1-6 alkyl or benzyl ester.

12. A compound according to claim 1 wherein Q is NR 2 , and R 2 and R 3 together with the nitrogen atom to which they are attached, form a pyrrolidin-1-yl ring substituted at the 2-position with C(O)OR 11 , wherein R 11 is as defined in claim 1 ; and/or
wherein R 1 is Q′R 3′ , Q′ is NR 2 , and R 2 and R 3′ together with the nitrogen atom to which they are attached, form a pyrrolidin-1-yl ring substituted at the 2-position with C(O)OR 11 , wherein R 11 is as defined in claim 1 .

13. A compound according to claim 1 wherein Q is O or S and R 3 is C 1-10 alkyl substituted with, —OC(O)—R 13 , —SC(O)R 13 or —S—S—R 13 , where R 13 is H or C 1-6 alkyl; and/or
wherein R 1 is Q′R 3′ , Q′ is O or S and R 3′ is C 1-10 alkyl substituted with, —OC(O)—R 13 , —SC(O)R 13 or —S—S—R 13 , where R 13 is H or C 1-6 alkyl.

14. A compound according to claim 1 wherein at least one of R 5 and R 6 is H.

15. A compound according to claim 1 wherein, independently or in any combination:
R 4 is OH;
R 5 is H;
R 6 is H;
R 1 is —OAr 2 and —Ar 2 is phenyl;
Ar 1 is phenyl and the R 7 moiety is positioned at the 4-position of the phenyl ring with respect to the —CH 2 CH 2 —linker group;
R 7 is C 6-10 alkyl or C 3-5 alkyl substituted with (C 1-2 alkyl) phenyl;
the C* centre has S stereochemistry; and
a moiety —O—CH 2 —C(CH 2 R 4 )(NR 5 R 6 )—CH 2 CH 2 —Ar 1 —R 7 that is

or an S enantiomer thereof:

16. A compound according to claim 1 selected from the group consisting of:
(2S)-methyl 2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy)(phenoxy)phosphoryl)amino)propanoate;
benzyl 2-(((2-amino-2(hydroxymethyl)-4-(4-octylphenyl)butoxy)(phenoxy) phosphoryl)amino)acetate;
(2S) benzyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (phenoxy)phosphoryl)amino)-4-methylpentanoate;
(2S) benzyl-1-((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (phenoxy)phosphoryl)pyrrolidine-2-carboxylate;
(2S) ethyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy)(phenoxy) phosphoryl)amino)-propanoate;
(2R)-benzyl 2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (naphthalen-1-yloxy)phosphoryl)amino)propanoate;
(2R)-neopentyl 2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (naphthalen-1-yloxy)phosphoryl)amino) propanoate;
methyl 3-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy)(naphthalen-1-yloxy)phosphoryl)amino)propanoate;
(2R)-neopentyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) ((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)phosphoryl) amino)propanoate;
isopropyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (phenoxy)phosphoryl)amino)-2-methylpropanoate;
(2R)-benzyl-2-(((2-amino-2-(hydroxymethy

Assignees

• Univ College Cardiff Consultants Ltd

Inventors

• Lloyd-Evans Emyr
• Pertusati Fabrizio
• James Edward
• Maguire Emily
• Mcguigan Christopher

Classifications

• C07F9/26 Primary

  containing P-halide groups · CPC title

• C07F9/2429

  of arylalkanols · CPC title

• C07F9/2458

  of aliphatic amines · CPC title

• C07F9/5728

  condensed with carbocyclic rings or carbocyclic ring systems · CPC title

• C07F9/572

  Five-membered rings · CPC title