# US 11,078,221 B2 · Phosphorodiamidates and other phosphorus derivatives of fingolimod and related S1P receptor modulators

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- Number: US 11,078,221 B2
- Document ID: US11078221B2
- Status: Granted
- Kind: B2
- Application number: 16/651,058
- Filed: 2018-09-28
- Published: 2020-08-13
- Granted: 2021-08-03
- Earliest claimed: 2017-09-29
- Assignees: University College Cardiff Consultants Limited
- Applicants: University College Cardiff Consultants Ltd
- Inventors: Emyr Lloyd-Evans; Fabrizio Pertusati; Edward James; Emily Maguire; Christopher McGuigan
- Web page: https://patentgrep.com/patent/US11078221B2

## CPC

- C07F 9/26: containing P-halide groups
- C07F 9/12: with hydroxyaryl compounds
- C07F 9/2429: {of arylalkanols}
- C07F 9/2458: {of aliphatic amines}
- C07F 9/572: Five-membered rings
- C07F 9/5728: {condensed with carbocyclic rings or carbocyclic ring systems}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Compounds of general formula (I): (Formula I)) wherein R1, Q, R3, R4, R5, R6, R7 and Ar1 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.

## Claims

### Claim 1

A compound of general formula (I) including all stereoisomers thereof and all isotopic variants thereof:
wherein
R1 is —OAr2 or -Q′R3′;
wherein Ar2 is a C6-10 aryl or a 5-10 membered heteroaryl group optionally substituted with one or more substituents selected from OH, halo, nitro, C1-6 alkyl, C1-6 haloalkyl, —O(C1-6 alkyl), —O(C1-6 haloalkyl), NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2 or SF5;
Q and Q′ are each independently O, S or NR2;
R2 is H or C1-6 alkyl optionally substituted by one or more halo, OH or phenyl substituents;
R3 and R3′ are each independently C1-10 alkyl or C1-10 alkyl—C(O)OR11, either of which is optionally substituted by one or more substituents R12;
R11 is C1-6 alkyl, C1-6 haloalkyl or benzyl;
R12 is —O—R13, —SR13, Z, —Z—O—R13, —O—Z—R13, —Z—R13, —C(O)R13, —C(O)OR13, NR13R14,
C(O)NR13R14, —NHC(O)R13, —NHC(O)OR13, NH(C═NH)NR13R14, —OC(O)—R13, —SC(O)R13 or —S—S—R13;
R13 and R14 are each independently H or C1-6 alkyl;
Z is a C6-10 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 NR2, R2 and R3 or R2 and R3′ together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring substituted with C(O)OR11, wherein R11 is as defined above;
R4 is OH or a group:
where R1, Q and R3 are as defined above;
each of R5 and R6 is independently selected from hydrogen or C1-4 alkyl; or
R5 and R6 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;
Ar1 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, C1-4 alkyl or C1-4 haloalkyl; and
R7 is C1-10 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, NO2, OH, C1-4 alkyl, C1-4 haloalkyl, O(C1-4 alkyl) or phenyl optionally substituted with halo, OH, C1-4 alkyl, C1-4 haloalkyl or O(C1-4 alkyl) and optionally labelled with a fluorescent, visible or isotopic detectable label;
or a pharmaceutically or veterinarily acceptable salt or hydrate thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein the asymmetric carbon atom (*) to which the NR5R6, CH2R4, —CH2CH2—Ar1—R7 and the phosphate moiety:
are attached is in the S-orientation.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein R1 is OAr2.

### Claim 4 (depends on 1, 3)

A compound according to claim 3 wherein Ar2 is phenyl, naphthyl, or tetrahydronaphthyl, any of which is optionally substituted with one or more substituents as defined in claim 1.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein R1 is -Q′R3′.

### Claim 6 (depends on 1)

A compound according to claim 1 wherein Q and/or Q′ (when present) is NR2 where R2 is H or C1-4 alkyl optionally substituted with one or more halo, OH or phenyl substituents.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein R3 and/or R3′ (when present) is a group C1-10 alkyl—C(O)OR11.

### Claim 8 (depends on 7)

A compound according to claim 7 wherein R3 and/or R3′ (when present) is —C(R12aR12b)C(O)OR11 or —C(R12aR12b)CH2C(O)OR11;
wherein R11 is as defined above;
R12a is H or C1-6 alkyl optionally substituted by a group R12 as defined above; and
R12b is C1-4 alkyl or H.

### Claim 9 (depends on 8)

A compound according to claim 8 wherein R12a 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.

### Claim 10 (depends on 8)

A compound according to claim 8 wherein R12b is H, methyl or ethyl.

### Claim 11 (depends on 9)

A compound according to claim 9 wherein the R12a side chain is modified such that OH and/or SH groups are replaced with O—C1-6 alkyl or S—C1-6 alkyl and/or carboxylic acid groups are esterified as a C1-6 alkyl or benzyl ester.

### Claim 12 (depends on 1)

A compound according to claim 1 wherein Q is NR2, and R2 and R3 together with the nitrogen atom to which they are attached, form a pyrrolidin-1-yl ring substituted at the 2-position with C(O)OR11, wherein R11 is as defined in claim 1; and/or
wherein R1 is Q′R3′, Q′ is NR2, and R2 and R3′ together with the nitrogen atom to which they are attached, form a pyrrolidin-1-yl ring substituted at the 2-position with C(O)OR11, wherein R11 is as defined in claim 1.

### Claim 13 (depends on 1)

A compound according to claim 1 wherein Q is O or S and R3 is C1-10 alkyl substituted with, —OC(O)—R13, —SC(O)R13 or —S—S—R13, where R13 is H or C1-6 alkyl; and/or
wherein R1 is Q′R3′, Q′ is O or S and R3′ is C1-10 alkyl substituted with, —OC(O)—R13, —SC(O)R13 or —S—S—R13, where R13 is H or C1-6 alkyl.

### Claim 14 (depends on 1)

A compound according to claim 1 wherein at least one of R5 and R6 is H.

### Claim 15 (depends on 1)

A compound according to claim 1 wherein, independently or in any combination:
R4 is OH;
R5 is H;
R6 is H;
R1 is —OAr2 and —Ar2 is phenyl;
Ar1 is phenyl and the R7 moiety is positioned at the 4-position of the phenyl ring with respect to the —CH2CH2—linker group;
R7 is C6-10 alkyl or C3-5 alkyl substituted with (C1-2 alkyl) phenyl;
the C* centre has S stereochemistry; and
a moiety —O—CH2—C(CH2R4)(NR5R6)—CH2CH2—Ar1—R7 that is
or an S enantiomer thereof:

### Claim 16 (depends on 1)

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-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (naphthalen-1-yloxy)phosphoryl)amino)propanoate;
(2S)-ethyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (phenoxy)phosphoryl)amino)-4-(methylthio) butanoate;
(2S)-methyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (phenoxy)phosphoryl)amino)-3-(4-(tert-butoxy)phenyl)propanoate;
(2R)-dimethyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (phenoxy)phosphoryl)amino)pentanedioate;
(2S)-methyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (phenoxy)phosphoryl)amino)-3-(1H-indol-3-yl)propanoate;
(2S,3R)-methyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (naphthalen-1-yloxy)phosphoryl)amino)-3-(tert-butoxy)butanoate;
(2R)-methyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (phenoxy)phosphoryl)amino)-6-((tert-butoxycarbonyl) amino)hexanoate;
S-(2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy)(phenoxy) phosphoryl)oxy)ethyl) 2,2-dimethylpropanethioate;
pentyl (2S)-2-[({2-amino-3-hydroxy-2-[2-(4-octylphenyl)ethyl]propoxy}(4-methoxyphenoxy)phosphoryl)amino]propanoate;
methyl 2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy)(phenoxy) phosphoryl)amino)acetate;
ethyl 2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy)(phenoxy) phosphoryl)amino)acetate;
(3S)-methyl 2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (phenoxy)phosphoryl)amino)-3-methylpentanoate;
(2S) pentyl-2-(((2-amino-2-(hydroxymethyl)-4-(4-octylphenyl)butoxy) (phenoxy)phosphoryl)amino)-3-phenylpropanoate;
and their pharmaceutically acceptable salts, hydrates, and stereoisomers.

### Claim 17 (depends on 1)

A process for the preparation of a compound according to claim 1 comprising:
i. for compounds of general formula (I) in which R5 and R6 are both H:
reacting an analogue of the compound of general formula (I) in which one of R5 and R6 is replaced with —C(O)OR15, wherein R15 is C1-6 alkyl or C6-14 aryl optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl or halo;
to remove the protecting group; or
ii. for all compounds of general formula (I): reacting a compound of general formula (II):
wherein R5, R6, Ar1 and R7 are as defined for general formula (I);
with a compound of general formula (III):
wherein:
Q, R1 and R3 are as defined for general formula (I); and
X1 is halo;
wherein the compound of general formula (II) may firstly be reacted with a hindered base, following which the product is reacted with the compound of general formula (III).

### Claim 18 (depends on 1)

A method for the treatment of lysosomal storage disorders selected from the group consisting of: Niemann-Pick type C1, Niemann-Pick type C2, Niemann-Pick types A and B, neuronal ceroid lipofuscinoses (NCL), mucolipidoses, lipidoses and sphingolipidoses, Gaucher disease, Fabry disease, Tay-Sachs disease, defective autophagy, accumulation of free cholesterol and endocytic transport defects, mycobacterial diseases, tuberculosis and BCG, the method comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient or carrier.

### Claim 20 (depends on 19)

A pharmaceutical composition according to claim 19 which is formulated for oral administration.

### Claim 21 (depends on 15)

The compound according to claim 15 wherein the moiety —O—CH2—C(CH2R4)(NR5R6)—CH2CH2—Ar1—R7 is the S enantiomer: