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

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.