Process for the preparation of phenylalanine enamide derivatives

1. A process for the preparation of a compound of formula 1):

wherein:

Ar 1 is an optionally substituted aromatic or heteroaromatic group;

L 2 is a linker group selected from —N(R 4 )—, —CON(R 4 )— and —S(O) 2 N(R 4 )—;

R 4 is a hydrogen atom or an a optionally substituted straight or branched C 1-6 alkyl group;

R 1 is a carboxylic acid (—CO 2 H) or an acyclic or cyclic carboxylic acid ester, an amide, tetrazole, phosphonic acid, phosphinic acid, sulphonic acid, sulphinic acid, boronic acid, or an acylsulphonamide group;

R 2 is a hydrogen atom or a C 1-6 alkyl group;

R x , R y and R z , which may be the same or different, are each -L 1 (Alk 1 ) n (R 3 ) v , or R z is -L 1 (Alk 1 ) n (R 3 ) v and R x and R y are joined together to form an optionally substituted spiro linked cycloaliphatic or heterocycloaliphatic group;

L 1 is a covalent bond or —O—, —S—, or —Se— atom or an —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —CON(R 8 )—, —OC(O)N(R 8 )—, —CSN(R 8 ), —N(R 8 )CO—, —N(R 8 )C(O)O—, —N(R 8 )CS—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —, —N(R 8 )O—, —ON(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CON(R 8 )—, —N(R 8 )CSN(R 8 )—, or —N(R 8 )SO 2 N(R 8 )— group;

R 8 is a hydrogen atom or optionally substituted straight or branched C 1-6 alkyl group;

Alk 1 is an optionally substituted aliphatic chain or an optionally substituted heteroaliphatic chain containing one to four —O— or —S— atoms or —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —CON(R 8 )—, —OC(O)N(R 8 )—, —CSN(R 8 ), —N(R 8 )CO—, —N(R 8 )C(O)O—, —N(R 8 )CS—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —, —N(R 8 )O—, —ON(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CON(R 8 )—, —N(R 8 )CSN(R 8 )—, or —N(R 8 )SO 2 N(R 8 )— groups that interrupt or are at the terminus of the aliphatic chain;

R 3 is a hydrogen or halogen atom or group selected from —OR 3a , —SR 3a , —CN and an optionally substituted cycloaliphatic, heterocycloahiphatic, polycycloaliphatic, heteropolycycloaliphatic, aromatic or heteroaromatic group;

R 3a is hydrogen atom or an optionally substituted straight or branched C 1-6 alkyl group or C 3-8 cycloalkyl group;

n is zero or the integer 1; and

v is the integer 1, 2 or 3;

provided that when n is zero and L 1 is a covalent bond, v is the integer 1;

and the salts, solvates, hydrates and N-oxides thereof;

which comprises reacting a compound of formula (2):

wherein:

Q a is a group —N(R 4 )H;

and the salts, solvates, hydrates and N-oxides thereof;

with a compound Ar 1 W wherein

W is a group selected from X 1 , —COX 2 and —SO 2 X 3;

X 1 is a leaving atom or group;

X 2 is a halogen atom or a —OH group; and

X 3 is a halogen atom.

2. A process according to claim 1 wherein the reaction is carried out in a solvent in the presence of an acid when W is the group X 1 .

3. A process according to claim 2 wherein the solvent is selected from an alcohol, ether, acetic acid, water, acetonitrile, substituted amide or ester.

4. A process according to claim 2 wherein the reaction is carried out in an alcohol in the presence of an acid catalyst.

5. A process according to claim 1 wherein the reaction is carried out in the presence of a base, an organic amine or a cyclic amine and an organic solvent when W is the group COX 2 and X 2 is a halogen atom.

6. A process according to claim 5 wherein the organic solvent is selected from a halogenated hydrocarbon, a dipolar aprotic solvent, an ether or an ester.

7. A process according to claim 1 wherein the reaction is carried out in the presence of a condensing agent and a halogenated hydrocarbon, dipolar aprotic or an ether solvent when W is the group CO 2 H.

8. A process according to claim 1 wherein the reaction is carried out in the presence of a base, an organic amine or a cyclic amine and a halogenated hydrocarbon, dipolar aprotic or an ether solvent when W is the group SO 2 X 3 .

9. A process according to any one of claim 1 wherein the compound of formula (2) is prepared by reduction of a compound of formula (4):

10. A process according to claim 9 wherein the reduction is carried out by catalytic hydrogenation or by chemical reduction.

11. A process according to claim 1 wherein R 4 is a hydrogen atom.

12. A process according to claim 9 wherein the compound of formula (4) is prepared by reaction of a compound of formula (5):

with a compound of formula (6a) or (6b):

wherein R a represents a C 1-6 alkyl group or a silyl group.

13. A process according to claim 12 wherein the reaction is carried out in the presence of an organic solvent.

14. A process according to claim 13 wherein the solvent is selected from an aromatic hydrocarbon, a halogenated hydrocarbon or an ester.

15. A process according to claim 1 wherein R 1 is the group —CO 2 Alk 7 ; and

Alk 7 is a straight or branched optionally substituted C 1-8 alkyl group, an optionally substituted C 2-8 alkenyl group, an optionally substituted C 2-8 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 heterocycloalkyl group, an optionally substituted C 3-8 cycloalkylC 1-8 alkyl group, an optionally substituted C 3-8 heterocycloalkylC 1-8 alkyl group, an optionally substituted C 1-6 alkyloxyC 1-6 alkyl group, an optionally substituted hydroxyC 1-6 alkyl group, an optionally substituted C 1-6 alkylthioC 1-6 alkyl group, an optionally substituted C 1-6 alkylsulfinylC 1-6 alkyl group, an optionally substituted C 1-6 alkylsulfonylC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyloxy C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkylthioC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkylsulfinylC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkylsulfonylC 1-6 alkyl group, an optionally substituted C 1-6 alkyloxycarbonylC 1-6 alkyl group, an optionally substituted C 1-6 alkyloxycarbonylC 1-6 alkenyl group, an optionally substituted C 1-6 alkyloxycarbonyloxyC 1-6 alkyl group, an optionally substituted C 1-6 alkyloxycarbonyloxyC 1-6 alkenyl group, an optionally substituted C 3-8 cycloalkyloxycarbonyloxyC 1-6 alkyl group, an optionally substituted N-di-C 1-8 alkylaminoC 1-8 alkyl group, an optionally substituted N—C 6-12 aryl-N—C 1-6 alkylaminoC 1-6 alkyl group, an optionally substituted N-di-C 1-8 alkyl-carbamoylC 1-8 alkyl group, an optionally substituted C 6-12 arylC 1-6 alkyl group, an optionally substituted heteroC 6-10 arylC 1-6 alkyl group, an optionally substituted C 6-12 aryl group, an optionally substituted C 6-12 aryloxyC 1-8 alkyl group, an optionally substituted C 6-12 arylthioC 1-8 alkyl group, an optionally substituted C 6-12 arylsulfinylC 1-8 alkyl group, an optionally substituted C 6-12 arylsulfonylC 1-8 alkyl group, an optionally substituted C 1-8 alkanoyloxyC 1-8 alkyl group, an optionally substituted C 4-8 imidoC 1-8 group, an optionally substituted C 6-12 aroyloxyC 1-8 alkyl group, or a triglyceride.

16. A process according to claim 1 which comprises hydrolysing a compound of formula (1) in which R 1 is —CO 2 Alk 7 and Alk 7 is a straight or branched optionally substituted C 1-8 alkyl group, an optionally substitute C 2-8 alkenyl group, an optionally substituted C 2-8 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 heterocycloalkyl group, an optionailly substituted C 3-8 cycloalkylC 1-8 alkyl group, an optionally substituted C 3-8 heterocycloalkylC 1-8 alkyl group, an optionally substituted C 1-6 alkyloxyC 1-6 alkyl group, an optionally substituted hydroxyC 1-6 alkyl group, an optionally substituted C 1-6 alkylthioC 1-6 group, an optionally substituted C 1-6 alkylsulfinylC 1-6 alkyl group, an optionally substituted C 1-6 alkylsulfonylC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyloxyC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkylthioC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkylsulfinylC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkylsulfonylC 1-6 alkyl group, an optionally substituted C 1-6 akyloxycarbonylC 1-6 alkyl group, an optionally substituted C 1-6 alkyloxycarbonylC 1-6 alkenyl group, an optionally substitut C 1-6 alkyloxycarbonyloxyC 1-6 alkyl group, an optionally substituted C 1-6 alkyloxycarbonyloxyC 1-6 alkenyl group, an optionally substituted C 3-8 cycloalkyloxycarbonyloxyC 1-6 alkyl group, an optionally substituted N-di-C 1-8 alkylaminoC 1-8 alkyl group, an optionally substituted N—C 6-12 aryl-N—C 1-6 alkylaminoC 1-6 alkyl group, an optionally substituted N-di-C 1-8 alkyl-carbamoylC 1-8 alkyl group, an optionally substituted C 6-12 arylC 1-6 alkyl group, an optionally substituted heteroC 6-10 arylC 1-6 alkyl group, an optionally substituted C 6-12 aryl group, an optionally substituted C 6-12 aryloxyC 1-8 alkyl group, an optionally substituted C 6-12 arylthioC 1-8 alkyl group, an optionally substituted C 6-12 arylsulfinylC 1-8 alkyl group, an optionally substituted C 6-12 arylsulfonylC 1-8 alkyl group, an optionally substituted C 1-8 alkanoyloxyC 1-8 alkyl group, an optionally substituted C 4-8 imidoC 1-8 alkyl group, an optionally substituted C 6-12 aroyloxyC 1-8 alkyl group, or a triglyceride.

to produce a compound of formula (1) in which R 1 is —CO 2 H.

17. A process according to claim 1 which comprises esterifying a compound of formula (1) in which R 1 is —CO 2 H to produce a compound of formula (1) in which R 1 is —CO 2 Alk 7 and Alk 7 is a straight or branched optionally substituted C 1-8 alkyl group, an optionally substituted C 2-8 alkenyl group, an optionally substituted C 2-8 alkynyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 heterocycloalkyl group, an optionally substituted C 3-8 cycloalkylC 1-8 alkyl group, an optionally substituted C 3-8 hetrocycloalklyC 1-8 alkyl group, an optionally susbstituted C 1-6 alkyloxyC 1-6 alkyl group, an optionally substituted hydroxyC 1-6 alkyl group, an optionally substituted C 1-6 alkyltyhioC 1-6 alkyl group, an optionally substituted C 1-6 alkylsulfinylC 1-6 alkyl group, an optionally substituted C 1-6 alkylsulfonylC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyloxyC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkylthioC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkylsulfinylC 1-6 alkyl group, an optionally substituted C 3-8 cycloalkylsulfonylC 1-6 alkyl group, an optionally substituted C 1-6 alkyloxycarbonylC 1-6 alkyl group, an optionally substituted C 1-6 alkyloxycarbonylC 1-6 alkenyl group, an optionally substituted C 1-6 alkyloxycarbonyloxyC 1-6 alkyl group, an optionally substituted C 1-6 alkyloxycarbonyloxyC 1-6 alkenyl group, an optionally substituted C 3-8 cycloalkyloxycarbonyloxyC 1-6 alkyl group, an optionally substituted N-di-C 1-8 alkylaminoC 1-8 alkyl group, an optionally substituted N—C 6-12 aryl-N—C 1-6 alkylaminoC 1-6 alkyl group, an optionally substituted N-di-C 1-8 alkyl-carbamoylC 1-8 alkyl group, an optionally substituted C 6-12 arylC 1-6 alkyl group, an optionally substituted heteroC 6-10 arylC 1-6 alkyl group, an optionally substituted C 6-12 aryl group, an optionally substituted C 6-12 aryloxyC 1-8 alkyl group, an optionally substituted C 6-12 arylthioC 1-8 alkyl group, an optionally substituted C 6-12 arylsulfinylC 1-8 alkyl group, an optionally substituted C 6-12 arylsulfonylC 1-8 alkyl group, an optionally substituted C 1-8 alkanoyloxyC 1-8 alkyl group, an optionallly substituted C 4-8 imidoC 1-8 alkyl group, an optionally substituted C 6-12 aroyloxyC 1-8 alkyl group, or a triglyceride.

18. A process according to claim 1 for the preparation of compounds of formula (1b):

wherein

—G═ is —CR 18 ═, —N═ or 13 N(O)═;

R 16 , R 17 and R 18 , which may be the same of different, are each a hydrogen atom or -L 3 (Alk 2 ) t L 4 (R 5 ) u ;

L 3 and L 4 are, independently, a covalent bond, an —O— or —S— atom, or a —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —CON(R 8 )—, —OC(O)N(R 8 )—, —CSN(R 8 ), —N(R 8 )CO—, —N(R 8 )C(O)O—, —N(R 8 )CS—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —, —N(R 8 )O—, —ON(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CON(R 8 )—, —N(R 8 )CSN(R 8 )—, or —N(R 8 )SO 2 N(R 8 )— group;

R 8 is a hydrogen atom or an optionally substituted straight or branched C 1-6 alkyl group;

t is zero or the interger 1;

u is an interger 1, 2 or 3;

Alk 2 is an optionally substituted aliphatic chain or an optionally substituted heteroaliphatic chain containing one to four —O— or —S— atoms or —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —CON(R 8 )—, —OC(O)N(R 8 )—, —CSN(R 8 ), —N(R 8 )CO—, —N(R 8 )C(O)O—, —N(R 8 )CS—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —, —N(R 8 )O—, —ON(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CON(R 8 )—, —N(R 8 )CSN(R 8 )—, or —N(R 8 )SO 2 N(R 8 )— groups that interrupt or are at the terminus of the aliphatic chain;

R 5 is a hydrogen or halogen atom or an optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, —OR 6 , —SR 6 , —NR 6 R 7 , —NO 2 , —CN, —CO 2 R 6 , —SO 3 H, —SOR 6 , —SO 2 R 6 , —SO 3 R 6 , —OCO 2 R 6 , —CONR 6 R 7 , —OCONR 6 R 7 , —CSNR 6 R 7 , —COR 6 , —OCOR 6 , —N(R 6 )COR 7 , —N(R 6 )CSR 7 , —SO 2 N(R 6 )(R 7 ), —N(R 6 )SO 2 R 7 , N(R 6 )CON(R 7 )(R 19 ), —N(R 6 )CSN(R 7 )(R 19 ), or —N(R 6 )SO 2 N(R 7 )(R 19 ) group; and

R 6 , R 7 , and R 19 are, independently, a hydrogen atom or an optionally substituted C 1-6 alkyl or C 3-8 cycloalkyl group;

provided that when t is zero and each of the L 3 and L 4 is a covalent bond, then u is the integer 1 and R 5 is other than a hydrogen atom; and the salts, solvates, hydrates and N-oxides thereof.

19. A process according to claim 1 for the preparation of compounds of formula (1d):

wherein

g is the integer 1, 2, 3 or 4;

R 16 is -L 3 (Alk 2 ) t L 4 (R 5 ) u ;

L 3 and L 4 are, independently, a covalent bond, an —O— or —S— atom, or a —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —CON(R 8 )—, —OC(O)N(R 8 )—, —CSN(R 8 ), —N(R 8 )CO—, —N(R 8 )C(O)O—, —N(R 8 )CS—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —, —N(R 8 )O—, —ON(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CON(R 8 )—, —N(R 8 )CSN(R 8 )—, or —N(R 8 )SO 2 N(R 8 )— group;

R 8 is a hydrogen atom or an optionally substituted straight or branched C 1-6 alkyl group;

t is zero or the integer 1;

u is an integer 1, 2 or 3;

Alk 2 is an optionally substituted aliphatic chain or an optionally substituted heteroaliphatic chain containing one to four —O— or —S— atoms or —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —CON(R 8 )—, —OC(O)N(R 8 )—, —CSN(R 8 ), —N(R 8 )CO—, —N(R 8 )C(O)O—, —N(R 8 )CS—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —, —N(R 8 )O—, —ON(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CON(R 8 )—, —N(R 8 )CSN(R 8 )—, or —N(R 8 )SO 2 N(R 8 )— groups that interrupt or are at the terminus of the aliphatic chain;

R 5 is a hydrogen or halogen atom or an optionally substituted C 1-6 alkyl, optionally substituted (C 3-8 cycloalkyl, —OR 6 , —SR 6 , —NR 6 R 7 , —NO 2 , —CN, —CO 2 R 6 , —SO 3 H, —SOR 6 , —SO 2 R 6 , —SO 3 R 6 , —OCO 2 R 6 , —CONR 6 R 7 , —OCONR 6 R 7 , —CSNR 6 R 7 , —COR 6 , —OCOR 6 , —N(R 6 )COR 7 , —N(R 6 )CSR 7 , —SO 2 N(R 6 )(R 7 ), —N(R 6 )SO 2 R 7 , N(R 6 )CON(R 7 )(R 19 ) —N(R 6 )CSN(R 7 )(R 19 ), or —N(R 6 )SO 2 N(R 7 )(R 19 ) group; and

R 6 , R 7 , and R 19 are, independently, a hydrogen atom or an optionally substituted C 1-6 alkyl or C 3-8 cycloalkyl group;

provided that when t is zero and each of L 3 and L 4 is a covalent bond, then u is the integer 1 and R 5 is other than a hydrogen atom; and the salts, solvates, hydrates and N-oxides thereof.

20. A process according to claim 1 for the preparation of:

ethyl (2S)-2-[(2-bromo-3-oxospiro[3.5]non-1-en-1-yl)amino]-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate;

and the salts, solvates, hydrates and N-oxides thereof.

21. A process according to any one of the preceding claim 1 for the preparation of:

ethyl (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-[4([2,7]naphthyridin-1-ylamino)phenyl]propanoate;

and the salts, solvates, hydrates and N-oxides thereof.

22. A process according to claim 1 for the preparation of:

ethyl (2S)-2-[(2-isopropylsulfanyl-3-oxo-7-oxa-spiro[3.5]non-1-en-1yl)amino]-3-[4-([2,7]naphthyridin-1-ylamino)phenyl]propanoate;

and the salts, solvates, hydrates and N-oxides thereof.

23. A process according to claim 1 for the preparation of:

2-hydroxyethyl (2S)-2-(2-bromo-3-oxo-spiro[3.5]non-1-en-1-ylamino)-3-{4-[(3,5-dichloroisonicotinoyl)amino]phenyl}propanoate;

and the salts, solvates, hydrates and N-oxides thereof.

24. A compound of formula (2):

wherein:

R 1 is a carboxylic acid (—CO 2 H) or an acyclic of cyclic carboxylic acid ester, an amide, tetrazole, phosphonic acid, phosphinic acid, sulphonic acid, sulphinic acid, boronic acid, or an acylsulphonamide group;

R 2 is a hydrogen atom or a C 1-6 alkyl group;

R x , R y , and R z , which may be the same or different, are each —L 1 (Alk 1 ) n (R 3 ) v , or R z is —L 1 (Alk 1 ) n (R 3 ) v and R x and R y are joined together to form a optionally substituted spiro linked cycloaliphatic or heterocycloaliphatic group;

L 1 is a covalent bond or an —O—, —S—, or —Se— atom or an —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —CON(R 8 )—, —OC(O)N(R 8 )—, —CSN(R 8 ), —N(R 8 )CO—, —N(R 8 )C(O)O—, —N(R 8 )CS—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —, —N(R 8 )O—, —ON(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CON(R 8 )—, —N(R 8 )CSN(R 8 )—, or —N(R 8 ) SO 2 N(R 8 )— group;

R 8 is a hydrogen atom or an optionally substituted straight or branched C 1-6 alkyl group;

Alk 1 is an optionally substituted aliphatic chain or an optionally substituted heteroaliphatic chain containing one to four —O— or —S— atoms or —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —CON(R 8 )—, —OC(O)N(R 8 )—, —CSN(R 8 ), —N(R 8 )CO—, —N(R 8 )C(O)O—, —N(R 8 )CS—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —, —N(R 8 )O—, —ON(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CON(R 8 )—, —N(R 8 )CSN(R 8 )—, or —N(R 8 )SO 2 N(R 8 )— groups that interrupt or are at the terminus of the aliphatic chain;

R 3 is a hydrogen or halogen atom or group selected from —OR 3a —SR 3a , —CN and an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, heteropolycycloaliphatic, aromatic or heteroaromatic group;

R 3a is a hydrogen atom or an optionally substituted straight or branched C 1-6 alkyl group or C 3-8 cycloalkyl group;

n is zero or the integer 1; and

v is the integer 1, 2 or 3;

provided that when n is zero and L 1 is a covalent bond, v is the integer 1;

Q a is a group —N(R 4 )H;

R 4 is a hydrogen atom or an optionally substituted straight or branched C 1-6 alkyl group;

and the salts, solvates, hydrates and N-oxides thereof.

25. A compound according to claim 24 which is:

3-(4-aminophenyl)-2(S)-(3-oxo-7-oxaspiro[3.5]non-1-en-1-ylamino)propionic acid hydroxyethyl ester.

26. A compound of formula (4):

wherein:

R 1 is a carboxylic acid (—CO 2 H) or an acyclic or cyclic carboxylic acid ester, an amide, tetrazole, phosphonic acid, phosphinic acid, sulphonic acid, sulphinic acid, boronic acid, or an acylsulphonamide group;

R 2 is a hydrogen atom or a C 1-6 alkyl group;

R x , R y and R z , which may be the same or different, are each -L 1 (Alk 1 ) n (R 3 ) v , or R z is -L 1 (Alk 1 ) n (R 3 ) y and R x and R y are joined together to form an optionally substituted spiro linked cycloaliphatic or heterocycloaliphatic group;

L 1 is a covalent bond or an —O—, —S—, or —Se— atom or an —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —CON(R 8 )—, —OC(O)N(R 8 )—, —CSN(R 8 ), —N(R 8 )CO—, —N(R 8 )C(O)O—, —N(R 8 )CS—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —, —N(R 8 , —ON(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CON(R 8 )—, —N(R 8 )CSN(R 8 )—, or —N(R 8 )SO 2 N(R 8 )— group

R 8 is a hydrogen atom or an optionally substituted straight or branched C 1-6 alkyl group;

Alk 1 is an optionally substituted aliphatic chain or an optionally substituted heteroaliphatic chain containing one to four —O— or —S— atoms or —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —N(R 8 )—, —CON(R 8 )—, —OC(O)N(R 8 )—, —CSN(R 8 ), N(R 8 )CO—, —N(R 8 )C(O)O—, N(R 8 )CS—, —S(O) 2 N(R 8 )—, —N(R 8 )S(O) 2 —, —N(R 8 )O—, —ON(R 8 )—, —N(R 8 )N(R 8 )—, —N(R 8 )CON(R 8 )—, —N(R 8 )CSN(R 8 )—, or —N(R 8 )SO 2 N(R 8 )— groups that interrrupt or are at the terminus of the aliphatic chain;

R 3 is a hydrogen or halogen atom or group selected from —OR 3a , —SR 3a , —CN and an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, heteropolycycloaphatic, aromatic or heteroaromatic group;

R 3a is a hydrogen atom or an optionally substituted straight or branched C 1-6 alkyl group or C 3-8 cycloalkyl group;

n is zero or the integer 1; and

v is the integer 1, 2 or 3;

provided that when n is zero and L 1 is a covalent bond, v is the integer 1;

and the salts, solvates, hydrates and N-oxides thereof.

27. A compound according to claim 26 which is:

3-(4-nitrophenyl)-2(S)-(3-oxo-7-oxaspiro[3.5]non-1-en-1-ylamino)propionic acid hydroxyethyl ester.