Spirocyclic nitriles as protease inhibitors

1. A compound of the formula Ia,

where

the

 the radical is a spiro compound,

in which the sub-rings

 are combined to form a 6-azaspiro[2.5]octane or 5-azaspiro[2.5]octane ring which is unsubstituted or independently, according to the ring size, mono-, di-, tri-, or tetrasubstituted by R4, where

R4 is —NO 2 , —CN, ═O, ═S, —OH, —CF 3 , —SF 5 , —(C 0 -C 3 )-alkylene-S—R10, —O—CF 3 , —Si—(CH 3 ) 3 , —(C 0 -C 5 )-alkylene-O—C(O)—R21, —(C 0 -C 5 )-alkylene-C(O)—O—R10, —(C 0 -C 3 )-alkylene-O—R10, —(C 0 -C 3 )-alkylene-N(R21)-R22, —(C 0 -C 3 )-alkylene-N(R10)-S(O 2 )—R10, —(C 0 -C 5 )-alkylene-(C 3 -C 8 )-cycloalkyl-R23, —S—CF 3 , —(C 0 -C 5 )-alkylene-(C 1 -C 3 )-fluoroalkyl, —(C 0 -C 5 )-alkylene-N(R10)-C(O)—R21, —(C 0 -C 3 )-alkylene-C(O)—N(R21)-R22, —(C 0 -C 4 )-alkyl where alkyl is unsubstituted or mono-, di- or trisubstituted independently by R9, —(C 0 -C 4 )-alkylene-aryl where aryl is selected from the group of phenyl, indanyl, indenyl, and naphthyl, where aryl is unsubstituted or mono-, di- or trisubstituted independently by R8, or —(C 0 -C 4 )-alkylene-Het where Het is selected from the group of azetidinyl, benzimidazolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, dioxolyl, dioxanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, octahydroisoquinolinyl, oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, thiazolyl, thienyl, thienopyridinyl, thiomorpholinyl, and thiophenyl, and this Het radical is unsubstituted or independently mono-, di- or trisubstituted by R8;

R8 is halogen, carbamimidoyl, —NO 2 , ═O, —CF 3 , —SF 5 , —C(O)—O—R10, —CN, —C(O)—NH 2 , —OH, —NH 2 , —O—CF 3 , —C(O)—N(R10)-R20, —N(R10)-R20, —(C 3 -C 8 )-cycloalkyl, —O—(C 1 -C 8 )-alkyl, —O—(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl, —(C 1 -C 8 )-alkyl, or —(C 0 -C 4 )-alkylene-(C 3 -C 8 )-cycloalkyl, where the alkyl radicals mentioned are each unsubstituted or mono-, di- or trisubstituted independently by halogen, NH 2 , —OH, —O—CH 3 , —SO 2 —CH 3 or —SO 2 —CF 3 ;

R9 is halogen, —NO 2 , —CN, ═O, —OH, —CF 3 , —C(O)—O—R10, —C(O)—N(R21)-R22, —N(R21)-R22, —(C 3 -C 8 )-cycloalkyl, —(C 0 -C 3 )-alkylene-O—R10, —Si—(CH 3 ) 3 , —N(R10)-S(O) u —R10 where u is the integer 1 or 2, —S—R10, —SO r —R10 where r is the integer 1 or 2, —S(O) v —N(R10)-R20 where v is the integer 1 or 2, —C(O)—R10, —(C 1 -C 8 )-alkyl, —(C 1 -C 8 )-alkoxy, phenyl, phenyloxy-, —(C 1 -C 3 )-fluoroalkyl, —O—R19, —NH—C(O)—NH—R10, —(C 0 -C 4 )-alkyl-C(O)—O—C(R11, R19)-O—C(O)—R12, —NH—C(O)—NH—R21, —N(R21)-C(O)—R22, —(C 0 -C 4 )-alkyl-C(O)—O—C(R11, R19)-O—C(O)—O—R12, —NH—C(O)—O—R10, —O—CF 3 or Het where Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently by R8;

R10 and R20 are the same or different and are each independently a hydrogen atom, —(C 1 -C 6 )-alkyl, —(C 0 -C 4 )-alkyl-OH, —(C 1 -C 3 )-fluoroalkyl, —(C 0 -C 4 )-alkyl-O—(C 1 -C 4 )-alkyl, —(C 0 -C 5 )-alkyl-(C 3 -C 8 )-cycloalkyl, —(C 0 -C 2 )-alkylene-aryl where aryl is as defined above and is unsubstituted or mono-, di- or trisubstituted independently by —(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkyl, halogen or —(C 3 -C 8 )-cycloalkyl, or —(C 0 -C 2 )-alkylene-Het where Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently by —(C 1 -C 6 )-alkyl, —O—(C 1 -C 6 )-alkyl, halogen or —(C 3 -C 8 )-cycloalkyl;

R11 and R19 are the same or different and are each independently a hydrogen atom or —(C 1 -C 6 )-alkyl;

R12 is —(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-alkyl-OH, —(C 1 -C 6 )-alkyl-O—(C 1 -C 6 )-alkyl, —(C 3 -C 8 )-cycloalkyl, —(C 1 -C 6 )-alkyl-O—(C 1 -C 8 )-alkyl-(C 3 -C 8 )-cycloalkyl, or —(C 1 -C 6 )-alkyl-(C 3 -C 8 )-cycloalkyl, where the cycloalkyl radical is unsubstituted or mono-, di- or trisubstituted independently by —OH, —O—(C 1 -C 4 )-alkyl or R10;

R21 and R22 are the same or different and are each independently a hydrogen atom, —(C 1 -C 6 )-alkyl where alkyl is unsubstituted or mono-, di- or trisubstituted independently by R8, —(C 0 -C 6 )-alkylene-(C 3 -C 8 )-cycloalkyl, —SO t —R10 where t is the integer 1 or 2, —(C 1 -C 3 )-fluoroalkyl, —O—R12, —(C 0 -C 6 )-alkylene-aryl where aryl is as defined above and alkylene and aryl are each unsubstituted or mono-, di- or trisubstituted independently by R8 or —(C 0 -C 6 )-alkylene-Het where Het is as defined above and alkylene and Het are each unsubstituted or mono-, di- or trisubstituted independently by R8;

R21 and R22, together with the nitrogen atom to which they are bonded, form a four- to eight-membered monocyclic heterocyclic ring which, as well as the nitrogen atom, additionally, according to the ring size, may contain one or two identical or different heteroatoms selected from the group of oxygen, nitrogen and sulfur and in which the heterocycle is unsubstituted or mono-, di- or trisubstituted independently by R8;

R23 is a hydrogen atom, —OH or —O—(C 1 -C 4 )-alkyl;

X is a covalent bond, —N(R7)- or —O—, where

R7 is a hydrogen atom, —(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl or —(C 1 -C 4 )-alkyl;

Y is —C(O)—, —C(S)—or —S(O 2 )—;

p is the integer 1 or 2;

R27 is a hydrogen atom, —(C 1 -C 6 )-alkyl, halogen, —(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl, —(C 0 -C 4 )-alkylene-Het where Het is as defined above and is unsubstituted or substituted by halogen, —(C 1 -C 6 )-alkyl, —O—(C 1 -C 3 )-fluoroalkyl or —O—(C 1 -C 6 )-alkyl, or —(C 0 -C 2 )-alkylene-phenyl where phenyl is unsubstituted or substituted by halogen, —(C 1 -C 6 )-alkyl, —O—(C 1 -C 3 )-fluoroalkyl or —O—(C 1 -C 6 )-alkyl;

R26 is a hydrogen atom, —(C 1 -C 4 )-alkyl or —(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl;

R24 and R25 are the same or different and are each independently a hydrogen atom, —(C 1 -C 6 )-alkyl, —(C 1 -C 3 )-fluoroalkyl, —(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl, —(C 0 -C 4 )-alkylene-aryl where aryl is as defined above and is unsubstituted or mono-, di- or trisubstituted independently by R8, or —(C 0 -C 4 )-alkylene-Het where Het is as defined above and is unsubstituted or mono-, di- or trisubstituted independently by R8; or

R24 and R25, together with the carbon atom to which they are bonded, form a three- to six-membered cycloalkyl ring which is unsubstituted or mono-, di- or trisubstituted independently by R10 or fluorine; or

R24 and R25, together with the carbon atom to which they are bonded, form a three- to six-membered heterocycloalkyl radical which is unsubstituted or mono-, di- or trisubstituted independently by R10 or fluorine;

or a physiologically tolerated salt thereof.

2. The compound of claim 1 wherein

the sub-rings

 are combined to form a 6-azaspiro[2.5]octane or 5-azaspiro[2.5]octane ring which is unsubstituted or independently, according to the ring size, mono-, di- or trisubstituted by R4;

R4 is ═O, ═S, —(C 0 -C 3 )-alkylene-C(O)—O—R10, —(C 0 -C 3 )-alkylene—N(R21)-R22, —(C 0 -C 3 )-alkylene-NH—C(O)—R21, —(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl-R23, —(C 0 -C 3 )-alkylene-O—R10, —(C 0 -C 4 )-alkylene-phenyl, where phenyl is unsubstituted or mono-, di- or trisubstituted independently by R8, or —(C 0 -C 4 )-alkyl where alkyl is unsubstituted or mono-, di- or trisubstituted independently by R9;

R8 is fluorine, chlorine, bromine, —O—(C 1 -C 3 )-fluoroalkyl or —O—(C 1 -C 4 )-alkyl;

R9 is halogen, —NO 2 , —CN, ═O, —OH, —CF 3 , —C(O)—O—R10, —C(O)—N(R21)-R22, —N(R21)-R22, —(C 3 -C 8 )-cycloalkyl, —(C 0 -C 3 )-alkylene-O—R10, —Si—(CH 3 ) 3 , —N(R10)-S(O) u —R10 where u is the integer 1 or 2, —S—R10, —SO r —R10 where r is the integer 1 or 2, —S(O) v —N(R10)-R20 where v is the integer 1 or 2, —C(O)—R10, —(C 1 -C 8 )-alkyl, —(C 1 -C 8 )-alkoxy, phenyl, phenyloxy-, —(C 1 -C 3 )-fluoroalkyl, —O—R19, —NH—C(O)—NH—R10, —(C 0 -C 4 )-alkyl-C(O)—O—C(R11, R19)-O—C(O)—R12, —NH—C(O)—NH—R21, —N(R21)-C(O)—R22, —(C 0 -C 4 )-alkyl-C(O)—O—C(R11, R19)-O—C(O)—O—R12, —NH—C(O)—O—R10 or —O—CF 3 ;

R10 and R20 are the same or different and are each independently a hydrogen atom or —(C 1 -C 6 )-alkyl;

R11 and R19 are the same or different and are each independently a hydrogen atom or —(C 1 -C 6 )-alkyl;

R12 is —(C 1 -C 6 )-alkyl, —(C 1 -C 6 )-alkyl-OH, —(C 1 -C 6 )-alkyl-O—(C 1 -C 6 )-alkyl, —(C 3 -C 8 )-cycloalkyl, —(C 1 -C 6 )-alkyl-O—(C 1 -C 8 )-alkyl-(C 3 -C 8 )-cycloalkyl, —(C 1 -C 6 )-alkyl-(C 3 -C 8 )-cycloalkyl, where the cycloalkyl radical is unsubstituted or mono-, di- or trisubstituted independently by —OH, —O—(C 1 -C 4 )-alkyl or R10;

R21 and R22 are the same or different and are each independently a hydrogen atom, —(C 1 -C 6 )-alkyl, —O—R12, —(C 0 -C 6 )-alkylene-(C 3 -C 8 )-cycloalkyl, —SO t —R10 where t is the integer 1 or 2, or —(C 1 -C 3 )-fluoroalkyl;

R23 is a hydrogen atom, —OH or —O—(C 1 -C 4 )-alkyl;

X is a covalent bond or —N(R7)- where

R7 is a hydrogen atom or —(C 1 -C 4 )-alkyl;

Y is —C(O)—or —S(O 2 )—;

p is the integer 1 or 2;

R26 is a hydrogen atom;

R27 is a hydrogen atom, —(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl, —(C 1 -C 6 )-alkyl, —(C 0 -C 2 )-alkylene-phenyl where phenyl is unsubstituted or substituted by halogen, —(C 1 -C 6 )-alkyl, —O—(C 1 -C 3 )-fluoroalkyl or —O—(C 1 -C 6 )-alkyl, or —(C 0 -C 2 )-alkylene-pyridyl;

R24 and R25 are the same or different and are each independently a hydrogen atom, —(C 1 -C 4 )-alkyl or —(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl, or

R24 and R25, together with the carbon atom to which they are bonded, form a cycloalkyl ring which is selected from the group of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and is unsubstituted or mono-, di- or trisubstituted independently by R10 or fluorine, or

R24 and R25, together with the carbon atom to which they are bonded, form a three- to six-membered heterocycloalkyl radical selected from the group of aziridine, azetidine, diazetidine, diaziridine, hexohydropyridazine, hexohydropyrimidine, imidazolidine, morpholine, oxadiazinane, oxadiazolidine, oxathianane, oxathiolane, oxazetidine, oxazolidine, oxetane, oxirane, piperazine, piperidine, pyrazolidine, pyrrolidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, tetrazinane, thiadiazolidine, thiazetidine, thiaziridine, thiazolidine, thietane, thiirane, thiomorpholine, triazetidine, triazinane or triazolidine, which is unsubstituted or mono-, di- or trisubstituted independently by R10 or fluorine;

or a physiologically tolerated salt thereof.

3. The compound of claim 1 wherein

the sub-rings

 are combined to form a 6-azaspiro[2.5]octane or 5-azaspiro[2.5]octane ring are unsubstituted or independently, according to the ring size, mono-, di- or tri-substituted by R4 where

R4 is —O—(C 1 -C 4 )-alkyl, ═O, —(C 0 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl, —(C 1 -C 4 )-alkyl or —(C 0 -C 4 )-alkylene-phenyl where phenyl is unsubstituted or substituted by F, Cl, Br or —O—(C 1 -C 4 )-alkyl,

X is a covalent bond or —NH—,

Y is —C(O)— or —S(O 2 )—,

p is the integer 1,

R27 is a hydrogen atom, —(C 1 -C 6 )-alkyl, 4-F-benzyl or benzyl,

R26 is a hydrogen atom,

R24 and R25 are the same or different and are each independently a hydrogen atom, methyl or ethyl, or

R24 and R25, together with the carbon atom to which they are bonded, form a cyclopropyl or cyclobutyl radical, or

R24 and R25, together with the carbon atom to which they are bonded, form a piperidine ring which is unsubstituted or substituted by —(C 1 -C 4 )-alkyl;

or a physiologically tolerated salt thereof.

4. The compound of claim 1 selected from the group consisting of:

N—[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-6-azaspiro[2.5]octane-6-carboxamide,

N—[(S)-1-(cyanomethylcarbamoyl)-3,3-difluoro-butyl]-6-azaspiro[2.5]octane-6-carboxamide,

N—[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-6-azaspiro[2.5]octane-6-carboxamide,

N—[(S)-1-(4-cyano-1-methylpiperidin-4-ylcarbamoyl)-3,3-difluorobutyl]-6-azaspiro[2.5]octane-6-carboxamide,

N—[(S)-1-(4-cyano-1-methylpiperidin-4-ylcarbamoyl)-3,3-difluorohexyl]-6-azaspiro[2.5]octane-6-carboxamide, and

N—[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoropentyl]- or N—[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-6-azaspiro[2.5]octane-6-carboxamide;

or a physiologically tolerated salt thereof.

5. A process for preparing the compound of claim 1 or an N-oxide thereof, which comprises

a) reacting a compound of the formula II:

 where A and B are each as defined in claim 1 for the compound of the formula Ia, with a compound of the formula IIIa or IIIb or IIIc:

 where R1 is hydrogen, R2 is hydrogen, R3 is (CH 2 ) p F 2 R27, and X and R27 are each as defined in claim 1 for the compound of the formula Ia, PG is an ester protecting group and “activated” means that the amine is present in an activated form, to give a compound of the formula IVa or IVb:

 and reacting the resulting compound of the formula IVa or IVb, after converting the ester to the carboxylic acid, with Z to give the compound of the formula Ia, wherein Z is H—N(R26)-(C(R24)(R25))-CN, and wherein R24, R25, and R26 are as defined in claim 1 , or

b) reacting a compound of the formula Va or Vb where A, B, X and Y are each as defined in claim 1 for the compound of the formula Ia

 with a compound of the formula VI where R1, R2 and R3 are each as defined above and PG is an ester protecting group

 to give a compound of the formula IVa or IVb, and reacting the resulting compound of the formula IVa or IVb, after converting the ester protecting group to the carboxylic acid, with Z to give the compound of the formula Ia, or

c) reacting a compound of the formula VIIa or VIIb where A, B and X are each as defined in claim 1 for the compound of the formula Ia

 with a compound of the formula VI

 to give a compound of the formula VIIIa or VIIIb and reacting the resulting compound of the formula VIIIa or VIIIb, after converting the ester to the corresponding carboxylic acid, with Z to give the compound of the formula Ia, or

d) reacting a compound of the formula IX:

 with an amine Z where Z is as define above to give a compound of the formula X:

 and then converting the compound X thus obtained by a protecting group elimination to give a compound of the formula XI:

 and then reacting this compound XI with a compound Va or Vb, as detailed under b), to give the compound of the formula Ia, or

e) separating a compound of the formula Ia prepared by processes a), b), c) or d), into the pure enantiomers or diastereomers by salt formation with enantiomerically pure salts or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds, separating the diastereomers thus obtained, and eliminating the chiral auxiliary groups, or

f) either isolating the compound of the formula Ia prepared by processes a), b), c) or d) in free form or releasing it from physiologically incompatible salts or, in the case of the presence or acidic or basic groups, converting it to physiologically acceptable salts, or

g) converting the compound of the formula Ia prepared by processes a), b), c) or d), in the case of the presence of an N-oxide, to the free amine or the salt of an amine.

6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.

7. The compound of claim 1 which is N—[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorobutyl]-6-azaspiro[2.5]octane-6-carboxamide or a physiologically tolerated salt thereof.

8. The compound of claim 1 which is N—[(S)-1-(cyanomethylcarbamoyl)-3,3-difluoro-butyl]-6-azaspiro[2.5]octane-6-carboxamide or a physiologically tolerated salt thereof.

9. The compound of claim 1 which is N—[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluorohexyl]-6-azaspiro[2.5]octane-6-carboxamide or a physiologically tolerated salt thereof.

10. The compound of claim 1 which is N—[(S)-1-(4-cyano-1-methylpiperidin-4-ylcarbamoyl)-3,3-difluorobutyl]-6-azaspiro[2.5]octane-6-carboxamide or a physiologically tolerated salt thereof.

11. The compound of claim 1 which is N—[(S)-1-(4-cyano-1-methylpiperidin-4-ylcarbamoyl)-3,3-difluorohexyl]-6-azaspiro[2.5]octane-6-carboxamide or a physiologically tolerated salt thereof.

12. The compound of claim 1 which is N—[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoropentyl]-6-azaspiro[2.5]octane-6-carboxamide or a physiologically tolerated salt thereof.

13. The compound of claim 1 which is N—[(S)-1-(1-cyanocyclopropylcarbamoyl)-3,3-difluoro-4-phenylbutyl]-6-azaspiro[2.5]octane-6-carboxamide or a physiologically tolerated salt thereof.

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 2 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 3 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 4 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 7 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 8 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 9 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 10 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 11 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 12 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 13 or a physiologically tolerated salt thereof and a pharmaceutically acceptable carrier.