Carboxamide compounds and their use as calpain inhibitors v

Abstract

The present invention relates to novel carboxamide compounds and their use for the manufacture of a medicament. The carboxamide compounds are inhibitors of calpain (calcium dependant cysteine proteases). The invention therefore also relates to the use of these carboxamide compounds for treating a disorder associated with an elevated calpain activity. The carboxamide compounds are compounds of the general formula I in which R 1 , R 2 , R 3 R 4 , R 5 , m and n have the meanings mentioned in the claims and the description, the tautomers thereof, the hydrates thereof and the pharmaceutically suitable salts thereof. Of these compounds those are preferred wherein R 1 is optionally substituted phenyl-C 1 -C 2 -alkyl or hetaryl-C 1 -C 2 -alkyl, R 2 is optionally substituted aryl, hetaryl, aryl-C 1 -C 6 -alkyl, aryl-C 2 -C 6 -alkenyl or hetaryl-C 1 -C 4 -alkyl, R 3 is C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 2 -C 4 -alkenyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 2 -alkyl, or phenyl-C 1 -C 3 -alkyl, R 4 and R 5 independently of one another are halogen, CF 3 , CHF 2 , CH 2 F, C 1 -C 2 -alkyl or C 1 -C 2 -alkoxy, and m and n independently of one another are 0 or 1.

1 . A carboxamide compound of the formula I 
       
         
           
           
               
               
           
         
         in which 
         R 1  is C 1 -C 10 -alkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, where the last 3 radicals mentioned may be partly or completely halogenated and/or have 1, 2 or 3 substituents R 1a ,
 C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, where a CH 2  group in the cycloalkyl moiety of the last two radicals mentioned may be replaced by O, NH, or S, or two adjacent C atoms may form a double bond, where the cycloalkyl moiety may further have 1, 2, 3 or 4 radicals R 1b , 
 aryl, hetaryl, aryl-C 1 -C 6 -alkyl, aryl-C 2 -C 6 -alkenyl, hetaryl-C 1 -C 4 -alkyl or hetaryl-C 2 -C 6 -alkenyl, where aryl and hetaryl in the last 6 radicals mentioned may be unsubstituted or carry 1, 2, 3 or 4 identical or different radicals R 1c ; where 
 R 1a  is selected independently of one another from OH, SH, COOH, CN, OCH 2 COOH, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 3 -C 7 -cycloalkyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, COOR a1 , CONR a2 R a3 , SO 2 NR a2 R a3 ,
 —NR a2 —SO 2 —R a4 , NR a2 —CO—R a5 , SO 2 —R a4  and NR a6 R a7 , 
 
 R 1b  is selected independently of one another from OH, SH, COOH, CN, OCH 2 COOH, halogen, phenyl which optionally has 1, 2 or 3 substituents R 1d ,
 C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, where the alkyl moieties in the last 3 substituents mentioned may be partly or completely halogenated and/or have 1, 2 or 3 substituents R 1a , 
 COOR b1 , CONR b2 R b3 , SO 2 NR b2 R b3 , NR b2 —SO 2 —R b4 , NR b2 —CO—R b5  SO 2 —R b4  and NR b6 R b7 , 
 in addition two R 1b  radicals may together form a C 1 -C 4 -alkylene group, or 2 R 1b  radicals bonded to adjacent C atoms of cycloalkyl may form together with the carbon atoms to which they are bonded also a benzene ring, 
 
 R 1c  is selected independently of one another from OH, SH, halogen, NO 2 , NH 2 , CN, COOH, OCH 2 COOH, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkylthio, where the alkyl moieties in the last 4 substituents mentioned may be partly or completely halogenated and/or have 1, 2 or 3 substituents R 1a ,
 C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 7 -cycloalkyloxy, where the cycloalkyl moiety of the last three radicals mentioned may have 1, 2, 3 or 4 R 1b  radicals, 
 aryl, hetaryl, O-aryl, O—CH 2 -aryl, where the last three radicals mentioned are unsubstituted in the aryl moiety or may carry 1, 2, 3 or 4 R 1d  radicals, 
 COOR c1 , CONR c2 R c3 , SO 2 NR c2 R c3 , NR c2 —SO 2 —R c4  NR c2 —CO—R c5 , SO 2 —R c4 , 
 —(CH 2 ) p —NR c6 R c7  with p=0, 1, 2, 3, 4, 5 or 6 and 
 O—(CH 2 )—NR c6 R c7  with q=2, 3, 4, 5 or 6; where 
 R a1 , R b1  and R c1  are independently of one another H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl which has 1, 2 or 3 substituents R 1a , or C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 7 -heterocycloalkyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, aryl, aryl-C 1 -C 4 -alkyl, hetaryl or hetaryl-C 1 -C 4 -alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rid, 
 R a2 , R b2  and R c2  are independently of one another H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl which has 1, 2 or 3 substituents R 1a , or C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 7 -heterocycloalkyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, aryl, aryl-C 1 -C 4 -alkyl, hetaryl or hetaryl-C 1 -C 4 -alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rd, and 
 R a3 , R b3  and R c3  are independently of one another H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl which has 1, 2 or 3 substituents R 1a , or C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 7 -heterocycloalkyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, aryl, aryl-C 1 -C 4 -alkyl, hetaryl or hetaryl-C 1 -C 4 -alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R 1d , or the two radicals R a2  and R a3 , or R b2  and R b3  or R c2  and R c3  form together with the N atom a 3 to 7-membered, optionally substituted nitrogen heterocycle which may optionally have 1, 2 or 3 further different or identical heteroatoms from the group of O, N, S as ring members, 
 R a4 , R b4  and R c4  are independently of one another C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl which has 1, 2 or 3 substituents R 1a , or C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 7 -heterocycloalkyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, aryl, aryl-C 1 -C 4 -alkyl, hetaryl or hetaryl-C 1 -C 4 -alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rd, and 
 R a5 , R b5  and R c5  have independently of one another one of the meanings mentioned for R a1 , R b1  and R c1 ; 
 R a6 , R b6  and R c6  are independently of one another H, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl which has 1, 2 or 3 substituents R 1a , or C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 7 -heterocycloalkyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl, SO 2 —C 1 -C 6 -alkyl, aryl, hetaryl, O-aryl, OCH 2 -aryl, aryl-C 1 -C 4 -alkyl, hetaryl-C 1 -C 4 -alkyl, CO-aryl, CO-hetaryl, CO-(aryl-C 1 -C 4 -alkyl), CO-(hetaryl-C 1 -C 4 -alkyl), CO—O-aryl, CO—O-hetaryl, CO—O-(aryl-C 1 -C 4 -alkyl), CO—O-(hetaryl-C 1 -C 4 -alkyl), SO 2 -aryl, SO 2 -hetaryl, SO 2 -(aryl-C 1 -C 4 -alkyl) or SO 2 -(hetaryl-C 1 -C 4 -alkyl), where aryl and hetaryl in the last 18 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R 1d , and 
 R a7 , R b7  and R c7  are independently of one another H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkyl which has 1, 2 or 3 substituents R 1a , or C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 7 -heterocycloalkyl-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, aryl, aryl-C 1 -C 4 -alkyl, hetaryl or hetaryl-C 1 -C 4 -alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R 1d , or the two radicals R a6  and R a7 , or R b6  and R b7  or R c6  and R c7  form together with the N atom a 3 to 7-membered, optionally substituted nitrogen heterocycle which may optionally have 1, 2 or 3 further different or identical heteroatoms from the group of O, N and S as ring members, 
 or two radicals R 1b  or two radicals R 1c  bonded to adjacent C atoms form together with the C atoms to which they are bonded a 4, 5, 6 or 7-membered, optionally substituted carbocycle or an optionally substituted heterocycle which has 1, 2 or 3 different or identical heteroatoms from the group of O, N and S as ring members; 
 
 R 1d  is selected from halogen, OH, SH, NO 2 , COOH, C(O)NH 2 , CHO, CN, NH 2 , OCH 2 COOH, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl, NH—C 1 -C 6 -alkyl, NHCHO, NH—C(O)C 1 -C 6 -alkyl, and SO 2 —C 1 -C 6 -alkyl; 
 
         R 2  is C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 4 -alkyl, where a CH 2  group in the cycloalkyl moiety of the last two radicals mentioned may be replaced by O, NH, or S, or two adjacent C atoms may form a double bond, where the cycloalkyl moiety may additionally have 1, 2, 3 or 4 R 2b  radicals;
 aryl, O-aryl, O—CH 2 -aryl, hetaryl, aryl-C 1 -C 6 -alkyl, aryl-C 2 -C 6 -alkenyl, hetaryl-C 1 -C 4 -alkyl or hetaryl-C 2 -C 6 -alkenyl, where aryl and hetaryl in the last 8 radicals mentioned may be unsubstituted or carry 1, 2, 3 or 4 identical or different R 2c  radicals; where 
 R 2b  has one of the meanings indicated for R 1b , and 
 R 2c  has one of the meanings indicated for R 1c ; 
 
         R 3  is C 1 -C 4 -haloalkyl or C 1 -C 6 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 2 -alkyl, C 3 -C 6 -heterocycloalkyl-C 1 -C 2 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 2 -alkyl, where alkyl, alkenyl, alkoxy, alkynyl, cycloalkyl, heterocycloalkyl in the last 7 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R xa ,
 aryl, aryl-C 1 -C 4 -alkyl, hetaryl or hetaryl-C 1 -C 4 -alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R xd , 
 where R xa  has one of the meanings indicated for R 1a , and R xd  has one of the meanings indicated for R 1d ; 
 
         R 4  and R 5  are selected independently of one another from halogen, NH 2 , CN, CF 3 , CHF 2 , CH 2 F, O—CF 3 , O—CHF 2 , O—CH 2 F, COOH, OCH 2 COOH, C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl, C 1 -C 2 -alkylthio, CH 2 NRR′, where
 R and R′ are selected independently of one another from hydrogen and C 1 -C 4 -alkyl; 
 
         m is 0, 1 or 2; 
         n is 0, 1 or 2; and 
         the tautomers thereof, the hydrates thereof, the prodrugs thereof and the pharmaceutically suitable salts thereof. 
       
     
     
         2 . The carboxamide compound of  claim 1 , in which m is 0 or 1 and, when m=1, R 5  is selected from F, Cl, CN, CF 3 , C 1 -C 2 -alkyl and C 1 -C 2 -alkoxy. 
     
     
         3 . The carboxamide compound of  claim 1 , in which n is 0 or 1 and, when n=1, R 4  is selected from F, Cl, CN, CF 3 , C 1 -C 2 -alkyl and C 1 -C 2 -alkoxy. 
     
     
         4 . The carboxamide compound of  claim 1 , in which R 3  is selected from C 1 -C 6 -alkyl, C 1 -C 3 -haloalkyl, C 3 -C 5 -alkenyl, C 3 -C 5 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 2 -alkyl, C 3 -C 6 -heterocycloalkyl-C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl, aryl and aryl-C 1 -C 3 -alkyl. 
     
     
         5 . The carboxamide compound of  claim 4 , in which R 3  is selected from methyl, ethyl, n-propyl, isopropyl, propenyl, but-2-enyl, but-3-enyl, propinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-methyl and 2-(morpholin-4-yl)ethyl. 
     
     
         6 . The carboxamide compound of  claim 4 , in which R 3  is selected from C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 3 -C 5 -alkenyl, C 3 -C 5 -alkynyl, C 3 -C 6 -cycloalkyl, C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl, aryl and aryl-C 1 -C 3 -alkyl. 
     
     
         7 . The carboxamide compound of  claim 6 , in which R 3  is selected from methyl, ethyl, propenyl, but-2-enyl, but-3-enyl, propinyl, cyclopropanyl, cyclopropanyl-methyl, phenyl and benzyl. 
     
     
         8 . The carboxamide compound of  claim 1 , in which R 1  is selected from C 1 -C 10 -alkyl which may be partly or completely halogenated and/or have 1, 2 or 3 substituents R 1a ,
 C 3 -C 7 -cycloalkyl-methyl, where the cycloalkyl moiety may have 1, 2, 3 or 4 radicals R 1b ,   benzyl and hetaryl-methyl, where phenyl and hetaryl in the last 2 radicals mentioned may be unsubstituted or carry 1, 2, 3 or 4 identical or different radicals R 1c .   
     
     
         9 . The carboxamide compound of  claim 8 , in which R 1  is benzyl, which may be unsubstituted or carry 1 or 2 identical or different radicals selected from halogen, C 1 -C 2 -alkyl and C 1 -C 2 -alkoxy. 
     
     
         10 . The carboxamide compound of  claim 1 , in which R 2  is selected from aryl, hetaryl, aryl-C 1 -C 6 -alkyl, aryl-C 2 -C 6 -alkenyl and hetaryl-C 1 -C 4 -alkyl, where aryl and hetaryl in the last 5 radicals mentioned may be unsubstituted or carry 1, 2, 3 or 4 identical or different radicals R 2c . 
     
     
         11 . The carboxamide compound of  claim 10 , in which R 2  is phenyl, which may be unsubstituted or carry 1 or 2 identical or different radicals R 2c . 
     
     
         12 . The carboxamide compound of  claim 10 , in which R 2  is phenyl, which may be unsubstituted or carry 1 or 2 identical or different radicals selected from halogen, C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy and
 —(CH 2 ) p —NR c6 R c7  with p=0, 1 or 2, where   R c6  is selected from the group consisting of H and C 1 -C 4 -alkyl and.   R c7  is selected from the group consisting of H and C 1 -C 4 -alkyl or   the two radicals R c6  and R c7  form together with the N atom a 5, 6 or 7-membered,   saturated nitrogen heterocycle which may optionally have further different or identical heteroatom from the group of O, N and S as ring member and where the nitrogen heterocycle is unsubstituted or carries 1, 2 or 3 substituents selected from C 1 -C 4 -alkyl.   
     
     
         13 . The carboxamide compound of  claim 1 , which has the S configuration at the carbon atom carrying the group R 1 . 
     
     
         14 . A carboxamide compound which is selected from the group consisting of
 2-[3-(4-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]pyridine-3-carboxamide,   (2R)-2-[3-(4-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]pyridine-3-carboxamide,   (2S)-2-[3-(4-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]pyridine-3-carboxamide,   N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-(4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   2-(4-Fluoro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide,   (2R)-2-(4-Fluoro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide,   (2S) 2-(4-Fluoro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide,   N-[4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(4-methyl-3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,   (2R)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(4-methyl-3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,   (2S)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(4-methyl-3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,   N-(1-(4-Fluorophenyl)-4-(methoxyamino)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-(1-(4-Fluorophenyl)-4-(methoxyamino)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-(1-(4-Fluorophenyl)-4-(methoxyamino)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-(1-(3-Fluorophenyl)-4-(methoxyamino)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-(1-(3-Fluorophenyl)-4-(methoxyamino)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-(1-(3-Fluorophenyl)-4-(methoxyamino)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-(4-(Ethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-(4-(Ethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-(4-(Ethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-(4-(Allyloxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-(4-(Allyloxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-(4-(Allyloxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-(4-(Methoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-(4-(Methoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-(4-(Methoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   2-(4-Chloro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide,   (2R)-2-(4-Chloro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide,   (2S)-2-(4-Chloro-3-phenyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide,   N-[4-(Isopropoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-[4-(Isopropoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-[4-(Isopropoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-[3,4-Dioxo-1-phenyl-4-(propoxyamino)-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-[3,4-Dioxo-1-phenyl-4-(propoxyamino)-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-[3,4-Dioxo-1-phenyl-4-(propoxyamino)-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[4-(4-morpholinyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,   (2R)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[4-(4-morpholinyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,   (2S)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[4-(4-morpholinyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,   N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[4-(4-morpholinylmethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,   (2R)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[4-(4-morpholinylmethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,   (2S)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[4-(4-morpholinylmethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,   2-(3-{4-[(Diethylamino)methyl]phenyl}-1H-pyrazol-1-yl)-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide,   (2R)-2-(3-{4-[(Diethylamino)methyl]phenyl}-1H-pyrazol-1-yl)-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide,   (2S)-2-(3-{4-[(Diethylamino)methyl]phenyl}-1H-pyrazol-1-yl)-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide,   N-(4-{[(2-Methyl-2-propanyl)oxy]amino}-3,4-dioxo-1-phenyl-2-butanyl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-(4-{[(2-Methyl-2-propanyl)oxy]amino}-3,4-dioxo-1-phenyl-2-butanyl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-(4-{[(2-Methyl-2-propanyl)oxy]amino}-3,4-dioxo-1-phenyl-2-butanyl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-{4-[(Cyclopentyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-{4-[(Cyclopentyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-{4-[(Cyclopentyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-[4-(Ethoxyamino)-1-(4-fluorophenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-[4-(Ethoxyamino)-1-(4-fluorophenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-[4-(Ethoxyamino)-1-(4-fluorophenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-[4-(Ethoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-[4-(Ethoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-[4-(Ethoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-{4-[(Cyclobutyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-{4-[(Cyclobutyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-{4-[(Cyclobutyloxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-{4-[(2,2-Dimethylpropoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-{4-[(2,2-Dimethylpropoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-{4-[(2,2-Dimethylpropoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-(4-{[2-(4-Morpholinyl)ethoxy]amino}-3,4-dioxo-1-phenyl-2-butanyl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-(4-{[2-(4-Morpholinyl)ethoxy]amino}-3,4-dioxo-1-phenyl-2-butanyl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-(4-{[2-(4-Morpholinyl)ethoxy]amino}-3,4-dioxo-1-phenyl-2-butanyl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-{4-[(Cyclopropylmethoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2R)—N-{4-[(Cyclopropylmethoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   (2S)—N-{4-[(Cyclopropylmethoxy)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,   N-[4-(Ethoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamid   (2R)—N-[4-(Ethoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamid   (2S)—N-[4-(Ethoxyamino)-1-(4-methoxyphenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamid   2-[3-(2-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide,   (2R)-2-[3-(2-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide,   (2S)-2-[3-(2-Fluorophenyl)-1H-pyrazol-1-yl]-N-[4-(methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide,   N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,   (2R)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,   (2S)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,   N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-[3-(2-pyridinyl)-1H-pyrazol-1-yl]nicotinamide,   (2R)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-[3-(2-pyridinyl)-1H-pyrazol-1-yl]nicotinamide,   (2S)—N-[4-(Methoxyamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-[3-(2-pyridinyl)-1H-pyrazol-1-yl]nicotinamide,   1-benzyl-N-(4-(ethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   (2R)-1-benzyl-N-(4-(ethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   (2S)-1-benzyl-N-(4-(ethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   1-benzyl-N-(4-(isopropoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   (2R)-1-benzyl-N-(4-(isopropoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   (2S)-1-benzyl-N-(4-(isopropoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   1-benzyl-N-(4-(cyclopropylmethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   (2R)-1-benzyl-N-(4-(cyclopropylmethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   (2S)-1-benzyl-N-(4-(cyclopropylmethoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   1-(2-fluorobenzyl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   (2R)-1-(2-fluorobenzyl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   (2-S)-1-(2-fluorobenzyl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   1-(2-chlorobenzyl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   (2R)-1-(2-chlorobenzyl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   (2S)-1-(2-chlorobenzyl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide,   N-(3,4-Dioxo-1-phenyl-4-(thiazol-2-ylamino)butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide   (2R)—N-(3,4-Dioxo-1-phenyl-4-(thiazol-2-ylamino)butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide   (2S)—N-(3,4-Dioxo-1-phenyl-4-(thiazol-2-ylamino)butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide   the tautomers thereof, the hydrates thereof, the prodrugs thereof and the pharmaceutically suitable salts thereof.   
     
     
         15 . The carboxamide compound of  claim 1  for use in therapy. 
     
     
         16 . A pharmaceutical composition comprising at least one carboxamide compound of  claim 1  and a carrier. 
     
     
         17 . The carboxamide compound of  claim 1  for the treatment of a disorder, an impairment or a condition which is associated with an elevated calpain activity. 
     
     
         18 . The carboxamide compound of  claim 1  for the treatment of neurodegenerative disorders or impairments. 
     
     
         19 . The carboxamide compound of  claim 18 , where a neurodegenerative disorder occurring as a result of a chronic brain supply deficit, an ischemia or a trauma is involved. 
     
     
         20 . The carboxamide compound of  claim 18  for the treatment of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or Huntington's disease. 
     
     
         21 . The carboxamide compound of  claim 18  for the treatment of multiple sclerosis and concomitant damage to the nervous system. 
     
     
         22 . The carboxamide compound of  claim 1  for the treatment of epilepsy. 
     
     
         23 . The carboxamide compound of  claim 1  for the treatment of pain. 
     
     
         24 . The carboxamide compound of  claim 1  for the treatment of damage to the heart following cardiac ischemias, skeletal muscle damage, muscular dystrophies, damage resulting from proliferation of smooth muscle cells, coronary vasospasms, cerebral vasospasms, macular degeneration, cataracts of the eyes, or restenosis of the blood vessels following angioplasty. 
     
     
         25 . The carboxamide compound of  claim 1  for the treatment of damages to the kidney or chronic kidney diseases. 
     
     
         26 . The carboxamide compound of  claim 1  for the chemotherapy of tumors and metastasis thereof. 
     
     
         27 . The carboxamide compound of  claim 1  for the treatment of HIV patients. 
     
     
         28 . The carboxamide compound of  claim 1  for the treatment of a disorder or an impairment associated with an elevated interleukin-I, TNF or Aβ level. 
     
     
         29 . The carboxamide compound of  claim 1  for the treatment of a disorder or an impairment associated with a protozoan infection such as malaria or toxoplasmosis. 
     
     
         30 . A method for the therapeutic and/or prophylactic treatment of a mammal requiring a treatment, by administering an effective amount of at least one compound of formula I for the treatment of a disease, of a condition or of an impairment as set forth in any of  claim 17 .