Carboxamide compounds and their use as calpain inhibitors

摘要

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 R1, R2, R3a, R3b, W, Y and X have the meanings mentioned in the claims and the description, the tautomers thereof and the pharmaceutically suitable salts thereof. In particular, the compounds have the general formula I-A.a′ and I-A.a″
;
in which m, E, R1, R3a, R3b, R2, Ry, Rw and Rw6*have the meanings mentioned in the claims, n is 0, 1 or 2, the tautomers thereof and the pharmaceutically suitable salts thereof.

主权项

1. A carboxamide compound of the formula I-A″, in which n is 0, 1 or 2, m is 0, 1 or 2, one of the variables Y1, Y2, Y3 and Y4 is a nitrogen atom, and the remaining variables Y1, Y2, Y3 and Y4 are CH, R1 is hydrogen, C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, where the last 3 radicals mentioned may be partly or completely halogenated and/or have 1, 2 or 3 substituents R1a,
C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, where cycloalkyl in the last two radicals mentioned may additionally have 1, 2, 3 or 4 identical or different R1b radicals, may have a CH2 group replaced by O, NH, or S, or may have two adjacent C atoms form a double bond,aryl, hetaryl, aryl-C1-C6-alkyl, aryl-C2-C6-alkenyl, hetaryl-C1-C4-alkyl or hetaryl-C2-C6-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 R1c; whereR1a is selected independently of one another from OH, SH, COOH, CN, OCH2COOH, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C7-cycloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, COORa1, CONRa2Ra3, SO2NRa2Ra3, —NRa2—SO2Ra4, NRa2—CO—Ra5, SO2—Ra4, and NRa6Ra7,R1b is selected independently of one another from OH, SH, COOH, CN, OCH2COOH, halogen, phenyl which optionally has 1, 2 or 3 substituents C1-C6-alkyl, C1-C6-alkoxy, C1-C6-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 R1a, COORb1, CONRb2Rb3, SO2NRb2Rb3, NRb2Rbb3, NRb2—SO2—Rb4, NRb2—CO—Rb5, SO2—Rb4, and NRb6Rb7, where
in addition two R1b radicals may together form a C1-C4-alkylene group, or 2 R1b radicals bonded to adjacent C atoms of cycloalkyl may form together with the carbon atoms to which they are bonded a benzene ring,R1c is selected independently of one another from OH, SH, halogen, NO2, NH2, CN, CF3, CHF2, CH2F, O—CF3, O—CHF2, O—CH2F, COOH, OCH2COOH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-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 R1a,
C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, C3-C7-cycloalkoxy, where the cycloalkyl moiety of the last three radicals mentioned may have 1, 2, 3 or 4 R1b radicals,aryl, hetaryl, O-aryl, O—CH2-aryl, where the last three radicals mentioned are unsubstituted in the aryl moiety or may carry 1, 2, 3 or 4 R1d radicals, COORc1, CONRc2Rc3, SO2NRc2Rc3, NRc2—SO2—Rc4, NRc2—CO—R5, SO2—Rc4,—(CH2)p—NRc6Rc7 with p=0, 1, 2, 3, 4, 5 or 6, andO—(CH2)q—NRc6Rc7 with q=2, 3, 4, 5 or 6; whereRa1, Rb1 and Rc1 are independently of one another H, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents R1a, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, aryl, aryl-C1-C4-alkyl, hetaryl or hetaryl-C1-C4-alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R1d,Ra2, Rb2 and Rc2 are independently of one another H, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents R1a, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, aryl, aryl-C1-C4-alkyl, hetaryl or hetaryl-C1-C4-alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R1d, andRa3, Rb3 and Rc3 are independently of one another H, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents R1a, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7- cycloalkyl-C1-C4-alkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6- alkoxy-C1-C4-alkyl, aryl, aryl-C1-C4-alkyl, hetaryl or hetaryl-C1-C4-alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R1d, or
the two radicals Ra2 and Ra3, or Rb2 and Rb3 or Rc2 and Rc3 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 selected from the group consisting of O, N, and S as ring members,Ra4, Rb4 and Rc4 are independently of one another C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents R1a, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, aryl, aryl-C1-C4-alkyl, hetaryl or hetaryl-C1-C4-alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R1d, andRa5, Rb5 and Rc5 have independently of one another one of the meanings mentioned for Ra1, Rb1 and Rc1;Ra6, Rb6 and Rc6 are independently of one another H, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents R1a, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl, aryl, hetaryl, O-aryl, OCH2-aryl, aryl-C1-C4-alkyl, hetaryl-C1-C4-alkyl, CO-aryl, CO-hetaryl, CO-(aryl-C1-C4-alkyl), CO-(hetaryl-C1-C4-alkyl), CO—O-aryl, CO—O-hetaryl, CO—O-(aryl-C1-C4-alkyl), CO—O-(hetaryl-C1-C4-alkyl), SO2-aryl, SO2-hetaryl, SO2-(aryl-C1-C4-alkyl) or SO2-(hetaryl-C1-C4-alkyl), where aryl and hetaryl in the last 18 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R1d, andRa7, Rb7 and Rc7 are independently of one another H, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents R1a, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, aryl, aryl-C1-C4-alkyl, hetaryl or hetaryl-C1-C4-alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R1d, or
the two radicals Ra6 and Ra7, or Rb6 and Rb7 or Rc6 and Rc7 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 R1b and R1c 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;R1d is selected from halogen, OH, SH, NO2, COOH, C(O)NH2, CHO, CN, NH2, OCH2COOH, C1C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, CO—C1-C6-alkyl, NH—C1-C6-alkyl, NHCHO, NH—C(O)C1-C6-alkyl, and SO2-C1-C6-alkyl; R3a and R3b are independently of one another hydroxy or C1-C4-alkoxy, or together with the carbon atom to which they are bonded are C═O; or R3a and R3b together form a group O-Alk-O, S-Alk-O or S-Alk-S, where Alk is linear C2-C5-alkanediyl, which may be unsubstituted or substituted with 1, 2, 3 or 4 radicals selected from C1-C4-alkyl and halogen; or R3a and R3b together with the carbon atom to which they are bonded form a group C═NR3, where R3 is selected from H, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C2-C6-alkenyloxy, C3-C6-cycloalkoxy and C3-C6-cycloalkyl-C1-C4-alkyloxy; X is hydrogen or a radical of the formulae C(═O)—O—Rx1, C(═O)—NRx2Rx3, C(═O)—N(Rx4)—C1-C6-alkylene)-NRx2Rx3or C(═O)—N(Rx4)NRx2Rx3, in which
Rx1 is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents Rxa, C2-C6-alkenyl, C2-C6-alkynyl, C1 C4-alkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6- alkoxy-C1-C4-alkyl, where alkyl, alkenyl, alkoxy, alkynyl, cycloalkyl, heterocycloalkyl in the last 6 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rxa, aryl, aryl-C1-C4-alkyl, hetaryl or hetaryl-C1-C4-alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rxd,Rx2 is H, OH, CN, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents Rxa, C2-C6-alkenyl, C2-C6-alkynyl, C3C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, CO—C1-C6-alkyl, CO—O-C1-C6-alkyl, SO2-C1-C6-alkyl, O—C1-C6-alkyl, where alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl in the last 10 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rxa, aryl, O-aryl, O—CH2-aryl, hetaryl, O—CH2-hetaryl, aryl-C1-C4-alkyl, hetaryl-C1-C4-alkyl, CO-aryl, CO-hetaryl, CO-(aryl-C1-C4-alkyl), CO-(hetaryl-C1-C4-alkyl), CO—O-aryl, CO—O-hetaryl, CO—O-(aryl-C1-C4-alkyl), CO—O(hetaryl-C1-C4-alkyl), SO2-aryl, SO2-hetaryl, SO2-(aryl-C1-C4-alkyl) or SO2-(hetaryl-C1-C4-alkyl), where aryl and hetaryl in the last 19 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rxd, andRx3 is H, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents Rxa, C2-C6-alkenyl, C2-C6-alkynyl, C3C7-cycloalkyl, C3C7-cycloalkyl-C1-C4-alkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6- alkoxy-C1-C4-alkyl, where alkyl, alkenyl, alkoxy, alkynyl, cycloalkyl, heterocycloalkyl in the last 6 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rxa, aryl, aryl-C1-C4-alkyl, hetaryl or hetaryl-C1-C4-alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rxd, or
the two radicals Rx2 and Rx3 form together with the N atom a 3 to 7-membered nitrogen heterocycle which may optionally have 1, 2 or 3 further different or identical heteroatoms selected from the group consisting of O, N and S as ring members, and which may have 1, 2 or 3 substituents Rxb,Rx4 is H, OH, CN, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents Rxa, or C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, SO2-C1-C6-alkyl, where alkyl, alkenyl, alkoxy, alkynyl, cycloalkyl, heterocycloalkyl in the last 9 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rxa, aryl, O-aryl, O—CH2-aryl, hetaryl, aryl-C1-C4-alkyl, hetaryl-C1-C4-alkyl, CO-aryl, CO-hetaryl, CO-(aryl-C1-C4-alkyl), CO-(hetaryl-C1-C4-alkyl), CO—O-aryl, CO—O-hetaryl, CO—O-(aryl-C1-C4-alkyl), CO—O-(hetaryl-C1-C4-alkyl), SO2-aryl, SO2-hetaryl, SO2-(aryl-C1-C4-alkyl) or SO2-(hetaryl-C1-C4-alkyl), where aryl and hetaryl in the last 18 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents Rxd, andwhere Rxa has one of the meanings indicated for R1a, Rxb has one of the meanings indicated for R1b, and Rxd has one of the meanings indicated for R1d;Ry is selected independently of one another from the group consisting of OH, SH, halogen, NO2, NH2, CN, CF, CHF2, CH2F, O—CF3, O—CHF2, O—CH2F, COOH, OCH2COOH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-alkylthio, where the last 4 radicals mentioned may be partly or completely halogenated and/or have 1, 2 or 3 substituents Rya, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, C3-C7-cycloalkyl-O, where the cycloalkyl moiety in the last three radicals mentioned may have 1, 2, 3 or 4 Ryb radicals, aryl, O-aryl, CH2-aryl, O—CH2-aryl, where the last 4 radicals mentioned are unsubstituted in the aryl moiety or may carry 1, 2, 3 or 4 radicals Ryd,
COORy1, CONRy2Ry3, SO2NRy2Ry3, —NH—SO2—Ry4,NH—CO—Ry5, SO2—Ry4,—(CH2)p—NRy6Ry7 with p=0, 1, 2, 3, 4, 5 or 6 andO—(CH2)q—NRy6Ry7 with q=2, 3, 4, 5 or 6;or two W radicals 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 heterocycle which has 1, 2 or 3 different or identical heteroatoms selected from the group consisting of O, N, and S as ring members, whereRya has one of the meanings indicated for R1a,Ryb has one of the meanings indicated for R1b,Ryd has one of the meanings indicated for R1d,Ry1 has one of the meanings indicated for Rc1,Ry2 has one of the meanings indicated for Rc2,Ry3 has one of the meanings indicated for Rc3,Ry4 has one of the meanings indicated for Rc4,Ry5 has one of the meanings indicated for Rc5,Ry6 has one of the meanings indicated for Rc6, andRy7 has one of the meanings indicated for Rc7;Rw6* is selected from OH, SH, halogen, NO2, NH2, CN, CF3, CHF2, CH2F, O—CF3, O—CHF2, O—CH2F, COOH, OCH2COOH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-alkylthio, where the last 4 radicals mentioned may be partly or completely halogenated and/or have 1, 2 or 3 substituents Rwa, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, C3-C7-cycloalkoxy, where the cycloalkyl moiety of the last three radicals mentioned may have 1, 2, 3 or 4 radicals Rwb, aryl, O-aryl, O—CH2-aryl, hetaryl, where the last four radicals mentioned are unsubstituted in the aryl moiety or may carry 1, 2, 3 or 4 radicals Rwd,
COORw1, CONRw2Rw3, SO2NRw2Rw3, NRw2—SO2Rw4,NRw2—CO—Rw5, SO2—Rw4,—(CH2)p—NRw6Rw7 with p=0, 1, 2, 3, 4, 5 or 6 andO—(CH2)q—NRw6Rw7 with q=2, 3, 4, 5 or 6;or two Rw6* radicals 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 selected from the group consisting of O, N, and S as ring members, whereRwa has one of the meanings indicated for R1a,Rwb has one of the meanings indicated for R1b,Rwd has one of the meanings indicated for R1d,Rw1 has one of the meanings indicated for Rc1,Rw2 has one of the meanings indicated for Rc2,Rw3 has one of the meanings indicated for Rc3,Rw4 has one of the meanings indicated for Rc4,Rw5 has one of the meanings indicated for Rc5,Rw6 has one of the meanings indicated for Rc6,Rw7 has one of the meanings indicated for Rc7,E has one of the following meanings: —CRE2RE3—, —CHRE2—CHRE3, CH2—CH2—CH2—, —CO—, —CO—NRE1—, —NRE1—CO—, —O—, —CH2—O—, —O—CH2, —S—, —S—CH2—, —CH2—S—, —SO—, CH2—SO—, —SO—CH2—, —SO2—, —CH2—SO2—, —SO2—CH2—, —NRE1—NRE1—CH2—, —CH2—NRE1, —SO2—NRE1—, —NRE1—SO2—, —CO—O—, —O—CO—, —C(═CRE2RE3)—, —CRE2═CRE3—, whereRE1 is H, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents RE1a, C2-C6-alkenyl, C2-C6-alkynyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, SO2—C1-C6-alkyl, aryl, hetaryl, aryl-C1-C4-alkyl, hetaryl-C1-C4-alkyl, CO-aryl, CO-hetaryl, CO-(aryl-C1-C4-alkyl), CO-(hetaryl-C1-C4-alkyl), CO—O-aryl, CO—O-hetaryl, CO—O-(aryl-C1-C4-alkyl), CO—O-(hetaryl-C1-C4-alkyl), SO2-aryl, SO2-hetaryl, SO2-(aryl-C1-C4-alkyl) or SO2-(hetaryl-C1-C4-alkyl), where aryl and hetaryl in the last 16 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents RE1d, andRE2, RE3 are independently of one another selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, where the last 4 radicals mentioned may be partly or completely halogenated and/or have 1, 2 or 3 substituents RE1a, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, C3-C7-cycloalkyl-O, where a CH2 group in the cycloalkyl moiety of the last three 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 RE1b radicals,
aryl, hetaryl, aryl-C1-C6-alkyl, or hetaryl-C1-C4-alkyl, where aryl and hetaryl in the last 4 radicals mentioned may be unsubstituted or carry 1, 2, 3 or 4 identical or different radicals RE1d; and whereRE1a has one of the meanings indicated for R1a, RE1b has one of the meanings indicated for R1b, and RE1d has one of the meanings indicated for R1d;where aryl means a mono-, bi- or tricyclic aromatic hydrocarbon radical;or a tautomer thereof or a pharmaceutically suitable salt thereof.