US 2014/0179702 A1Published application

Carboxamide compounds and their use as calpain inhibitors iv

OwnerAndreas Kling, Katja Jantos +6inventors

InventorsAndreas Kling, Katja Jantos, Helmut Mack, Achim Möller, Wilfried Hornberger, Gisela Backfisch, Yanbin Lao, Marjoleen Nijsen

Life of this patent

Estimating the term…

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.

Claims28

Dependent claims

A carboxamide compound of the formula I

in which
R1 is 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 a CH2 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 R1b,
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;
where
R1a is selected independently of one another from OH, SH, COOH, CN, OCH2COOH, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C7-cycloalkyloxy, C1-C6-alkylthio, C1-C6-haloalkylthio, COORa1, CONRa2Ra3, SO2NRa2Ra3, —NRa2—SO2—Ra4, NRa2—CO—Ras, 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 R1d,
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, NRb2—SO2—Rb4, NRb2—CO—Rb5, SO2—Rb4 and NRb6Rb7,
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 also a benzene ring,
R1c is selected independently of one another from OH, SH, halogen, NO2, NH2, CN, 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-cycloalkyloxy, 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—Rc5, SO2—Rc4,
—(CH2)p—NRc6Rc7 with p=0, 1, 2, 3, 4, 5 or 6 and
O—(CH2)q—NRc6Rc7 with q=2, 3, 4, 5 or 6;
where
Ra1, 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, or 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,
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, or 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, and
Ra3, 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, or 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 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 from the group of O, N, 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, or 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, and
Ra5, Rb5 and Rc5 have independently of one another one of the meanings mentioned for Ra1, Rb1 and Rc1;
Ra6, Rb6 and Rcb 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, or 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, and
Ra7, 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, or 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 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 or two radicals 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, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, NH—C1-C6-alkyl, NHCHO, NH—C(O)C1-C6-alkyl, and SO2—C1-C6-alkyl;
R2 is C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, where a CH2 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 R2b radicals;
aryl, O-aryl, O—CH2-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 8 radicals mentioned may be unsubstituted or carry 1, 2, 3 or 4 identical or different R2c radicals;
where
R2b has one of the meanings indicated for R1b, and
R2c has one of the meanings indicated for R1c;
R3 is C3-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents Rxa, or C3-C7-cycloalkyl-C1-C4-alkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, where the cycloalkyl moiety or heterocycloalkyl moiety of the last 3 radicals mentioned may have 1, 2, 3 or 4 radicals Rxb, C2-C6-alkenyl, C2-C6-alkynyl or C1-C6-alkoxy-C1-C4-alkyl, where alkyl, alkenyl, alkoxy, alkynyl, in the last 3 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;
where 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 or two radicals Rxd which are bound to adjacent carbon atoms of aryl or hetaryl may form a fused benzene ring which is unsubstituted or carries 1, 2 or 3 substituents selected from halogen, C1-C4-alkyl C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;
R4 and R5 are selected independently of one another from halogen, NH2, CN, CF3, CHF2, CH2F, O—CF3, O—CHF2, O—CH2F, COOH, OCH2COOH, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-alkoxy-C1-C2-alkyl, C1-C2-alkylthio, CH2NRR′, where
R and R′ are selected independently of one another from hydrogen and C1-C4-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.

36 more elements

A carboxamide compound which is selected from the group consisting of

N-{3,4-Dioxo-1-phenyl-4-[(2-phenylethyl)amino]butan-2-yl}-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
N-{3,4-Dioxo-1-phenyl-4-[pyridin-2-ylmethyl)amino]butan-2-yl}-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
N-(3,4-Dioxo-1-phenyl-4-{[2-(pyridin-2-yl)ethyl]amino}butan-2-yl)-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
N-(3,4-Dioxo-1-phenyl-4-{[3-(pyridin-2-yl)propyl]amino}butan-2-yl)-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
N-[3,4-Dioxo-1-phenyl-4-(prop-2-en-1-ylamino)butan-2-yl]-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
N-[4-(Pyridin-2-ylmethylamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
N-(4-(Cyclopropylmethylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-(4-(Cyclobutylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-(3,4-Dioxo-1-phenyl-4-(propylamino)butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-(4-(Cyclopropylamino)-1-(4-fluorophenyl)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-(4-(Cyclopropylamino)-1-(3-fluorophenyl)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-{4-[(1,3-Benzoxazol-2-ylmethyl)amino]-3,4-dioxo-1-phenylbutan-2-yl}-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
N-(3,4-Dioxo-4-(phenethylamino)-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]nicotinamide,
N-{4-[(1H-Benzimidazol-2-ylmethyl)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
Methyl N-[2-oxo-4-phenyl-3-({[2-(3-phenyl-1H-pyrazol-1-yl)-3-pyridinyl]carbonyl}amino)butanoyl]glycinat,
N-[4-(Cyclopropylamino)-1-(4-methoxyphenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-[4-(Cyclopropylamino)-1-{4-[2-(4-morpholinyl)ethoxy]phenyl}-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-{4-[(1,3-Oxazol-2-ylmethyl)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-{4-(Cyclopropylamino)-1-[4-(4-morpholinylmethyl)phenyl]-3,4-dioxo-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(4-morpholinyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,
N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-[3-(2-fluorophenyl)-1H-pyrazol-1-yl]nicotinamide,
N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,
N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-(pyridin-2-yl)-1H-pyrazol-1-yl)nicotinamide,
2-(3-Cyclopropyl-1H-pyrazol-1-yl)-N-[4-(methylamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide,
2-(3-Cyclopropyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide,
(2R)-N-{3,4-Dioxo-1-phenyl-4-[(2-phenylethyl)amino]butan-2-yl}-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
(2R)-N-{3,4-Dioxo-1-phenyl-4-[(pyridin-2-ylmethyl)amino]butan-2-yl}-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
(2R)-N-(3,4-Dioxo-1-phenyl-4-{[2-(pyridin-2-yl)ethyl]amino}butan-2-yl)-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
(2R)-N-(3,4-Dioxo-1-phenyl-4-{[3-(pyridin-2-yl)propyl]amino}butan-2-yl)-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
(2R)-N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
(2R)-N-[3,4-Dioxo-1-phenyl-4-(prop-2-en-1-ylamino)butan-2-yl]-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
(2R)-N-[4-(Pyridin-2-ylmethylamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
(2R)-N-(4-(Cyclopropylmethylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-(4-(Cyclobutylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-(3,4-Dioxo-1-phenyl-4-(propylamino)butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-(4-(Cyclopropylamino)-1-(4-fluorophenyl)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-(4-(Cyclopropylamino)-1-(3-fluorophenyl)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-{4-[(1,3-Benzoxazol-2-ylmethyl)amino]-3,4-dioxo-1-phenylbutan-2-yl}-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
(2R)-N-(3,4-Dioxo-4-(phenethylamino)-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]nicotinamide,
(2R)-N-{4-[(1H-Benzimidazol-2-ylmethyl)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-Methyl N-[2-oxo-4-phenyl-3-({[2-(3-phenyl-1H-pyrazol-1-yl)-3-pyridinyl]carbonyl}amino)butanoyl]glycinat,
(2R)-N-[4-(Cyclopropylamino)-1-(4-methoxyphenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-[4-(Cyclopropylamino)-1-{4-[2-(4-morpholinyl)ethoxy]phenyl}-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-{4-[(1,3-Oxazol-2-ylmethyl)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-{4-(Cyclopropylamino)-1-[4-(4-morpholinylmethyl)phenyl]-3,4-dioxo-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(4-morpholinyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,
(2R)-N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-[3-(2-fluorophenyl)-1H-pyrazol-1-yl]nicotinamide,
(2R)-N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,
(2R)-N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-(pyridin-2-yl)-1H-pyrazol-1-yl)nicotinamide,
(2R)-N-{3,4-Dioxo-1-phenyl-4-[(2-phenylethyl)amino]butan-2-yl}-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
(2R)-2-(3-Cyclopropyl-1H-pyrazol-1-yl)-N-[4-(methylamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide,
(2R)-2-(3-Cyclopropyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide,
(2S)-N-{3,4-Dioxo-1-phenyl-4-[(pyridin-2-ylmethyl)amino]butan-2-yl}-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
(2S)-N-(3,4-Dioxo-1-phenyl-4-{[2-(pyridin-2-yl)ethyl]amino}butan-2-yl)-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
(2S)-N-(3,4-Dioxo-1-phenyl-4-{[3-(pyridin-2-yl)propyl]amino}butan-2-yl)-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]pyridine-3-carboxamide,
(2S)-N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
(2S)-N-{3,4-Dioxo-1-phenyl-4-(prop-2-en-1-ylamino)butan-2-yl}-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
(2S)-N-[4-(Pyridin-2-ylmethylamino)-3,4-dioxo-1-phenylbutan-2-yl]-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
(2S)-N-(4-(Cyclopropylmethylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-(4-(Cyclobutylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-(3,4-Dioxo-1-phenyl-4-(propylamino)butan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-(4-(Cyclopropylamino)-1-(4-fluorophenyl)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-(4-(Cyclopropylamino)-1-(3-fluorophenyl)-3,4-dioxobutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-{4-[(1,3-Benzoxazol-2-ylmethyl)amino]-3,4-dioxo-1-phenylbutan-2-yl}-2-(3-phenyl-1H-pyrazol-1-yl)pyridine-3-carboxamide,
(2S)-N-(3,4-Dioxo-4-(phenethylamino)-1-phenylbutan-2-yl)-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-[3-(4-fluorophenyl)-1H-pyrazol-1-yl]nicotinamide,
(2S)-N-{4-[(1H-Benzimidazol-2-ylmethyl)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-Methyl N-[2-oxo-4-phenyl-3-({[2-(3-phenyl-1H-pyrazol-1-yl)-3-pyridinyl]carbonyl}amino)butanoyl]glycinat,
(2S)-N-[4-(Cyclopropylamino)-1-(4-methoxyphenyl)-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-[4-(Cyclopropylamino)-1-{4-[2-(4-morpholinyl)ethoxy]phenyl}-3,4-dioxo-2-butanyl]-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-{4-[(1,3-Oxazol-2-ylmethyl)amino]-3,4-dioxo-1-phenyl-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-{4-(Cyclopropylamino)-1-[4-(4-morpholinylmethyl)phenyl]-3,4-dioxo-2-butanyl}-2-(3-phenyl-1H-pyrazol-1-yl)nicotinamide,
(2S)-N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(4-morpholinyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,
(2S)-N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-[3-(2-fluorophenyl)-1H-pyrazol-1-yl]nicotinamide,
(2S)-N-[4-(Cyclopropylamino)-3,4-dioxo-1-phenyl-2-butanyl]-2-{3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}nicotinamide,
(2S)-N-(4-(Cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-2-(3-(pyridin-2-yl)-1H-pyrazol-1-yl)nicotinamide,
(2S)-2-(3-Cyclopropyl-1H-pyrazol-1-yl)-N-[4-(methylamino)-3,4-dioxo-1-phenyl-2-butanyl]nicotinamide,
(2S)-2-(3-Cyclopropyl-1H-pyrazol-1-yl)-N-(4-(methoxyamino)-3,4-dioxo-1-phenylbutan-2-yl)nicotinamide,
N-(4-(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxamide,
(2R)-N-(4-(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxamide,
(2S)-N-(4-(cyclopropylamino)-3,4-dioxo-1-phenylbutan-2-yl)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxamide,
the tautomers thereof, the hydrates thereof, the prodrugs thereof and the pharmaceutically suitable salts thereof.

85 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/054,460Filed 15 Oct 2013
Priority: 22 Dec 2009
Published: 26 Jun 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification30 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/04
Drugs for disorders of the cardiovascular system: inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Family

Application61/288,918Us provisional application · filed 22 Dec 2009
Application61/410,476Us provisional application · filed 5 Nov 2010
Application12/972,679Division · filed 20 Dec 2010
Application14/054,460Division
US 2011/0152325 A1Published application
US 8,598,211 B2Related patent
US 2014/0179702 A1This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Abstract

A carboxamide compound of the formula I

in which
R1 is 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 a CH2 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 R1b,
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;
where
R1a is selected independently of one another from OH, SH, COOH, CN, OCH2COOH, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C7-cycloalkyloxy, C1-C6-alkylthio, C1-C6-haloalkylthio, COORa1, CONRa2Ra3, SO2NRa2Ra3, —NRa2—SO2—Ra4, NRa2—CO—Ras, 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 R1d,
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, NRb2—SO2—Rb4, NRb2—CO—Rb5, SO2—Rb4 and NRb6Rb7,
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 also a benzene ring,
R1c is selected independently of one another from OH, SH, halogen, NO2, NH2, CN, 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-cycloalkyloxy, 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—Rc5, SO2—Rc4,
—(CH2)p—NRc6Rc7 with p=0, 1, 2, 3, 4, 5 or 6 and
O—(CH2)q—NRc6Rc7 with q=2, 3, 4, 5 or 6;
where
Ra1, 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, or 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,
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, or 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, and
Ra3, 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, or 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 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 from the group of O, N, 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, or 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, and
Ra5, Rb5 and Rc5 have independently of one another one of the meanings mentioned for Ra1, Rb1 and Rc1;
Ra6, Rb6 and Rcb 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, or 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, and
Ra7, 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, or 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 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 or two radicals 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, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkylthio, C1-C6-haloalkylthio, CO—C1-C6-alkyl, CO—O—C1-C6-alkyl, NH—C1-C6-alkyl, NHCHO, NH—C(O)C1-C6-alkyl, and SO2—C1-C6-alkyl;
R2 is C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C4-alkyl, where a CH2 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 R2b radicals;
aryl, O-aryl, O—CH2-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 8 radicals mentioned may be unsubstituted or carry 1, 2, 3 or 4 identical or different R2c radicals;
where
R2b has one of the meanings indicated for R1b, and
R2c has one of the meanings indicated for R1c;
R3 is C3-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkyl which has 1, 2 or 3 substituents Rxa, or C3-C7-cycloalkyl-C1-C4-alkyl, C3-C7-heterocycloalkyl-C1-C4-alkyl, where the cycloalkyl moiety or heterocycloalkyl moiety of the last 3 radicals mentioned may have 1, 2, 3 or 4 radicals Rxb, C2-C6-alkenyl, C2-C6-alkynyl or C1-C6-alkoxy-C1-C4-alkyl, where alkyl, alkenyl, alkoxy, alkynyl, in the last 3 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;
where 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 or two radicals Rxd which are bound to adjacent carbon atoms of aryl or hetaryl may form a fused benzene ring which is unsubstituted or carries 1, 2 or 3 substituents selected from halogen, C1-C4-alkyl C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;
R4 and R5 are selected independently of one another from halogen, NH2, CN, CF3, CHF2, CH2F, O—CF3, O—CHF2, O—CH2F, COOH, OCH2COOH, C1-C2-alkyl, C1-C2-alkoxy, C1-C2-alkoxy-C1-C2-alkyl, C1-C2-alkylthio, CH2NRR′, where
R and R′ are selected independently of one another from hydrogen and C1-C4-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.

36 more elements

Facts

Application

14/054,460Filed 15 Oct 2013

Priority

22 Dec 2009

Published

26 Jun 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification30 codes

C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/04
Drugs for disorders of the cardiovascular system: inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…

Family

Application61/288,918Us provisional application · filed 22 Dec 2009

Application61/410,476Us provisional application · filed 5 Nov 2010

Application12/972,679Division · filed 20 Dec 2010

Application14/054,460Division

US 2011/0152325 A1Published application

US 8,598,211 B2Related patent

US 2014/0179702 A1This patent

From the US filing history. Foreign family members aren’t listed.