IP Library › Granted Patent US 9,067,931
Granted Patent B2
US 9,067,931 · App. 14/261,616 · Granted Jun 30, 2015

2-heteroaryl carboxamides

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Quick Facts
Patent No.
US 9,067,931
App. No.
14/261,616
Granted
Jun 30, 2015
Kind
B2
Abstract

The invention relates to novel 2-heteroaryl carboxamides and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning and/or memory.

Claims (106)

1. A method for improving memory in patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound represented by a compound of formula (I):

wherein:

R 1 is 1-azabicyclo[2.2.2]oct-3-yl, which is optionally substituted via the nitrogen atom by a radical selected from the group of C 1 -C 4 -alkyl, benzyl and oxy,

R 2 is hydrogen or C 1 -C 6 -alkyl,

R 3 is hydrogen, halogen or C 1 -C 6 -alkyl,

R 4 is hydrogen, halogen, cyano, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylamino, formyl, hydroxycarbonyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 4 -alkylsulphonylamino, C 3 -C 8 -cycloalkylcarbonylamino, C 3 -C 6 -cycloalkylaminocarbonyl, pyrrolyl, C 1 -C 6 -alkylaminocarbonylamino, hydroxyl, phenyl morpholinyl, oxypiperidinyl, oxopyrrolidinyl, oxomorpholinyl, pyrrolidinyl, morpholinylcarbonyl, piperidinyl, pyridinyl, dihydropyrrolylcarbonyl, C 1 -C 6 -alkylpiperizinylcarbonyl, isoxazolecarbonylamino, tetrahydrofuranylcarbonylamino, furoylamino, piperidinylcarbonyl, or piperidinylcarbonyl ,

where C 1 -C 6 -alkyl may optionally be substituted by hydroxyl, cyano, amino, C 1 -C 6 -alkylaminocarbonylamino, C 1 -C 6 -alkylaminocarboxyl, morpholinyl or aryl,

C 1 -C 6 -alkylaminocarbonyl may optionally be substituted by C 1 -C 6 -alkoxy or C 1 -C 6 -alkylamino, and

C 1 -C 6 -alkylcarbonylamino may optionally be substituted by C 1 -C 6 -alkoxy,

A is oxygen or sulphur,

the ring B is benzo or pyrido, each of which are optionally substituted by radicals from the series halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,

and

E is C≡C, phenylene, thienylene, oxadizolylene, pyrrolylene, furanylene, pyrimidinylene, or pyridinylene wherein each ring system respectively may be substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkoxy and C 1 -C 6 -alkyl,

or a salt thereof.

2. The method of claim 1 , wherein the patient suffers from Alzheimer's disease or schizophrenia.

3. The method of claim 1 , wherein:

R 1 is 1-azabicyclo[2.2.2]oct-3-yl,

R 2 is hydrogen or C 1 -C 4 -alkyl,

R 3 is hydrogen, fluorine, chlorine, bromine or C 1 -C 4 -alkyl,

R 4 is hydrogen, fluorine, chlorine, bromine, cyano, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylamino, formyl, hydroxycarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylsulphonylamino, C 3 -C 6 -cycloalkylcarbonylamino, C 3 -C 6 -cycloalkylaminocarbonyl, pyrrolyl, C 1 -C 4 -alkylaminocarbonylamino, hydroxyl, phenyl morpholinyl, oxypiperidinyl, oxopyrrolidinyl, oxomorpholinyl, pyrrolidinyl, morpholinylcarbonyl, piperidinyl, pyridinyl, dihydropyrrolylcarbonyl, C 1 -C 4 -alkylpiperizinylcarbonyl, isoxazolecarbonylamino, tetrahydrofuranylcarbonylamino, furoylamino, piperidinylcarbonyl, or piperidinylcarbonyl ,

where C 1 -C 4 -alkyl may optionally be substituted by hydroxyl, cyano, amino, C 1 -C 4 -alkylaminocarbonylamino, C 1 -C 4 -alkylaminocarboxyl, morpholinyl or aryl,

C 1 -C 4 -alkylaminocarbonyl may optionally be substituted by C 1 -C 4 -alkoxy or C 1 -C 4 -alkylamino, and

C 1 -C 4 -alkylcarbonylamino may optionally be substituted by C 1 -C 4 -alkoxy,

A is oxygen or sulphur,

the ring B is benzo or pyrido, each of which are optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy and C 1 -C 4 -alkyl,

and

E is C≡C, phenylene, thienylene, oxadizolylene, pyrrolylene, furanylene, pyrimidinylene, or pyridinylene wherein each ring system respectively may be substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 4 -alkoxy and C 1 -C 4 -alkyl

or a salt thereof.

4. The method of claim 1 , wherein:

R 1 is 1-azabicyclo[2.2.2]oct-3-yl,

R 2 and R 3 are hydrogen,

R 4 is hydrogen, fluorine, chlorine, bromine, cyano, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylamino, formyl, hydroxycarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 1 -C 6 -alkylthio, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylsulphonylamino, C 3 -C 6 -cycloalkylcarbonylamino, C 3 -C 6 -cycloalkylaminocarbonyl, pyrrolyl, C 1 -C 4 -alkylaminocarbonylamino, hydroxyl, phenyl morpholinyl, oxypiperidinyl, oxopyrrolidinyl, oxomorpholinyl, pyrrolidinyl, morpholinylcarbonyl, piperidinyl, pyridinyl, dihydropyrrolylcarbonyl, C 1 -C 4 -alkylpiperizinylcarbonyl, isoxazolecarbonylamino, tetrahydrofuranylcarbonylamino, furoylamino, piperidinylcarbonyl, or piperidinylcarbonyl ,

where C 1 -C 4 -alkyl may optionally be substituted by hydroxyl, cyano, amino, C 1 -C 4 -alkylaminocarbonylamino, C 1 -C 4 -alkylaminocarboxyl, morpholinyl or aryl,

C 1 -C 4 -alkylaminocarbonyl may optionally be substituted by C 1 -C 4 -alkoxy or C 1 -C 4 -alkylamino, and

C 1 -C 4 -alkylcarbonylamino may optionally be substituted by C 1 -C 4 -alkoxy,

A is oxygen,

the ring B is benzo or pyrido, each of which are optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy and C 1 -C 4 -alkyl,

 and

E is C≡C, phenylene, thienylene, oxadizolylene, pyrrolylene, furanylene, pyrimidinylene, or pyridinylene wherein each ring system respectively may be substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 4 -alkoxy and C 1 -C 4 -alkyl

or a salt thereof.

5. The method of claim 1 , wherein which

R 1 is 1-azabicyclo[2.2.2]oct-3-yl,

R 2 is hydrogen or C 1 -C 6 -alkyl,

R 3 is hydrogen, halogen or C 1 -C 6 -alkyl,

R 4 is hydrogen, halogen, cyano, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylamino, formyl, hydroxycarbonyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylcarbonylamino, C 1 -C 4 -alkylsulphonylamino, C 3 -C 8 -cycloalkylcarbonylamino, pyrrolyl, C 1 -C 6 -alkylaminocarbonylamino, morpholinyl, oxypiperidinyl, oxopyrrolidinyl, oxomorpholinyl, pyrrolidinyl, morpholinylcarbonyl, piperidinyl, pyridinyl, dihydropyrrolylcarbonyl, C 1 -C 4 -alkylpiperizinylcarbonyl, isoxazolecarbonylamino, tetrahydrofuranylcarbonylamino, furoylamino, piperidinylcarbonyl, or piperidinylcarbonyl ,

where C 1 -C 6 -alkyl may optionally be substituted by hydroxyl, amino, C 1 -C 6 -alkyl-aminocarbonylamino, C 1 -C 6 -alkylaminocarboxyl, morpholinyl or aryl,and

C 1 -C 6 -alkylcarbonylamino may optionally be substituted by C 1 -C 6 -alkoxy,

A is oxygen or sulphur,

the ring B is benzo or pyrido, each of which are optionally substituted by radicals from the series halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,

and

E is C≡C, phenylene, thienylene, oxadizolylene, pyrrolylene, furanylene, pyrimidinylene, or pyridinylene wherein each ring system respectively is optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkoxy and C 1 -C 6 -alkyl

or a salt thereof.

6. The method of claim 1 , wherein:

R 1 is 1-azabicyclo[2.2.2]oct-3-yl,

R 2 is hydrogen or C 1 -C 6 -alkyl,

R 3 is hydrogen, halogen or C 1 -C 6 -alkyl,

R 4 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy morpholinyl, piperidinyl or pyrrolidinyl, where alkyl is optionally substituted by a hydroxyl radical,

A is oxygen or sulphur,

the ring B is benzo or pyrido, each of which are optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,

and

E is C≡C, phenylene, thienylene, oxadizolylene, pyrrolylene, furanylene, pyrimidinylene, or pyridinylene wherein each ring system respectively is optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy

or a salt thereof.

7. The method of claim 1 , wherein the compound of formula (I) is a compound represented by a compound of formula (Ia.):

wherein:

R 1 is (3R)-1-azabicyclo[2.2.2]oct-3-yl,

R 2 and R 3 are, independently of one another, hydrogen or methyl,

R 4 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or morpholinyl, piperidinyl or pyrrolidinyl, where alkyl is optionally substituted by a hydroxyl radical,

and

R B is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy,

or a salt thereof.

8. The method of claim 1 , wherein the compound of formula (I) is a compound represented by a compound of formula (Ib):

wherein:

R 1 is (3R)-1-azabicyclo[2.2.2]oct-3-yl,

R 2 and R 3 are, independently of one another, hydrogen or methyl,

R 4 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy morpholinyl, piperidinyl or pyrrolidinyl, where alkyl is optionally substituted by a hydroxyl radical, and

R B is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,

or a salt thereof.

9. The method of claim 1 , wherein:

R 1 is (3R)-1-azabicyclo[2.2.2]oct-3-yl,

R 2 and R 3 are hydrogen,

R 4 is hydrogen, fluorine, chlorine, bromine, trifluoromethoxy, hydroxymethyl, methoxy or morpholinyl or piperidinyl, and

R B is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy or C 1 -C 4 -alkyl

or a salt thereof.

10. The method of claim 1 , wherein the compound of formula (I) is a compound represented by a compound of formula (Ic):

wherein:

E is phenylene,

R 4 is C 1 -C 6 -alkoxy, aminomethyl, hydroxycarbonyl, C 3 -C 8 -cycloalkylcarbonylamino, a group of the formula

where

R 5 is C 1 -C 6 -alkyl,

n is zero, 1, 2, 3 or 4,

or

morpholinyl, piperidinyl or pyrrolidinyl, which is optionally substituted by oxo,

A is sulphur or oxygen,

or a salt thereof.

11. The method of claim 10 , wherein:

E is phenylene,

R 4 is C 1 -C 4 -alkoxy, aminomethyl, hydroxycarbonyl, C 3 -C 6 -cycloalkylcarbonylamino, a group of the formula

wherein:

R 5 is C 1 -C 4 -alkyl,

n is zero, 1 or 2,

or

morpholinyl, piperidinyl or pyrrolidinyl, which is optionally substituted by oxo,

A is sulphur or oxygen,

or a salt thereof.

12. The method of claim 1 , wherein the compound of formula (I) is a compound represented by:

or a salt thereof.