Substituted N-heteroaryl bipyrrolidine carboxamides, preparation and therapeutic use thereof

1. A compound of formula (I):

wherein:

m, p=1 or 2;

X is CO or SO 2 ;

Q 1 to Q 4 are independently CH or N provided that at least one of Q 1 to Q 4 is N;

R 1 is hydrogen, (C 1 -C 4 )alkyl, CF 3 , or (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl;

R 2 is hydrogen, halogen, (C 1 -C 4 )alkyl or CF 3 ;

R 3 is unsubstituted or substituted naphthyl, phenyl, benzyl, thiophenyl, isoxazolyl, cyclopropyl, cyclohexyl, tetrahydropyranyl or piperidinyl, wherein the substituents are selected from the group consisting of halogen, (C 1 -C 4 )alkyl and CH 3 CO; and

R 4 is H or (C 1 -C 4 )alkyl;

or a salt thereof or an enantiomer or a diastereomer thereof.

2. The compound according to claim 1 , wherein

m and p are 1;

X is CO;

R 1 is CH 3 ;

R 2 is CH 3 ; and

R 3 is unsubstituted or substituted naphthyl, phenyl, benzyl, thiophenyl, isoxazolyl, cyclopropyl, cyclohexyl, tetrahydropyranyl or piperidinyl, wherein the substituents are selected from the group consisting of halogen, (C 1 -C 4 )alkyl and CH 3 CO; and

R 4 is H;

or a salt thereof or an enantiomer or a diastereomer thereof.

3. The compound according to claim 1 , wherein

m and p are 1;

X is SO 2 ;

R 1 is CH 3 ;

R 2 is CH 3 ; and

R 3 is unsubstituted or substituted phenyl, cyclopropyl or cyclohexyl, wherein the substituents are selected from the group consisting of halogen, (C 1 -C 4 )alkyl and CH 3 CO; and

R 4 is H;

or a salt thereof or an enantiomer or a diastereomer thereof.

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

tetrahydro-pyran-4-carboxylic acid [2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

tetrahydro-pyran-4-carboxylic acid [5-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-2-yl]-amide;

naphthalene-1-carboxylic acid [2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

N-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2-phenyl-acetamide;

cyclohexanesulfonic acid [2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

3,4-difluoro-N-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzenesulfonamide;

N-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzamide;

1-acetyl-piperidine-4-carboxylic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

5-fluoro-2-methyl-N-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzamide;

thiophene-2-carboxylic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

4-fluoro-N-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzenesulfonamide; and

cyclopropanesulfonic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

or a salt thereof.

5. The compound according to claim 1 which has the formula (II):

wherein R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , Q 3 , Q 4 , X, m and p are as defined in claim 1 , or a salt thereof.

6. A pharmaceutical composition comprising a compound of formula (I):

wherein:

m, p=1 or 2;

X is CO or SO 2 ;

Q 1 to Q 4 are independently CH or N provided that at least one of Q 1 to Q 4 is N;

R 1 is hydrogen, (C 1 -C 4 )alkyl, CF 3 , or (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl;

R 2 is hydrogen, halogen, (C 1 -C 4 )alkyl or CF 3 ;

R 3 is unsubstituted or substituted naphthyl, phenyl, benzyl, thiophenyl, isoxazolyl, cyclopropyl, cyclohexyl, tetrahydropyranyl or piperidinyl, wherein the substituents are selected from the group consisting of halogen, (C 1 -C 4 )alkyl and CH 3 CO; and

R 4 is H or (C 1 -C 4 )alkyl; or

a pharmaceutically acceptable salt thereof or an enantiomer or a diastereomer thereof in combination with at least one pharmaceutically acceptable excipient, diluent or a carrier.

7. The composition according to claim 6 , wherein the compound is selected from the group consisting of:

tetrahydro-pyran-4-carboxylic acid [2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

tetrahydro-pyran-4-carboxylic acid [5-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-2-yl]-amide;

naphthalene-1-carboxylic acid [2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

N-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2-phenyl-acetamide;

cyclohexanesulfonic acid [2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

3,4-difluoro-N-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzenesulfonamide;

N-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzamide;

1-acetyl-piperidine-4-carboxylic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

5-fluoro-2-methyl-N-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzamide;

thiophene-2-carboxylic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

4-fluoro-N-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzenesulfonamide; and

cyclopropanesulfonic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide; or

a pharmaceutically acceptable salt thereof.

8. The composition according to claim 6 , wherein the compound is having the formula (II):

wherein R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , Q 3 , Q 4 , X, m and p are as defined in claim 6 , or a pharmaceutically acceptable salt thereof.

9. A method of treating a disease in a patient, said disease selected from the group consisting of cognitive impairment associated with schizophrenia (CIAS), anxiety disorders, generalized anxiety, panic disorder and post-traumatic stress disorder, major depressive disorder, dementia of Alzheimer type (DAT), cognitive deficits related to neurological diseases chosen from Alzheimer, Parkinson or Huntington, age related cognitive impairment, mild cognitive impairment, vascular dementia, Lewis Body dementia, cognition associated with cognitive deficits, sleep related disorders, attention deficit hyperactivity disorder and depression, and obesity, comprising administering to said patient a therapeutically effective amount of a compound of formula (I):

wherein:

m, p=1 or 2;

X is CO or SO 2 ;

Q 1 to Q 4 are independently CH or N provided that at least one of Q 1 to Q 4 is N;

R 1 is hydrogen, (C 1 -C 4 )alkyl, CF 3 , (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl;

R 2 is hydrogen, halogen, (C 1 -C 4 )alkyl or CF 3 ;

R 3 is unsubstituted or substituted naphthyl, phenyl, benzyl, thiophenyl, isoxazolyl, cyclopropyl, cyclohexyl, tetrahydropyranyl or piperidinyl, wherein the substituents are selected from the group consisting of halogen, (C 1 -C 4 )alkyl and CH 3 CO; and

R 4 is H or (C 1 -C 4 )alkyl; or

a pharmaceutically acceptable salt thereof or an enantiomer or a diastereomer thereof optionally in combination with one or more pharmaceutically acceptable excipient, diluent or a carrier.

10. The method according to claim 9 , wherein the sleep disorder is selected from the group consisting of narcolepsy, circadian rhythm sleep disorder, obstructive sleep apnea, periodic limb movement and restless leg syndrome, excessive sleepiness and drowsiness due to medication side-effect.

11. The method according to claim 10 , wherein the sleep disorder is narcolepsy.

12. The method according to claim 9 , wherein the disease is cognitive impairment associated with schizophrenia (CIAS).

13. The method according to claim 9 , wherein the disease is dementia of Alzheimer type (DAT).

14. The method according to claim 9 , wherein the compound is selected from the group consisting of:

tetrahydro-pyran-4-carboxylic acid [2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

tetrahydro-pyran-4-carboxylic acid [5-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-2-yl]-amide;

naphthalene-1-carboxylic acid [2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

N-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2-phenyl-acetamide;

cyclohexanesulfonic acid [2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

3,4-difluoro-N-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzenesulfonamide;

N-[2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzamide;

1-acetyl-piperidine-4-carboxylic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

5-fluoro-2-methyl-N-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzamide;

thiophene-2-carboxylic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide;

4-fluoro-N-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-benzenesulfonamide; and

cyclopropanesulfonic acid [2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-amide; or

a pharmaceutically acceptable salt thereof.

15. The method according to claim 9 , wherein the compound is having the formula (II):

wherein R 1 , R 2 , R 3 , R 4 , Q 1 , Q 2 , Q 3 , Q 4 , X, m and p are as defined in claim 9 , or a pharmaceutically acceptable salt thereof.