Tetraaza-cyclopenta[a]indenyl derivatives
The present invention provides compounds of Formula (I) as M1 receptor positive allosteric modulators for the treatment of diseases mediated by the muscarinic M1 mediator.
1. A compound of Formula (I):
wherein
R 1 and R 3 are independently from each other selected from the group consisting of H and linear or branched C 1 -C 6 -alkyl,
R 2 is selected from the group consisting of chloro, linear or branched C 1 -C 6 -alkyl and C 3 -C 7 cycloalkyl,
R 4 is selected from the group consisting of F and H, and
R 5 is selected from the group consisting of A and CH 2 CH 2 R 7 , wherein A is selected from the group consisting of:
wherein
R 6 is selected from the group consisting of H, CH 3 , CH 2 CH 2 R, CH(CH 2 R) 2 , CH 2 CR 3 , CH 2 -cyclopropyl, CH 2 CN, and CH 2 CHF 2 ,
R 6 ′ is selected from the group consisting of CH 2 CH 2 R′, CH(CH 2 R′) 2 , CH 2 CR 3 , and CH 2 CO 2 R 1 ,
R 6 ″ is selected from the group consisting of F, OH, OCH 3 , NH 2 , N(CH 3 ) 2 , N(R 1 ) 2 , and CO 2 R 1 ,
R 6 ′″ is selected from the group consisting of CH 2 CH 2 R, CH(CH 2 R) 2 , CH 2 CR 3 , CH 2 -cyclopropyl, CH 2 CN, and CH 2 CHF 2 ,
R is selected from the group consisting of H, CN, OH, OCH 3 , Cl, F, CHF 2 , CH 3 , CF 3 , CH 2 CH 3 and cyclopropyl,
R′ is selected from the group consisting of CN, OH, OCH 3 , Cl, CHF 2 , CH 3 , CF 3 and cyclopropyl, and
R 7 is selected from the group consisting of:
wherein R a and R b are each independently selected from the group consisting of H, F, CH 3 , OCH 3 , OH and 1-pyrrolidinyl and at least one of R a and R b is selected from the group consisting of F, CH 3 , OCH 3 , OH and 1-pyrrolidinyl,
or tautomers, salts, solvates, stereoisomers, diastereomers and enantiomers thereof.
2. The compound of claim 1 , wherein R 1 and R 3 are simultaneously either H or methyl.
3. The compound of claim 1 , wherein R 4 is F.
4. The compound of claim 1 , wherein R 5 is selected from the group consisting of:
5. The compound of claim 1 , wherein R 5 is A.
6. The compound of claim 1 , wherein the compound, or any diastereoisomer or enantiomer thereof, is selected from the group consisting of:
Ex
Structure
1
2
4
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8
13
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25
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35
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54a
54b
58
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70a
70b
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82
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7. A pharmaceutical composition comprising at least one compound of claim 1 , a tautomer, salt, solvate or stereoisomer thereof, or any mixtures thereof, and optionally at least one selected from the group consisting of an excipient and an adjuvant.
8. A pharmaceutical composition comprising at least one compound of claim 1 , a tautomer, salt, solvate or stereoisomer thereof, or any mixtures thereof, and at least one further active ingredient.
9. A kit comprising separate packs of
(a) at least one compound of claim 1 , a tautomer, salt, solvate or stereoisomer thereof, or any mixtures thereof; and
(b) a further medicament active ingredient.
10. A method of treating a muscarinic M1 receptor associated disorder in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of claim 1 , a tautomer, salt, solvate or stereoisomer thereof, or any mixtures thereof.
11. The method of claim 10 , wherein the muscarinic M1 receptor associated disorder is at least one central nervous system disorder.
12. A method of treating a cognitive impairment or decline, or a cholinergic dysfunction, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of claim 1 , a tautomer, salt, solvate or stereoisomer thereof, or any mixtures thereof.
13. The method of claim 12 , wherein the cognitive impairment or decline, or cholinergic dysfunction, is selected from the group consisting of Alzheimer's disease Parkinson disease, schizophrenia, chronic and neuropathic pain, sleep disorders, epilepsy, dementia in Alzheimer's disease, vascular dementia, unspecified dementia, organic amnesic syndrome not induced by alcohol and other psychoactive substances, schizotypal disorder, schizoaffective disorder, nociception disorder, dementia, hallucination, delusion and paranoia.
14. A method of preparing at least one compound of claim 1 , the method comprising reacting a compound of Formula (A)
wherein R 1 , R 2 , R 3 are as defined in claim 1 ,
with a compound of Formula (B)
wherein R 4 and R 5 are as defined in claim 1 ,
in the presence of a coupling agent,
wherein the compound of Formula (I) is prepared.