Compounds and their use as BACE1 inhibitors
The present invention relates to compounds of Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein X, Y, Z, Q, W, m, u, ring (A), R 2 , R 3 , R 4 , R 5 and R 6 , are as defined in the specification and claims. The present invention provides a pharmaceutical composition containing the compounds of Formula (I) and a therapeutic method of treating and/or preventing Downs syndrome, 3-amyloid angiopathy, disorders associated with cognitive impairment, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegenerative diseases, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, Alzheimer's disease and/or Down syndrome, age-related macular degeneration (AMD), glaucoma, olfactory function impairment, traumatic brain injury, progressive muscle diseases, Type II diabetes mellitus and cardiovascular diseases (stroke).
1. A compound according to Formula (VI):
Wherein
X is selected from the group consisting of C(O), S(O) 2 , CR 7 R 8 , O, NR 1 , and S(O);
Y is (CR 7 R 8 ) n ;
X and Y are optionally taken together to form a ring structure
Z is absent;
W is absent or present and when present is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, OR 9 , O, NR 9 R 10 , NR 9 , C(O)R 9 , C(O)NR 9 , NR 9 C(O), C(O)OR 9 , OC(O)R 9 and heterocycloalkyl;
Q is selected from O, S, NR 1 , (CR 14 R 15 ) t , C(O);
is selected from
wherein each of Ri, Rii, Riii, Riv, Rv, Rvi, Rvii, and Rviii, independently, is hydrogen, halogen, cyano group, amino group, amido group, C 1-6 alkyl, C 1-6 alkoxyl, C 2-6 alkenyl, or C 2-6 alkynyl, or is a moiety selected from C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally mono-, di-, or tri-substituted with halogen, nitro group, cyano group, amino group, amido group, C 1-6 alkyl, C 1-6 alkoxyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, or heteroaryl, or optionally fused with C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, or heteroaryl;
Gi is selected from CH 2 , O, and SO 2 ;
Gii is selected from CH 2 and O;
the bond between Gi and Gii is a single bond;
R 1 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, heteroalkyl, heterohaloalkyl and heteroalkynyl;
R 2 is selected from CN, alkyl, cycloalkyl, and aryl;
R 4 is independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxyl, CN, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl and heterocycloalkyl;
R 5 is selected from hydrogen, C 1-5 alkyl, C(O)R 14 and CR 17 R 16 OC(O)R 18 ;
a R 7 is independently selected from hydrogen, fluorine, and trifluoromethyl;
R 8 is independently selected from hydrogen, fluorine, and trifluoromethyl;
R 9 is independently selected from hydrogen, deuterium, halogen, C 1-5 alkyl and alkynyl;
R 10 is independently selected from hydrogen, deuterium, halogen and C 1-5 alkyl;
R 14 is a straight chain or branched alkyl group of 1 to 28 carbons, heterocycloalkyl and cycloalkyl, monocyclic aryl, multicyclic aryl, monocyclic heteroaryl, multicyclic heteroaryl, haloalkyl or heteroalkyl;
R 15 is independently selected from hydrogen, deuterium, halogen and C 1-5 alkyl; or
R 14 and R 15 are optionally taken together with the carbon atom they are attached to form a cycloalkyl or heterocycloalkyl ring structure;
R 16 is independently selected from hydrogen, deuterium, halogen and C 1-5 alkyl;
R 17 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl;
R 18 is a straight chain or branched alkyl group of 1 to 28 carbons, heterocycloalkyl and cycloalkyl, monocyclic aryl, multicyclic aryl, monocyclic heteroaryl, multicyclic heteroaryl, haloalkyl or heteroalkyl;
n is 1 or 2;
m is 0 or more;
t is 1;
or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, solvate, or solvate of a salt thereof.
2. A compound according to Formula (VI):
Wherein
X is selected from the group consisting of C(O) and S(O) 2 ;
Y is (CR 7 R 8 ) n ;
Z is absent;
W is absent or present and when present is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, OR 9 , O, NR 9 R 10 , NR 9 , C(O)R 9 , C(O)NR 9 , NR 9 C(O), C(O)OR 9 , OC(O)R 9 and heterocycloalkyl;
Q is selected from NR 1 , (CR 14 R 15 ) t ;
is selected from
wherein each of Ri, Rii, Riii, Riv, Rv, Rvi, Rvii, and Rviii, independently, is hydrogen, halogen, cyano group, amino group, amido group, C 1-6 alkyl, C 1-6 alkoxyl, C 2-6 alkenyl, or C 2-6 alkynyl, or is a moiety selected from C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally mono-, di-, or tri-substituted with halogen, nitro group, cyano group, amino group, amido group, C 1-6 alkyl, C 1-6 alkoxyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, or heteroaryl, or optionally fused with C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, or heteroaryl;
Gi is selected from CH 2 , O, and SO 2 ;
Gii is selected from CH 2 and O;
the bond between Gi and Gii is a single bond;
R 1 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, heteroalkyl, heterohaloalkyl and heteroalkynyl;
R 2 is selected from CN, alkyl, cycloalkyl, and aryl;
R 4 is independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxyl, CN, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl and heterocycloalkyl;
R 5 is selected from hydrogen, C 1-5 alkyl, C(O)R 14 and CR 17 R 16 OC(O)R 18 ;
R 7 is independently selected from hydrogen, fluorine, and trifluoromethyl;
R 8 is independently selected from hydrogen, fluorine, and trifluoromethyl;
R 9 is independently selected from hydrogen, deuterium, halogen, C 1-5 alkyl or alkynyl;
R 10 is independently selected from hydrogen, deuterium, halogen and C 1-5 alkyl;
R 14 is a straight chain or branched alkyl group of 1 to 28 carbons, heterocycloalkyl, cycloalkyl, monocyclic aryl, multicyclic aryl, monocyclic heteroaryl, multicyclic heteroaryl, haloalkyl or heteroalkyl;
R 15 is independently selected from hydrogen, deuterium, halogen and C 1-5 alkyl; or
R 14 and R 15 are optionally taken together with the carbon atom they are attached to form a cycloalkyl or heterocycloalkyl ring structure;
R 16 is independently selected from hydrogen, deuterium, halogen and C 1-5 alkyl;
R 17 is independently selected from hydrogen, deuterium, halogen and C 1-5 alkyl;
R 18 is a straight chain or branched alkyl group of 1 to 28 carbons, heterocycloalkyl and cycloalkyl, monocyclic aryl, multicyclic aryl, monocyclic heteroaryl, multicyclic heteroaryl, haloalkyl or heteroalkyl;
n is 1 or 2;
m is 0 or more;
t is 1;
or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, solvate, or solvate of a salt thereof.
3. A compound according to Formula (VI):
wherein
X is selected from the group consisting of C(O) and S(O) 2 ;
Y is CH 2 ;
Z is absent;
W is absent or present and when present is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, OR 9 , O, NR 9 R 10 , NR 9 , C(O)R 9 , C(O)NR 9 , NR 9 C(O), C(O)OR 9 , OC(O)R 9 and heterocycloalkyl;
Q is selected from NR 1 , or (CR 14 R 15 ) t ;
is selected from
wherein each of Ri, Rii, Riii, Riv, Rv, Rvi, Rvii, and Rviii, independently, is hydrogen, halogen, cyano group, amino group, amido group, C 1-6 alkyl, C 1-6 alkoxyl, C 2-6 alkenyl, or C 2-6 alkynyl, or is a moiety selected from C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally mono-, di-, or tri-substituted with halogen, nitro group, cyano group, amino group, amido group, C 1-6 alkyl, C 1-6 alkoxyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, or heteroaryl, or optionally fused with C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, aryl, or heteroaryl;
Gi is selected from CH 2 , O, and SO 2 ;
Gii is selected from CH 2 and O;
the bond between Gi and Gii is a single bond;
R 1 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, heteroalkyl, heterohaloalkyl and heteroalkynyl;
R 2 is alkyl;
R 4 is independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxyl, CN, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl and heterocycloalkyl;
R 5 is selected from hydrogen, C 1-5 alkyl, C(O)R 14 and CR 17 R 16 OC(O)R 18 ;
R 9 is independently selected from hydrogen, deuterium, halogen, C 1-5 alkyl and alkynyl;
R 10 is independently selected from hydrogen, deuterium, halogen and C 1-5 alkyl;
R 14 is a straight chain or branched alkyl group of 3 to 28 carbons, heterocycloalkyl, or cycloalkyl;
R 15 is independently selected from hydrogen, deuterium, halogen and C 1-5 alkyl; or
R 14 and R 15 are optionally taken together with the carbon atom they are attached to form a cycloalkyl or heterocycloalkyl ring structure;
R 16 is independently selected from hydrogen, deuterium, halogen and C 1-5 alkyl;
R 17 is independently selected from hydrogen and C 1-5 alkyl;
R 18 is a straight chain or branched alkyl group of 3 to 28 carbons, heterocycloalkyl or cycloalkyl;
m is 0 or more;
t is 1;
or a stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, solvate, or solvate of a salt thereof.
4. The compound according to claim 1 , wherein the compound is selected from:
(S)-2-Imino-3,6-dimethyl-6-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-4(1H)-one;
(S,Z)-N-(1,4-Dimethyl-6-oxo-4-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-2(1H)-ylidene)benzamide;
(S)-1-Benzoyl-2-imino-3,6-dimethyl-6-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-4(1H)-one;
(S,Z)-((1,4-Dimethyl-6-oxo-4-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-2(1H)-ylidene)amino)methyl benzoate;
(S,Z)-N-(1,4-Dimethyl-6-oxo-4-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-2(1H)-ylidene)palmitamide;
(S,Z)-((1,4-Dimethyl-6-oxo-4-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-2(1H)-ylidene)amino)methyl dodecanoate;
(S)-2-Imino-3,6-dimethyl-6-(8-(prop-1-yn-1-yl)dibenzo[b,d]furan-2-yl)tetrahydropyrimidin-4(1H)-one;
(R)-3-Imino-2,2,5-trimethyl-5-(7-methyl-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)thiomorpholine 1,1-dioxide;
(R)-5-(7-Fluoro-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-3-imino-2,2,5-trimethylthiomorpholine 1,1-dioxide;
(R)-3-Imino-2,2,5-trimethyl-5-(7-methyl-5,11-dihydrodibenzo[b,e][1,4]oxazepin-3-yl)thiomorpholine 1,1-dioxide;
(R)-3-Imino-2,2,5-trimethyl-5-(3-methyl-5,11-dihydrodibenzo[b,e][1,4]oxazepin-7-yl)thiomorpholine 1,1-dioxide;
(R)-7-(5-Imino-3,6,6-trimethyl-1,1-dioxidothiomorpholin-3-yl)-3-methyl-5,11-dihydrodibenzo[b,e][1,4]thiazepine 10,10-dioxide;
(S)-6-(3-chloro-8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-2-imino-3,6-dimethyltetrahydropyrimidin-4(1H)-one;
(S)-6-(3-fluoro-8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-2-imino-3,6-dimethyltetrahydropyrimidin-4(1N)-one;
(S)-6-(9-fluoro-8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-2-imino-3,6-dimethyltetrahydropyrimidin-4(1N)-one;
(S)-6-(5,5-di oxido-8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-2-imino-3,6-dimethyltetrahydropyrimidin-4(1H)-one;
(6S)-2-imino-3,6-dimethyl-6-(5-oxido-8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-4(1H)-one;
(S)-6-(9,9-Dimethyl-6-(prop-1-yn-1-yl)-9H-fluoren-3-yl)-2-imino-3,6-dimethyltetrahydropyrimidin-4(1H)-one;
(S)-6-(9,9-Difluoro-6-(prop-1-yn-1-yl)-9H-fluoren-3-yl)-2-imino-3,6-dimethyltetrahydropyrimidin-4(1H)-one;
(S)-8-(2-Imino-1,4-dimethyl-6-oxohexahydropyrimidin-4-yl)dibenzo[b,d]thiophene-2-carbonitrile;
(S)-2-imino-6-(8-(3-methoxyprop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-3, 6-dimethyltetrahydropyrimidin-4(1H)-one;
(S)-6-(8-(3-hydroxyprop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-2-imino-3, 6-dimethyltetrahydropyrimidin-4(1H)-one;
(S)-6-(8-Bromodibenzo[b,d]thiophen-2-yl)-2-imino-3,6-dimethyltetrahydropyrimidin-4(1H)-one, (S)-6-(8-cyclopropyldibenzo[b,d]thiophen-2-yl)-2-imino-3,6-dimethyltetrahydropyrimidin-4(1N)-one;
(S)-8-(2-Imino-1,4-dimethyl-6-oxohexahydropyrimidin-4-yl)dibenzo[b,d]thiophene-2-carboxamide;
(S)-6-(8-(Diethylamino)dibenzo[b,d]thiophen-2-yl)-2-imino-3,6-dimethyltetrahydropyrimidin-4(1N)-one;
(S)-2-Imino-3,6-dimethyl-6-(8-(trifluoromethyl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-4(1N)-one;
(R)-6-Cyclopropyl-2-imino-3-methyl-6-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-4(1N)-one;
(R)-5,5-difluoro-4-methyl-4-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-1,3-oxazinan-2-imine;
(R)-3-imino-2,2,5-trimethyl-5-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)thiomorpholine 1,1-dioxide;
(R)-3-Imino-2,5-dimethyl-5-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-1,2,4-thiadiazinane 1,1-dioxide;
(S)-3-(2,2-Difluoroethyl)-2-imino-6-methyl-6-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-4(1H)-one;
(S)-2-Imino-3-(2-methoxyethyl)-6-methyl-6-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-4(1H)-one;
(R)-5-(3-fluoro-8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-3-imino-2,2,5-trimethylthiomorpholine 1,1-dioxide;
(R)-3-Imino-1,5-dimethyl-5-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)piperazin-2-one;
(R)-5-(4-Fluoro-8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-3-imino-2,2,5-trimethylthiomorpholine 1,1-dioxide;
(R)-5-(7-fluoro-8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-3-imino-2,2,5-trimethylthiomorpholine 1,1-dioxide;
(R)-10-Imino-8-methyl-8-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-6-thia-9-azaspiro[4.5]decane 6,6-dioxide;
(R)-8-Imino-6-methyl-6-(8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-4-thia-7-azaspiro[2.5]octane 4,4-dioxide;
(R,E)-3-Imino-2,2,5-trimethyl-5-(8-(prop-1-en-1-yl)dibenzo[b,d]thiophen-2-yl)thiomorpholine 1,1-dioxide;
(R)-6-(7-Fluoro-8-(prop-1-yn-1-yl)dibenzo[b,d]thiophen-2-yl)-8-imino-6-methyl-4-thia-7-azaspiro[2.5]octane 4,4-dioxide; and
(S)-2-Imino-3,6-dimethyl-6-(8-propyldibenzo[b,d]thiophen-2-yl)tetrahydropyrimidin-4(1H)-one; as a stereoisomer, tautomer, or a prodrug or free base, or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.
5. A pharmaceutical composition comprising the compound according to claim 1 a pharmaceutically acceptable excipient.
6. A method of treating Alzheimer's disease in a patient, comprising administering to said patient an effective amount of the compound according to claim 1 .
7. A pharmaceutical composition comprising the compound according to claim 2 a pharmaceutically acceptable excipient.
8. A pharmaceutical composition comprising the compound according to claim 3 a pharmaceutically acceptable excipient.
9. A pharmaceutical composition comprising the compound according to claim 4 a pharmaceutically acceptable excipient.
10. A method of treating Alzheimer's disease in a patient, comprising administering to said patient an effective amount of the compound according to claim 2 .
11. A method of treating Alzheimer's disease in a patient, comprising administering to said patient an effective amount of the compound according to claim 3 .
12. A method of treating Alzheimer's disease in a patient, comprising administering to said patient an effective amount of the compound according to claim 4 .