# US 10,870,635 B2 · Compounds and their use as BACE1 inhibitors

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- Number: US 10,870,635 B2
- Document ID: US10870635B2
- Status: Granted
- Kind: B2
- Application number: 15/568,449
- Filed: 2016-04-20
- Published: 2018-07-19
- Granted: 2020-12-22
- Earliest claimed: 2015-04-21
- Assignees: Allgenesis Biotherapeutics Inc.
- Applicants: Allgenesis Biotherapeutics, Inc.
- Inventors: Madhu Cherukury; Hsiao-Wen Lin; Shu Chieh Yu; Riping Phang; Yesudoss Christu Rajan; Diane Dan-Shya Tang-Liu; Andrew D. White; Thomas Malone; Richard Beresis
- Web page: https://patentgrep.com/patent/US10870635B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 239/22: with hetero atoms directly attached to ring carbon atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/08: linked by a carbon chain containing alicyclic rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/08: linked by a carbon chain containing alicyclic rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 471/14: Ortho-condensed systems
- C07D 491/048: the oxygen-containing ring being five-membered
- C07D 495/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D 513/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

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), R2, R3, R4, R5 and R6, 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).

## Claims

### Claim 1

A compound according to Formula (VI):
Wherein
X is selected from the group consisting of C(O), S(O)2, CR7R8, O, NR1, and S(O);
Y is (CR7R8)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, OR9, O, NR9R10, NR9, C(O)R9, C(O)NR9, NR9C(O), C(O)OR9, OC(O)R9 and heterocycloalkyl;
Q is selected from O, S, NR1, (CR14R15)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, C1-6 alkyl, C1-6 alkoxyl, C2-6 alkenyl, or C2-6 alkynyl, or is a moiety selected from C3-10 cycloalkyl, C1-10 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally mono-, di-, or tri-substituted with halogen, nitro group, cyano group, amino group, amido group, C1-6 alkyl, C1-6 alkoxyl, C2-6 alkenyl, C2-6 alkynyl, aryl, or heteroaryl, or optionally fused with C3-10 cycloalkyl, C1-10 heterocycloalkyl, aryl, or heteroaryl;
Gi is selected from CH2, O, and SO2;
Gii is selected from CH2 and O;
the bond between Gi and Gii is a single bond;
R1 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, heteroalkyl, heterohaloalkyl and heteroalkynyl;
R2 is selected from CN, alkyl, cycloalkyl, and aryl;
R4 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;
R5 is selected from hydrogen, C1-5 alkyl, C(O)R14 and CR17R16OC(O)R18;
a R7 is independently selected from hydrogen, fluorine, and trifluoromethyl;
R8 is independently selected from hydrogen, fluorine, and trifluoromethyl;
R9 is independently selected from hydrogen, deuterium, halogen, C1-5 alkyl and alkynyl;
R10 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl;
R14 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;
R15 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl; or
R14 and R15 are optionally taken together with the carbon atom they are attached to form a cycloalkyl or heterocycloalkyl ring structure;
R16 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl;
R17 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl;
R18 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.

### Claim 2

A compound according to Formula (VI):
Wherein
X is selected from the group consisting of C(O) and S(O)2;
Y is (CR7R8)n;
Z is absent;
W is absent or present and when present is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, OR9, O, NR9R10, NR9, C(O)R9, C(O)NR9, NR9C(O), C(O)OR9, OC(O)R9 and heterocycloalkyl;
Q is selected from NR1, (CR14R15)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, C1-6 alkyl, C1-6 alkoxyl, C2-6 alkenyl, or C2-6 alkynyl, or is a moiety selected from C3-10 cycloalkyl, C1-10 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally mono-, di-, or tri-substituted with halogen, nitro group, cyano group, amino group, amido group, C1-6 alkyl, C1-6 alkoxyl, C2-6 alkenyl, C2-6 alkynyl, aryl, or heteroaryl, or optionally fused with C3-10 cycloalkyl, C1-10 heterocycloalkyl, aryl, or heteroaryl;
Gi is selected from CH2, O, and SO2;
Gii is selected from CH2 and O;
the bond between Gi and Gii is a single bond;
R1 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, heteroalkyl, heterohaloalkyl and heteroalkynyl;
R2 is selected from CN, alkyl, cycloalkyl, and aryl;
R4 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;
R5 is selected from hydrogen, C1-5 alkyl, C(O)R14 and CR17R16OC(O)R18;
R7 is independently selected from hydrogen, fluorine, and trifluoromethyl;
R8 is independently selected from hydrogen, fluorine, and trifluoromethyl;
R9 is independently selected from hydrogen, deuterium, halogen, C1-5 alkyl or alkynyl;
R10 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl;
R14 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;
R15 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl; or
R14 and R15 are optionally taken together with the carbon atom they are attached to form a cycloalkyl or heterocycloalkyl ring structure;
R16 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl;
R17 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl;
R18 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.

### Claim 3

A compound according to Formula (VI):
wherein
X is selected from the group consisting of C(O) and S(O)2;
Y is CH2;
Z is absent;
W is absent or present and when present is selected from the group consisting of alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, OR9, O, NR9R10, NR9, C(O)R9, C(O)NR9, NR9C(O), C(O)OR9, OC(O)R9 and heterocycloalkyl;
Q is selected from NR1, or (CR14R15)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, C1-6 alkyl, C1-6 alkoxyl, C2-6 alkenyl, or C2-6 alkynyl, or is a moiety selected from C3-10 cycloalkyl, C1-10 heterocycloalkyl, aryl, and heteroaryl, each of which is optionally mono-, di-, or tri-substituted with halogen, nitro group, cyano group, amino group, amido group, C1-6 alkyl, C1-6 alkoxyl, C2-6 alkenyl, C2-6 alkynyl, aryl, or heteroaryl, or optionally fused with C3-10 cycloalkyl, C1-10 heterocycloalkyl, aryl, or heteroaryl;
Gi is selected from CH2, O, and SO2;
Gii is selected from CH2 and O;
the bond between Gi and Gii is a single bond;
R1 is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, heteroalkyl, heterohaloalkyl and heteroalkynyl;
R2 is alkyl;
R4 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;
R5 is selected from hydrogen, C1-5 alkyl, C(O)R14 and CR17R16OC(O)R18;
R9 is independently selected from hydrogen, deuterium, halogen, C1-5 alkyl and alkynyl;
R10 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl;
R14 is a straight chain or branched alkyl group of 3 to 28 carbons, heterocycloalkyl, or cycloalkyl;
R15 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl; or
R14 and R15 are optionally taken together with the carbon atom they are attached to form a cycloalkyl or heterocycloalkyl ring structure;
R16 is independently selected from hydrogen, deuterium, halogen and C1-5 alkyl;
R17 is independently selected from hydrogen and C1-5 alkyl;
R18 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.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 a pharmaceutically acceptable excipient.

### Claim 6 (depends on 1)

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.

### Claim 7 (depends on 2)

A pharmaceutical composition comprising the compound according to claim 2 a pharmaceutically acceptable excipient.

### Claim 8 (depends on 3)

A pharmaceutical composition comprising the compound according to claim 3 a pharmaceutically acceptable excipient.

### Claim 9 (depends on 4)

A pharmaceutical composition comprising the compound according to claim 4 a pharmaceutically acceptable excipient.

### Claim 10 (depends on 2)

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.

### Claim 11 (depends on 3)

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.

### Claim 12 (depends on 4)

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.