# US 8,541,427 B2 · Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as BACE-1 inhibitors, compositions, and their use

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- Number: US 8,541,427 B2
- Document ID: US8541427B2
- Status: Granted
- Kind: B2
- Application number: 12/988,461
- Filed: 2009-04-21
- Published: 2011-05-12
- Granted: 2013-09-24
- Earliest claimed: 2008-04-22
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Andrew W. Stamford; Zhaoning Zhu; Mihirbaran Mandal; Yusheng Wu; Jared N. Cumming; Xiaoxiang Liu; Guoqing Li; Ulrich Iserloh
- Inventors: Andrew W. Stamford; Zhaoning Zhu; Mihirbaran Mandal; Yusheng Wu; Jared N. Cumming; Xiaoxiang Liu; Guoqing Li; Ulrich Iserloh
- Web page: https://patentgrep.com/patent/US8541427B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/08: Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 13/12: of the kidneys
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- 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
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

In its many embodiments, the present invention provides certain 2-imino-3-methyl pyrrolo pyrimidone compounds, including compounds Formula (II): and include tautomers, steroisomers, or pharmaceutically acceptable salts or solvates of said compounds, stereoisomers, or said tautomers, wherein R2, R3, R4, R5, R6, R7, R8, and R9 are each selected independently and as defined herein. Pharmaceutical compositions comprising one or more such compounds, and methods for their preparation and use in treating pathologies associated with amyloid beta (Aβ) protein, including Alzheimer's Disease, are also disclosed.

## Claims

### Claim 1

A compound, or a deuterate thereof, or a tautomer of said compound or said deuterate, or a pharmaceutically acceptable salt of said compound, said deuterate, or said tautomer, said compound having the structural Formula (II-A):
wherein R2, R3, R4, R5, R8, R7, and R8 are each selected independently and wherein:
R2 is selected from hydrogen, fluorine, chlorine, and cyano;
R3 is selected from hydrogen, fluorine, chlorine, and cyano;
R4 is selected from hydrogen, fluorine, chlorine, and cyano;
R5 is selected from hydrogen, fluorine, and chlorine;
R6 is selected from lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, and lower alkyl-OH;
R7 is selected from fluorine and chlorine; and
R8 is selected from lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, and —O-alkyl-cycloalkyl.

### Claim 2 (depends on 1)

A compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R6 is selected from lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, and lower alkyl-OH;
R7 is selected from fluorine and chlorine; and
R8 is selected from lower alkyl, lower alkoxy, and cyclopropyl.

### Claim 3 (depends on 1)

A compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R6 is selected from methyl, ethyl, methoxy, ethoxy, —CH2OH, —CF3, and —CF2CH3;
R7 is selected from fluorine and chlorine; and
R8 is selected from methoxy, ethoxy, cyclopropyl, and ethyl.

### Claim 4 (depends on 1)

A compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R6 is selected from methyl, ethyl, and methoxy;
R7 is selected from fluorine and chlorine; and
R8 is selected from methoxy and cyclopropyl.

### Claim 5 (depends on 1)

A compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
R6 is selected from methyl, ethyl, methoxy, ethoxy, —CH2OH, —CF3, and —CF2CH3;
R7 is selected from fluorine and chlorine; and
R8 is selected from methoxy, ethoxy, cyclopropyl, and ethyl;
and the moiety
shown in Formula (II-A) is selected from:

### Claim 6 (depends on 1)

A compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:
the moiety
shown in Formula (II-A) is selected from the group consisting of

### Claim 7

A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the structural Formula (II-AA):
wherein:
R2 is selected from hydrogen, fluorine, chlorine, and cyano;
R3 is selected from hydrogen, fluorine, chlorine, and cyano;
R4 is selected from hydrogen, fluorine, chlorine, and cyano; and
R5 is selected from hydrogen, fluorine, and chlorine.

### Claim 8 (depends on 7)

A compound of claim 7, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: the moiety
shown in Formula (II-AA) is selected from:

### Claim 9

A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the structural Formula (II-AB):
wherein each variable is selected independently of the others and wherein: the moiety
shown in (II-AB) is selected from the group consisting of
either R2 is F and R3 is H or R2 is H and R3 is F.

### Claim 10

A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound being selected from:
Ex
No.
Compound
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43

### Claim 11

A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having a structure selected from:
Ex
No.
Compound
1
2
8
9
10
15
16
17
18
19
20
31
35
38
39

### Claim 12

A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:

### Claim 13

A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:

### Claim 14

A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:

### Claim 15

A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:

### Claim 16

A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:

### Claim 17

A compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, said compound having the following structure:

### Claim 18

A deuterated compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said deuterated compound or said tautomer, said deuterated compound having the following structure:

### Claim 19

A deuterated compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said deuterated compound or said tautomer, said deuterated compound having the following structure:

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

A pharmaceutical composition comprising at least one compound of any one of claims 1-19, or a tautomer thereof, or pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable carrier or diluent.

### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

A pharmaceutical composition comprising a compound of any one of claims 1-19, or a tautomer thereof, or a stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt thereof, together with at least one additional therapeutic agent, wherein said at least one additional therapeutic agent is at least one agent selected from:
m1 agonists; m2 antagonists; cholinesterase inhibitors; galantamine; rivastigimine; N-methyl-D-aspartate receptor antagonists; combinations of cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists; gamma secretase modulators; gamma secretase inhibitors; non-steroidal anti-inflammatory agents; anti-inflammatory agents that can reduce neuroinflammation; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists; CB1 receptor antagonists; antibiotics; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors; Tau kinase inhibitors; Tau aggregation inhibitors; RAGE inhibitors; anti-Abeta vaccine; APP ligands; agents that upregulate insulin, cholesterol lowering agents; cholesterol absorption inhibitors; combinations of HMG-CoA reductase inhibitors and cholesterol absorption inhibitors; fibrates; combinations of fibrates and cholesterol lowering agents and/or cholesterol absorption inhibitors; nicotinic receptor agonists; niacin; combinations of niacin and cholesterol absorption inhibitors and/or cholesterol lowering agents; LXR agonists; LRP mimics; H3 receptor antagonists; histone deacetylase inhibitors; hsp90 inhibitors; 5-HT4 agonists; 5-HT6 receptor antagonists; mGluR1 receptor modulators or antagonists; mGluR5 receptor modulators or antagonists; mGluR2/3 antagonists; Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; agents that can induce Abeta efflux; Metal-protein attenuating compound; GPR3 modulators; and antihistamines.