# US 7,612,069 B2 · Acyl guanidines as beta-secretase inhibitors

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- Number: US 7,612,069 B2
- Document ID: US7612069B2
- Status: Granted
- Kind: B2
- Application number: 11/471,125
- Filed: 2006-06-20
- Published: 2007-01-18
- Granted: 2009-11-03
- Earliest claimed: 2005-06-21
- Assignees: Bristol-Myers Squibb Company
- Inventors: Samuel Gerritz; Weixu Zhai; Shuhao Shi; Shirong Zhu; Andrew C. Good; Lorin A. Thompson, III
- Web page: https://patentgrep.com/patent/US7612069B2

## CPC

- C07D 275/03: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- 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 231/14: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 261/18: Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

There is provided a series of substituted acyl guanidines of Formula (I) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4 and R5 as defined herein, their pharmaceutical compositions and methods of use. These compounds inhibit the processing of amyloid precursor protein (APP) by β-secretase and, more specifically, inhibit the production of Aβ-peptide. The present disclosure is directed to compounds useful in the treatment of neurological disorders related to β-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.

## Claims

### Claim 1

A compound of Formula (I); or a stereoisomer thereof
wherein
R1 is naphthyl optionally substituted with halogen, quinolyl, thienyl, 2,3-dimethyl-1H-indol-5-yl, or phenyl in which said phenyl is optionally substituted with one or more groups selected from halogen, CN, CF3, OH, —NH2, C3-6cycloalkyl, C1-6alkoxy, OR21, C1-6alkyl optionally substituted with OH or —NH2, —(CH2)m—NHC(═O)OR17, —(CH2)m—NHC(═O)Ophenyl optionally substituted with halogen, —(CH2)m—NHC(═O)R18, —NH(C═O)R19, —CH2NH(SO2)R20, R22, R23, and —CH2morpholino;
R2 and R3 are each independently hydrogen, methyl or hydroxymethyl;
R4 is hydrogen, C1-6alkyl optionally substituted with C1-4alkoxy or thiomethyl; or phenyl optionally substituted with one or more groups selected from halogen, C1-4alkyl, C1-4alkoxy, nitro and dimethylamino;
R5 is phenyl in which said phenyl is optionally substituted with one or more groups selected from halogen, —S(O)2methyl, C1-4alkyl and C1-4alkoxy;
X is O, S, NH or NHCH3;
m is 0 or 1;
R17 is C1-6 alkyl optionally substituted with C1-4alkoxy, halogen, C2-3alkynyl, 4-nitrophenyl, benzyloxy or benzothiophene 1,1-dioxide;
R18 is C1-6alkyl or C3-6cycloalkyl in which each is optionally substituted with a group selected from halogen, CN, CF3, —N(CH3)2, C1-4alkoxy, C3-6cycloalkyl, morpholino, thienyl, imidazolyl, pyridyl, azepinyl, benzothienyl, benzofuranyl, phenyl and methoxyphenyl;
R19 is C1-6alkyl optionally substituted with methoxyethyloxy or methylthio; C1-4alkoxy optionally substituted with halogen; C3-6cycloalkyl, phenyl, pyridyl optionally substituted with one or two halogen and C1-4alkyl; benzothienyl, 1-methyl-2-pyrrolyl or furanyl;
R20 is C1-6alkyl, 1,2-dimethyl-1H-imidazolyl, thienyl or phenyl in which said phenyl is optionally substituted with a group selected from acetyl, C1-4alkoxy, benzyloxy, halogen, NH(C═O)CH3 and nitro;
R21 is C1-6alkyl optionally substituted with a group selected from C1-4alkoxy, halogen, phenyl, furanyl and methylamino;
R22 is —CH═CH-phenyl or —CH═CH—C1-4alkyl optionally substituted with C1-4alkoxy or OH; and
R23 is pyridyl, thienyl, C2-6alkenyl, or phenyl optionally substituted with halogen;
or a nontoxic pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 of Formula (I); or a stereoisomer thereof,
wherein
R1 is naphthyl optionally substituted with halogen, quinolyl, thienyl, 2,3-dimethyl-1H-indol-5-yl, or phenyl in which said phenyl is optionally substituted with one or more groups selected from halogen, CN, CF3, OH, —NH2, C3-6cyclalkyl, C1-6alkoxy, OR21, C1-6alkyl optionally substituted with OH or —NH2, —(CH2)m—NHC(═O)OR17, —(CH2)m—NHC(═O)Ophenyl optionally substituted with halogen, —(CH2)m—NHC(═O)R18, —NH(C═O)R19, —CH2NH(SO2)R20, R22, R23, and —CH2morpholino;
R2 and R3are each hydrogen;
R4 is C1-6alkyl optionally substituted with C1-4alkoxy or thiomethyl;
R5 is phenyl optionally substituted with one or more groups selected from halogen, C1-4alkyl, —S(O)2methyl and C1-4alkoxy;
X is O, S, or NH;
m is 0 or 1;
R17 is C1-4alkoxy, halogen, C2-3alkynyl, 4-nitrophenyl, benzyloxy or benzothiophene 1,1-dioxide;
R18 is C1-6alkyl or C3-6cycloalkyl in which each is optionally substituted with a group selected from halogen, CN, CF3, —N(CH3)2, C1-4alkoxy, C3-6cycloalkyl, morpholino, thienyl, imidazolyl, pyridyl, azepinyl, benzothienyl, benzofuranyl, phenyl and methoxyphenyl;
R19 is C1-6alkyl optionally substituted with methoxyethyloxy or methylthio; C1-4alkoxy optionally substituted with halogen; C3-6cycloalkyl, phenyl, pyridyl optionally substituted with one or two halogen and C1-4alkyl; benzothienyl, 1-methyl-2-pyrrolyl or furanyl;
R20 is C1-6alkyl, 1,2-dimethyl-1H-imidazolyl, thienyl or phenyl in which said phenyl is optionally substituted with a group selected from acetyl, C1-4alkoxy, benzyloxy, halogen, NH(C═O)CH3 and nitro;
R21 is C1-6alkyl optionally substituted with a group selected from C1-4alkoxy, halogen, phenyl, furanyl and methylamino; R22 is —CH═CH-phenyl or —CHCH—C1-4alkyl optionally substituted with C1-4alkoxy or OH; and
R23 is pyridyl, thienyl, C2-6alkenyl, or phenyl optionally substituted with halogen;
or a nontoxic pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound according to claim 2 of Formula (I); or a stereoisomer thereof,
wherein
R1 is phenyl optionally substituted with one or more groups selected from halogen, CN, CF3, OH, —NH2, C3-6cycloalkyl, C1-6alkoxy, OR21, C1-6alkyl optionally substituted with OH or —NH2, —(CH2)m—NHC(═O)OR17, —(CH2)m—NHC(═O)Ophenyl optionally substituted with halogen, —(CH2)m—NHC(═O)R18, —NH(C═O)R19, —CH2NH(SO2)R20, R22, R23, and —CH2morpholino;
R2 and R3are hydrogen;
R4 is C1-3alkyl;
R5 is phenyl optionally substituted with one or more groups selected from halogen, C1-4alkyl, —S(O)2methyl and C1-4alkoxy;
X is O or S;
m is 0 or 1;
R17 is C1-4alkoxy, halogen, C2-3alkynyl, 4-nitrophenyl, benzyloxy or benzothiophene 1,1-dioxide;
R18 is C1-6alkyl or C3-6cycloalkyl in which each is optionally substituted with a group selected from halogen, CN, CF3, —N(CH3)2, C1-4alkoxy, C3-6cycloalkyl, morpholino, thienyl, imidazolyl, pyridyl, azepinyl, benzothienyl, benzofuranyl, phenyl and methoxyphenyl;
R19 is C1-6alkyl optionally substituted with methoxyethyloxy or methylthio; C1-4alkoxy optionally substituted with halogen; C3-6cycloalkyl, phenyl, pyridyl optionally substituted with one or two halogen and C1-4alkyl; benzothienyl, 1-methyl-2-pyrrolyl or furanyl;
R20 is C1-6alkyl, 1,2-dimethyl-1H-imidazolyl, thienyl or phenyl in which said phenyl is optionally substituted with a group selected from acetyl, C1-4alkoxy, benzyloxy, halogen, NH(C═O)CH3 and nitro;
R21 is C1-6alkyl optionally substituted with a group selected from C1-4alkoxy, halogen, phenyl, furanyl and methylamino;
R22 is —CH═CH-phenyl or —CH═CH—C1-4alkyl optionally substituted with C1-4alkoxy or OH; and
R23 is pyridyl, thienyl, C2-6alkenyl, or phenyl optionally substituted with halogen;
or a nontoxic pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

The compound according to claim 3 of Formula (Ib); or a stereoisomer thereof,
wherein
R5 is phenyl optionally substituted with one or more groups selected from halogen, C1-4alkyl, and C1-4alkoxy;
X is O or S; and
R19 is C1-6alkyl optionally substituted with methoxyethyloxy or methylthio; C1-4alkoxy optionally substituted with halogen; C3-6cycloalkyl, phenyl, pyridyl optionally substituted with one or two halogen and C1-4alky; benzothienyl, 1-methyl-2-pyrrolyl or furanyl;
or a nontoxic pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 3)

The compound according to claim 3 of Formula (1c); or a stereoisomer thereof,
wherein
R5 is phenyl optionally substituted with one or more groups selected from halogen, C1-4alkyl and C1-4alkoxy;
X is O or S; and
R18 is C1-6alkyl or C3-6cycloalkyl in which each is optionally substituted with a group selected from halogen,
CN, CF3, —N(CH3)2, C1-4alkoxy, C3-6cycloalkyl, morpholino, thienyl, imidazolyl, pyridyl, azepinyl, benzothienyl, benzofuranyl, phenyl and methoxyphenyl;
or a nontoxic pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 3)

The compound according to claim 3 of Formula (Id); or a stereoisomer thereof,
wherein
R5 is optionally substituted with one or more groups selected from halogen, C1-4alkyl and C1-4alkoxy;
X is O or S; and
R20 is C1-6alkyl, 1,2-dimethyl-1H-imidazolyl, thienyl or phenyl in which said phenyl is optionally substituted with a group selected from acetyl, C1-4alkoxy, benzyloxy, halogen, NH(C═O)CH3 and nitro;
or a nontoxic pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 3)

The compound according to claim 3 of Formula (Ie); or a stereoisomer thereof,
wherein
R5 is phenyl optionally substituted with one or more groups selected from halogen, C1-4alkyl and C1-4alkoxy;
X is O or S;
m is 0 or 1; and
R17 is C1-4alkyl optionally substituted with C1-4alkoxy, halogen, C2-3alkynyl, 4-nitrophenyl, benzyloxy or benzothiophene 1,1-dioxide;
or a nontoxic pharmaceutically acceptable salt thereof

### Claim 8 (depends on 3)

The compound according to claim 3 of Formula (Ih); or a stereoisomer thereof,
wherein
R5 is phenyl optionally substituted with one or more groups selected from halogen, C1-4alkyl and C1-4alkoxy;
A is R22 or R23;
m is 0 or 1;
X is O or S;
R22 is —CH═CH-phenyl, —CH═CH—C1-4alkyl optionally substituted with C1-4alkoxy or OH; and
R23 is pyridyl, thienyl, C2-6alkenyl, or phenyl optionally substituted with halogen;
or a nontoxic pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in association with a pharmaceutically acceptable adjuvant, carrier or diluent.

### Claim 10

A compound of the following formula; or a stereoisomer thereof:

### Claim 11 (depends on 10)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 10 in association with a pharmaceutically acceptable adjuvant, carrier or diluent.