Aminediols for the treatment of Alzheimer's disease

• US 20040019086A1
• Filed: 07/10/2002
• Published: 01/29/2004
• Est. Priority Date: 07/10/2001
• Status: Active Grant

• Current Assignee: Pharmacia & Upjohn LLC (Pfizer Inc.)
• Original Assignee: Pharmacia & Upjohn LLC (Pfizer Inc.)
• Inventors: Schostarez, Heinrich Josef, Chrusciel, Robert Alan
• Granted Patent: US 7,053,109 B2
• Time in Patent Office: Days
• US Class Current: 514/352
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: 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
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 263/06 with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 263/34 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
• CPC Class Codes: C07D 277/56 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 295/26 Sulfur atoms
• CPC Class Codes: C07D 317/30 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present invention relates to compounds of formula (I):

useful in treating Alzheimer'"'"'s disease and other similar diseases. These compounds include inhibitors of the beta-secretase enzyme that are useful in the treatment of Alzheimer'"'"'s disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention are useful in pharmaceutical compositions and methods of treatment to reduce A beta peptide formation.

Claims

1. A compound of the formula I:

2. A compound according to claim 1 wherein

R₂ at each occurrence is H;

and

R₁ is —

C₁-C₆ alkyl-aryl, —

C₁-C6 alkyl-heteroaryl, or —

C₁-C₆ alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

NO₂, —

NR₁₀₅R′

₁₀₅, —

CO₂R, —

N(R)COR′

, or —

N(R)SO₂R′

, —

C(═

O)—

(C₁-C₄) alkyl, —

SO₂-amino, —

SO₂-mono or dialkylamino, —

C(═

O)-amino, —

C(═

O)-mono or dialkylamino, —

SO₂—

(C₁-C₄) alkyl, or

C₁-C₆ alkoxy optionally substituted with 1, 2, or 3 groups which are independently selected from halogen, or

C₃-C₇ cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, amino, —

C₁-C₆ alkyl and mono- or dialkylamino, or

C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

CF₃, —

C₁-C₃ alkoxy, amino, mono- or dialkylamino and —

C₁-C₃ alkyl, or

C₂-C₁₀ alkenyl or C₂-C₁₀ alkynyl each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, amino, C₁-C₆ alkyl and mono- or dialkylamino; and

the heterocyclyl group is optionally further substituted with oxo, or

R₁ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, ═

O, —

SH, —

C≡

N, —

CF₃, —

C₁-C₃ alkoxy, —

S—

(C₁-C₃)alkyl, amino, mono- or dialkylamino,—

N(R)C(O)R′

—

, —

OC(═

O)-amino and —

OC(═

O)-mono- or dialkylamino;

with the proviso that R_N is not an alpha amino acid.

3. A compound according to claim 2 wherein

R₁′

is H or is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, ═

O, —

SH, —

C≡

N, —

CF₃, —

C₁-C₃ alkoxy, —

S—

(C₁-C₃)alkyl, amino, mono- or dialkylamino, —

N(R)C(O)R′

—

, —

OC(═

O)-amino and —

OC(═

O)-mono- or dialkylamino, or

C₂-C₆ alkenyl or C₂-C₆ alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, amino, and mono- or dialkylamino.

4. A compound according to claim 3 wherein

R_N is —

C(═

O)—

(CRR′

)_0-6R₁₀₀;

R₁₀₀ represents aryl, heteroaryl, or heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from

—

OR, —

NO₂, C₁-C₆ alkyl, halogen, —

C≡

N, —

OCF₃, —

CF₃, —

(CH₂)_0-4—

O—

P(═

O) (OR) (OR′

), —

(CH₂)_0-4—

CO—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

O—

(CH₂)_0-4—

CONR₁₀₂R₁₀₂′

, —

(CH₂)_0-4—

CO—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkenyl), —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkynyl), —

(CH₂)_0-4—

CO—

(CH₂)_0-4 (C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

R₁₁₀, —

(CH₂)_0-4—

R₁₂₀, —

(CH₂)_0-4—

R₁₃₀, —

(CH₂)_0-4—

CO—

R₁₁₀, —

(CH₂)_0-4—

CO—

R₁₂₀, —

(CH₂)_0-4—

CO—

R₁₃₀, —

(CH₂)_0-4—

CO—

R₁₄₀, —

(CH₂)_0-4—

CO—

O—

R₁₅₀, —

(CH₂)_0-4—

SO₂—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

SO—

(C₁-C₈ alkyl), —

(CH₂)_0-4—

SO₂—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

SO2—

(CH₂)_0-4—

(C₃-C₇ cycloalkyl), —

(CH₂)_0-4—

N(R₁₅₀)—

CO—

O—

R₁₅₀, —

(CH₂)_0-4—

N(R₁₅₀)—

CO—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀)—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀)—

CO—

R₁₀₅, —

(CH₂)_0-4—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

R₁₄₀, —

(CH₂)_0-4—

O—

CO—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

O—

P(O)—

(O—

R₁₁₀)₂, —

(CH₂)_0-4—

O—

CO—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

CS—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

CO—

(R₁₅₀), —

(CH₂)_0-4—

O—

R₁₅₀′

—

COOH, —

(CH₂)_0-4—

S—

(R₁₅₀), —

(CH₂)_0-4—

N(R₁₅₀)—

SO₂—

R₁₀₅, —

(CH₂)_0-4—

C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, or (C₂-C₁₀) alkynyl.

5. A compound according to claim 3 wherein

R_N is —

C(═

O)—

(CRR′

)_0-6R₁₀₀; and

R₁₀₀ is C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 R₁₁₅ groups.

6. A compound according to claim 4 wherein

R_N is —

C(═

O)-aryl or —

C(═

O)-heteroaryl where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from

—

OR, —

NO₂, C₁-C₆ alkyl, halogen, —

C≡

N, —

OCF₃, —

CF₃, —

(CH₂)_0-4—

CO—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

O—

(CH₂)_0-4—

CONR₁₀₂R₁₀₂′

, —

(CH₂)_0-4—

CO—

(C₁-C₁₂ alkyl), —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkenyl), —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkynyl), —

(CH₂)_0-4—

R₁₁₀, —

(CH₂)_0-4—

R₁₂₀, —

(CH₂)_0-4—

R₁₃₀, —

(CH₂)_0-4—

CO—

R₁₁₀, —

(CH₂)_0-4—

CO—

R₁₂₀, —

(CH₂)_0-4—

CO—

R₁₃₀, —

(CH₂)_0-4—

CO—

R₁₄₀, —

(CH₂)_0-4—

CO—

O—

R₁₅₀, —

(CH₂)_0-4—

SO₂—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

SO—

(C₁-C₈ alkyl), —

(CH₂)_0-4—

SO₂ (C₁-C₁₂ alkyl), —

(CH₂)_0-4—

N(R₁₅₀)—

CO—

O—

R₁₅₀, —

(CH₂)_0-4—

N(R₁₅₀)—

CO—

N(R₁₅₀)₂, —

(CH₂)_0-4—

N(R₁₅₀)—

CO—

R₁₀₅, —

(CH₂)_0-4—

NR₁₀₅R′

₁₀₅, —

(CH₂)_0-4—

R₁₄₀, —

(CH₂)_0-4—

O—

CO—

(C₁-C₆ alkyl), —

(CH₂)_0-4—

CO—

N(R₁₅₀)₂, —

(CH₂)_0-4—

O—

(R₁₅₀), —

(CH₂)_0-4—

N(R₁₅₀)—

SO₂—

R₁₀₅, —

(CH₂)_0-4—

C₃-C₇ cycloalkyl, (C₂-C₁₀)alkenyl, or (C₂-C₁₀)alkynyl.

7. A compound according to claim 5 wherein

R_N is —

C(═

O)—

C₁-C₁₀ alkyl optionally substituted with 1, 2, or 3 of halogen, —

OH, —

CO₂R₁₀₂, —

C₁-C₆ thioalkoxy, —

CO₂-phenyl, —

NR₁₀₅R′

₁₀₅, —

SO₂—

(C₁-C₈ alkyl), —

C(═

O) R₁₈₀, R₁₈₀, —

CONR₁₀₅R′

₁₀₅, —

SO₂NR₁₀₅R′

₁₀₅, —

NH—

CO—

(C₁-C₆ alkyl), —

NH—

CO—

R₁₁₀, —

NH—

CO—

R₁₂₀, —

NH—

C(═

O)—

OH, —

NH—

C(═

O)—

OR, —

NH—

C(═

O)—

O-phenyl, —

O—

C(═

O)—

(C₁-C₆ alkyl), —

O—

C(═

O)-amino, —

O—

C(═

O)-mono- or dialkylamino, —

O—

C(═

O)-phenyl, —

O—

(C₁-C₆ alkyl)—

CO₂H, —

NH—

SO₂—

(C₁-C₆ alkyl), C₁-C₆ alkoxy or C₁-C₆ haloalkoxy.

8. A compound according to claim 6 wherein

R_C is —

(CH₂)-aryl, —

(CH₂)-heteroaryl, or

C₂-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from C₁-C₆ alkyl, halogen, —

OH, —

O-phenyl, —

SH, —

S—

C₁-C₆ alkyl, —

C≡

N, —

CF₃, C₁-C₆ alkoxy, and NH₂, wherein

each aryl and heteroaryl is optionally substituted with 1, 2, or 3 groups selected from OH, —

NO₂, halogen, —

CO₂H, C≡

N, —

(CH₂)_0-4—

CO—

NR₂₂₀R₂₂₅, —

(CH₂)_0-4—

CO—

(C₁-C₁₂ alkyl), and —

(CH₂)_0-4—

SO₂—

NR₂₂₀R₂₂₅.

9. A compound according to claim 7 wherein

R_C is —

(CH₂)-aryl, —

(CH₂)-heteroaryl, or

C₂-C₁₀ alkyl optionally substituted with 1, 2, or 3 groups independently selected from C₁-C₆ alkyl, halogen, —

OH, —

O-phenyl, —

SH, —

S—

C₁-C₆ alkyl, C≡

N, —

CF₃, C₁-C₆ alkoxy, and NH₂, wherein

each aryl and heteroaryl is optionally substituted with 1, 2, or 3 groups selected from OH, —

NO₂, halogen, —

CO₂H, C≡

N, —

(CH₂)_0-4—

CO—

NR₂₂₀R₂₂₅—

(CH₂)_0-4—

CO—

(C₁-C₁₂ alkyl), and —

(CH₂)_0-4—

SO₂—

NR₂₂₀R₂₂₅.

10. A compound according to claims 8 or 9 selected from the group consisting of:

N-[(1S, 2R, 3R, 4R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-methyl-5-oxopentyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-5-(benzylamino)-1(3,5-difluorobenzyl)-2,3-dihydroxy-4-methyl-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl)benzamide,

N-[(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-4-(pyrrolidin-l-ylmethyl)benzamide,

N-[(1S, 2R, 3R, 4R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N′

-[(1S, 2R, 3R, 4R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-4-methyl-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N′

-[(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-4-methyl-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N-[1-({[(1S, 2R, 3R, 4R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-4-methyl-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-4-methyl-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-[1—

({[(1S, 2R, 3R, 4R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-4-methyl-5-oxopentyl]amino}carbonyl)heptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-4-methyl-5-oxopentyl]amino}carbonyl)heptyl]nicotinamide,

N³-[(1S, 2R, 3R, 4R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-4-methyl-5-oxopentyl]-N¹,N-dipropylbenzene-1,3,5-tricarboxamide,

N³-[(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-4-methyl-5-oxopentyl]-N¹₁,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N-[(1S, 2R, 3R, 4R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy- 4-methyl-5-oxopentyl]- 2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-4-methyl-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl)benzamide,

N-[(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl)benzamide,

N-[(1S, 2R, 3R, 4R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N′

-[(1S, 2R, 3R, 4R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-4-methyl-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N′

-[(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N-[1-({[(1S, 2R, 3R, 4R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-4-methyl-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R, 4R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-4-methyl-5-oxopentyl]amino}carbonyl)heptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]amino}carbonyl)heptyl]nicotinamide,

N³-[(1S, 2R, 3R, 4R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-4-methyl-5-oxopentyl] -N,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N³-[(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N-[(1S, 2R, 3R, 4R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-4-methyl-5-oxopentyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-4-methyl-5-oxopentyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-4-methyl-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl)benzamide,

N-[(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-4-methyl-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl)benzamide,

N-[(1S, 2R, 3R, 4R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-4-methyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N′

-[(1S, 2R, 3R, 4R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-methyl-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N′

-[(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N-[1-({[(1S, 2R, 3R, 4R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-methyl-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide

N-[1-({[(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide

N-[1-({[(1S, 2R, 3R, 4R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-methyl-5-oxopentyl]amino}carbonyl)heptyl]nicotinamide

N-[1-({[(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-4-dimethyl-5-oxopentyl]amino}carbonyl)heptyl]nicotinamide,

N³-[(1S, 2R, 3R, 4R)-5-(benzylamino)-1—

(3,5-difluorobenzyl)-2,3-dihydroxy-4-methyl-5-oxopentyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N³-[(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-4-methyl-5-oxopentyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N-[(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-methylhexyl]-2-[(methylsultonyl)amino]-1,3-thiazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-4-[(benzylamino) carbonyl]-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-methylhexyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-methylhexyl]-4-(pyrrolidin-1-ylmethyl)benzamide,

N-{(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}-4-(pyrrolidin-1-ylmethyl)benzamide,

N-[(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-methylhexyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N′

-{(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-2,3-dihydroxy-1-isobutyl-5-methylhexyl}-5-methyl-N,N-dipropylisophthalamide,

N′

-{(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-4-[(isobutylamino)carbonyl]-5-methylhexyl}-5-methyl-N,N-dipropylisophthalamide,

N-{1-[({(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-2,3-dihydroxy-1-isobutyl-5-methylhexyl}amino)carbonyl]-4-propylheptyl}nicotinamide,

N-{1-[({(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-4-[(isobutylamino)carbonyl]-5-methylhexyl}amino)carbonyl]-4-propylheptyl}nicotinamide,

N-{1-[({(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-2,3-dihydroxy-1-isobutyl-5-methylhexyl}amino)carbonyl]heptyl}nicotinamide,

N-{1-[({(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-4-[(isobutylamino)carbonyl]-5-methylhexyl}amino)carbonyl]heptyl}nicotinamide,

N³-{(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-2,3-dihydroxy-1-isobutyl-5-methylhexyl}-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N³-{(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-4-[(isobutylamino)carbonyl]-5-methylhexyl}-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N-{(1S, 2R, 3R, 4R)-1-benzyl-4-[(benzylamino)carbonyl]-2,3-dihydroxy-5-dimethylhexyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-1-benzyl-4-[(benzylamino)carbonyl]-2,3-dihydroxy-5-methylhexyl}-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-1-benzyl-4-[(benzylamino)carbonyl]-2,3-dihydroxy-5-methylhexyl}-4-(pyrrolidin-1-ylmethyl)benzamide,

N-{(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}-4-(pyrrolidin-1-ylmethyl)benzamide,

N-{(1S, 2R, 3R, 4R)-1-benzyl-4-[(benzylamino)carbonyl]-2,3-dihydroxy-5-methylhexyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N′

-{(1S, 2R, 3R, 4R)-1-benzyl-4-[(benzylamino)carbonyl]-2,3-dihydroxy-5-methylhexyl}-5-methyl-N,N-dipropylisophthalamide,

N′

-{(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}-5-methyl-N,N-dipropylisophthalamide,

N-{1-[({(1S, 2R, 3R, 4R)-1-benzyl-4-[(benzylamino)carbonyl]-2,3-dihydroxy-5-dimethylhexyl}amino)carbonyl]-4-propylheptyl}nicotinamide,

N-{1-[({(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}amino)carbonyl]-4-propylheptyl}nicotinamide,

N-{1-[({(1S, 2R, 3R, 4R)-1-benzyl-4-[(benzylamino)carbonyl]-2,3-dihydroxy-5-methylhexyl}amino)carbonyl]heptyl}nicotinamide,

N-{1-[({(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}amino)carbonyl]heptyl}nicotinamide,

N³-{(1S, 2R, 3R, 4R)-1-benzyl-4-[(benzylamino)carbonyl]-2,3-dihydroxy-5-methylhexyl}-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N³-{(1S, 2R, 3R, 4R)-1-benzyl-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-dimethylhexyl}-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N-{(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-2,3-dihydroxy-1-isobutyl-5-methylhexyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-4-[(isobutylamino)carbonyl]-5-methylhexyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-2,3-dihydroxy-1-isobutyl-5-methylhexyl}-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-4-[(isobutylamino)carbonyl]-5-methylhexyl}-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-2,3-dihydroxy-1-isobutyl-5-methylhexyl}-4-(pyrrolidin-1-ylmethyl)benzamide,

N-{(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-4-[(isobutylamino)carbonyl]-5-methylhexyl}-4-(pyrrolidin-1-ylmethyl)benzamide,

N-{(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-2,3-dihydroxy-1-isobutyl-5-methylhexyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N-{(1S, 2R, 3R, 4R)-2,3-dihydroxy-1-isobutyl-4-[(isobutylamino)carbonyl]-5-methylhexyl}-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N′

-[(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-1-(3,5difluorobenzyl)-2,3-dihydroxy-5-methylhexyl]-5-methyl-N,N-dipropylisophthalamide,

N′

-{(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-[(isobutylamino) carbonyl]-5-methylhexyl}-5-methyl-N,N-dipropylisophthalamide,

N-[1-({[(1S, 2R, 3R, 4R)-4-[(benzylamino) carbonyl]-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-methylhexyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-{1-[({(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-[(isobutylamino)carbonyl]-5-methylhexyl}amino)carbonyl]-4-propylheptyl}nicotinamide,

N-[1({[(1S, 2R, 3R, 4R)-4-[(benzylamino)carbonyl]-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-methylhexyl]amino}carbonyl) heptyl]nicotinamide,

N-{1-[({(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-[(isobutylamino) carbonyl]-5-methylhexyl}amino) carbonyl]heptyl}nicotinamide,

N³-[(1S, 2R, 3R, 4R)-4-[(benzylamino) carbonyl]-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-methylhexyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N³-{(1S, 2R, 3R, 4R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-4-[(isobutylamino) carbonyl]-5-methylhexyl}-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N-[(1S, 2R, 3R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-2-[(methylsulfonyl) amino]-1, 3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-5-(benzylamino)-1-(3, 5-difluorobenzyl)-2,3-dihydroxy-5-oxopentyl]-2-[methyl (methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-2-[methyl (methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-5-(benzylamino)-1-(3, 5-difluorobenzyl)-2,3-dihydroxy-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl) benzamide,

N-[(1S, 2R, 3R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl) benzamide,

N-[(1S, 2R, 3R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N-[(1S, 2R, 3R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-2-[(methylsulfonyl) amino]-1,3-oxazole-4-carboxamide,

N′

-[(1S, 2R, 3R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N′

-[(1S, 2R, 3R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N-[1-({[(1S, 2R, 3R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-5-oxopentyl]amino}carbonyl) heptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-5-oxopentyl]amino}carbonyl) heptyl]nicotinamide,

N³-[(1S, 2R, 3R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-5-oxopentyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N³-[(1S, 2R, 3R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-5-oxopentyl]-N¹,N¹-dipropylbenzene-1,3,5tricarboxamide,

N-[(1S, 2R, 3R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-5-oxopentyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl)benzamide,

N-[(1S, 2R, 3R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl)benzamide,

N-[(1S, 2R, 3R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N-[(1S, 2R, 3R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N′

-[(1S, 2R, 3R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N′

-[(1S, 2R, 3R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N-[1-({[(1S, 2R, 3R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-5-oxopentyl]amino}carbonyl)heptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]amino}carbonyl)heptyl]nicotinamide,

N³-[(1S, 2R, 3R)-1-benzyl-5-(benzylamino)-2,3-dihydroxy-5-oxopentyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N³-[(1S, 2R, 3R)-1-benzyl-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide,

N-[(1S, 2R, 3R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-5-oxopentyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-5-oxopentyl]-2-[methyl(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide,

N-[(1S, 2R, 3R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl)benzamide,

N-[(1S, 2R, 3R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-5-oxopentyl]-4-(pyrrolidin-1-ylmethyl)benzamide,

N-[(1S, 2R, 3R)-5-(benzylamino)-2,3-dihydroxy-1-isobutyl-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N-[(1S, 2R, 3R)-2,3-dihydroxy-1-isobutyl-5-(isobutylamino)-5-oxopentyl]-2-[(methylsulfonyl)amino]-1,3-oxazole-4-carboxamide,

N′

-[(1S, 2R, 3R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N′

-[(1S, 2R, 3R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-5-methyl-N,N-dipropylisophthalamide,

N-[1-({[(1S, 2R, 3R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]amino}carbonyl)-4-propylheptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-oxopentyl]amino}carbonyl)heptyl]nicotinamide,

N-[1-({[(1S, 2R, 3R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]amino}carbonyl)heptyl]nicotinamide,

N³-[(1S, 2R, 3R)-5-(benzylamino)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-oxopentyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide, and

N³-[(1S, 2R, 3R)-1-(3,5-difluorobenzyl)-2,3-dihydroxy-5-(isobutylamino)-5-oxopentyl]-N¹,N¹-dipropylbenzene-1,3,5-tricarboxamide.

11. A method for the treatment or prevention of Alzheimer'"'"'s disease, mild cognitive impairment Down'"'"'s syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, dementias of mixed vascular and degenerative origin, dementia associated with Parkinson'"'"'s disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer'"'"'s disease comprising administration of a therapeutically effective amount of a compound or salt according to claim 1, to a patient in need thereof.

12. A method of treatment as in claim 11, wherein the patient is a human.

13. A method of treatment according to claim 11, wherein the disease is dementia.

14. A method for making a compound of claim 1.

15. An intermediate of the formula C:

16. An intermediate of the formula D: