Compounds to treat alzheimer's disease

• US 6,846,813 B2
• Filed: 06/29/2001
• Issued: 01/25/2005
• Est. Priority Date: 06/30/2000
• Status: Expired due to Fees

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC), Pharmacia & Upjohn Company (Pfizer Inc.)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC), Pharmacia & Upjohn Company (Pfizer Inc.)
• Inventors: Maillard, Michel, Jagodzinska, Barbara, John, Varghese, Gailunas, Andrea, Beck, James P., Hom, Roy
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Patel, Sudhaker B.
• Application Number:
  US09/895,843
• Publication Number:
  US 20020143177A1
• Time in Patent Office: 1,306 Days
• Field of Search: 514/183, 514/616, 514/617, 514/252.12, 544/358, 544/398, 544/402
• US Class Current: 514/183
• 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: C07C 215/28 and containing six-membered aromatic rings
• CPC Class Codes: C07C 233/78 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 239/20 having oxygen atoms of hydroxylamino groups etherified
• CPC Class Codes: C07C 243/22 having nitrogen atoms of hydrazine groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 243/28 to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 271/18 to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 275/24 containing six-membered aromatic rings
• CPC Class Codes: C07C 311/03 having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 311/08 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/13 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 311/16 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/37 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/60 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 215/12 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 223/10 attached in position 2
• CPC Class Codes: C07D 277/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 303/36 : with hydrocarbon radicals, substituted by nitrogen atoms nitro, nitroso radicals C07D303/08
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/54 : 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
• CPC Class Codes: C07D 333/24 : 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 is disubstituted amines of formula (I)
and disubstituted amines of formula (II)
useful in treating Alzheimer'"'"'s disease and other similar diseases.

Claims

1. A compound of the formula

or a pharmaceutically acceptable salt thereof wherein where R_p represents

(1) C₁-C₆ alkyl, C₂-C₆ alkenyl with one or two double bonds, or C₂-C₆ alkynyl with one or two triple bonds, each of which is optionally substituted with one, two, or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

(2) —

CO—

(C₁-C₄ alkyl),

(3) —

SO₂—

NR_p1R_p2 where R_p1 and R_p2 are hydrogen or C₁-C₆ alkyl, or

(4) —

CO—

NR_p1R_p2 where R_p1 and R_p2 are hydrogen or C₁-C₆;

R₁ is —

CH₂-phenyl where the is phenyl optionally substituted with one, two, three, or four of

(A) C₁-C₆ alkyl optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are independently —

H or C₁-C₆ alkyl,

(B) C₂-C₆ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

(C) C₂-C₆ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

(D) —

F, Cl, —

Br or —

I,

(F) —

C₁-C₆ alkoxy optionally substituted with one, two, or three —

F,

(G) —

NR_N-2R_N-3 where R_N-2 and R_N-3 are as defined below,

(H) —

OH,

(I) —

C≡

N,

(J) C₃-C₇ cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl ,

(K) —

CO—

(C₁-C₄ alkyl),

(L) —

SO₂—

NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(M) —

CO—

NR_1-aR_1-b where R_1-a and R_1-b are as defined above, or

(N) —

SO₂—

(C₁-C₄ alkyl);

R₂ is

(I) —

H,

(II) C₁-C₆ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(III) —

(CH₂)_0-4-R_2-1 where R_2-1 is R_1-aryl or R_1-heteroaryl, where

R_1-aryl is is phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl, dihydronaphthalyl, or tetralinyl optionally substituted with one, two, three, or four of the following substituents on the aryl ring;

(A) C₁-C₆ alkyl optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(B) C₂-C₆ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

(C) C₂-C₆ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

(D) —

F, Cl, —

Br or —

I,

(F) —

C₁-C₆ alkoxy optionally substituted with one, two, or three —

F,

(G) —

NR_N-2R_N-3 where R_N-2 and R_N-3 are as defined below,

(H) —

OH,

(I) —

C≡

N,

(J) C₃-C₇ cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

(K) —

CO—

(C₁-C₄ alkyl),

(L) —

SO₂NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(M) —

CO—

NR_1-aR_1-b where R_1-a and R_1-b are as defined above, or

(N) —

SO₂—

(C₁-C₄ alkyl); and

R_1-heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, benzothienyl indolyl, indolinyl, pyridazinyl, pyrazinyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl dihydroquinolinyl, dihydroquinolinonyl dihydroisoquinolinonyj. dihydrocoumarinyl, dihydroisocoumarinyl isoindolinonyl benzodioxanyl, benzoxazolinonyl pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazoly N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl, N-oxide, triazolyl N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide, and heteroaryl is optionally substituted with one, two, three, or four of

(1) C₁-C₆ alkyl optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(2) C₂-C₆ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

(3) C₂-C₆ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

(4) —

F, Cl, —

BR, or —

I,

(6) —

C₁-C₆ alkoxy optionally substituted with one, two, or three —

F,

(7) —

NR_N-2R_N-3 where R_N-2 and R_N-3 are as defined below,

(8) —

OH,

(9) —

C≡

N,

(10) C₃-C₇ cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

(11) —

CO—

(C₁-C₄ alkyl),

(12) —

SO₂NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(13) —

CO—

NR_1-aR_1-b where R_1-a and R_1-b are as defined above, or

(14) —

SO₂—

(C₁-C₄ alkyl), with the proviso that when n₁ is zero R_1-heteroaryl is not bonded to the carbon chain by nitrogen;

(IV) C₂-C₆ alkenyl with one or two double bonds, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SN, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

(V) C₂-C₆ alkynyl with one or two triple bonds, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SN, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl, or

(VI) —

(CH₂)_0-4—

C₃-C₇ cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl,

R₃ is

(I) —

H,

(II) C₁-C₆ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(III) —

(CH₂)_0-4—

R_2-1 where R_2-1 is R_1-aryl or R_1-heteroaryl where R₁-aryl and R_1-heteroaryl are as defined above;

(IV) C₂-C₆ alkenyl with one or two double bonds,

(V) C₂-C₅ alkynyl with one or two triple bonds, or

(VI) —

(CH₂)_0-4—

C₃-C₇ cycloalkyl, optionally substituted with one, two or three substituents selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H or C₁-C₆ alkyl;

R_N is R_N-1—

CO—

;

where R_n-1 is selected from the group consisting of;

(A) R_N-aryl where R_N-aryl is phenyl, 1-naphthyl, 2-naphthyl, tetralinyl, indanyl, or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, or dihydronaphthyl optionally substituted with one, two or three of the following substituents which can be the same or different and are;

(1) C₁-C₆ alkyl, optionally substituted with one, two or three substituents selected from the group consisting of C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, and —

NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(2) —

OH,

(3) —

NO₂,

(4) —

F, —

Cl, —

Br, or —

I,

(5) —

CO—

OH,

(6) —

C≡

N,

(7) —

(CH₂)_0-4—

CO—

NR_N-2R_N-3 where R_N-2 and R_N-3 are the same or different and are selected from the group consisting of;

(a) —

H,

(b) —

C₁-C₆ alkyl optionally substituted with one substituent selected from the group consisting of;

(i) —

OH, and

(ii) —

NH₂,

(c) —

C₁-C₆ alkyl optionally substituted with one to three of —

F, —

Cl, —

Br, or —

I,

(d) —

C₃-C₇ cycloalkyl,

(e) —

(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

(f) —

(C₁-C₆ alkyl)-O—

(C₁-C₃ alkyl),

(g) —

C₂-C₆ alkenyl with one or two double bonds,

(h) —

C₂-C₆ alkynyl with one or two triple bonds,

(i) —

C₁-C₆ alkyl chain with one double bond and one triple bond,

(j) —

R_1-aryl where R_1-aryl is as defined above, and

(k) —

R_1-heteroaryl where R_1-heteroaryl is as defined above,

(8) —

(CH₂)_0-4—

CO—

(C₁-C₁₂ alkyl),

(9) —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkenyl with one, two or three double bonds),

(10) —

(CH₂)_0-4—

CO—

(C₂-C₁₂ alkynyl with one, two or three triple bonds),

(11) —

(CH₂)_0-4—

CO—

(C₃-C₇ cycloalkyl),

(12) —

(CH₂)_0-4—

CO—

R_1-aryl where R_1-aryl is as defined above,

(13) —

(CH₂)_0-4—

CO—

R_1-heteroaryl where R_1-heteroaryl is as defined above,

(14) —

(CH₂)_0-4—

CO—

R_{1-heterocycle} where R_{1-heterocycle} is as defined above,

(15) —

(CH₂)_0-4—

CO—

R_N-4 where R_N-4 is selected from the group consisting of morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where each group is optionally substituted with one, two, three, or four of;

C₁-C₆ alkyl,

(16) —

(CH₂)_0-4—

CO—

O—

R_N-5 where R_N-5 is selected from the group consisting of;

(a) C₁-C₆ alkyl,

(b) —

(CH₂)_0-2—

(R_1-aryl) where R_1-aryl is as defined above,

(c) C₂-C₆ alkenyl containing one or two double bonds,

(d) C₂-C₆ alkynyl containing one or two triple bonds,

(e) C₃C₇ cycloalkyl,

(f) —

(CH₂)_0-2—

(R_1-heteroaryl) where R_1-heteroaryl is as defined above,

(17) —

(CH₂)_0-4—

SO₂—

NR_N-2R_N-3 where R_N-2 and R_N-3 are as defined above,

(18) —

(CH₂)_0-4—

SO—

(C₁-C₈ alkyl),

(19) —

(CH₂)_0-4—

SO₂—

(C₁-C₁₂ alkyl)

(20) —

(CH₂)_0-4—

SO₂—

(C₃-C₇ cycloalkyl),

(21) —

(CH₂)_0-4—

N(H or R_N-5)—

CO—

O—

R_N-5 where R_N-5 can be the same or different and is as defined above,

(22) —

(CH₂)_0-4—

N(H or R_N-5)—

CO—

N(R_N-5)₂, where R_N-5 can be the same or different and is as defined above,

(23) —

(CH₂)_0-4—

N—

CS—

N(R_N-5)₂, where R_N-5 can be the same or different and is as defined above,

(24) —

(CH₂)_0-4—

N(—

H or R_N-5)—

CO—

R_N-2 where R_N-5 and R_N-2 can be the same or different and are as defined above,

(25) —

(CH₂)_0-4—

NR_N-2R_N-3 where R_N-2 and R_N-3 can be the same or different and are as defined above,

(26) —

(CH₂)_0-4—

R_N-4 where R_N-4 is as defined above,

(27) —

(CH₂)_0-4—

O—

CO—

(C₁-C₆ alkyl)

(28) —

(CH₂)_0-4—

O—

P(O)—

(OR_N-aryl-1)₂ where R_N-aryl-1 is —

H or C₁-C₄ alkyl,

(29) —

(CH₂)_0-4—

O—

CO—

N(R_N-5)₂ where R_N-5 is as defined above,

(30) —

(CH₂)_0-4—

O—

CS—

N(R_N-5)₂ where R_N-5 is as defined above,

(31) —

(CH₂)_0-4—

O—

(R_N-5)₂ where R_N-5 is as defined above,

(32) —

(CH₂)_0-4—

O—

(R_N-5)₂—

COOH where R_N-5 is as defined above,

(33) —

(CH₂)_0-4—

S—

(R_N-5)₂ where R_N-5 is as defined above,

(34) —

(CH₂)_0-4—

O—

(C₁-C₆ alkyl optionally substituted with one, two, three, tour, or five —

F),

(35) C₃-C₇ cycloalkyl,

(36) C₂-C₆ alkenyl with one or two double bonds optionally substituted with C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, or —

NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(37) C₂-C₆ alkynyl with one or two triple bonds optionally substituted with C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, or —

NR_1-aR_1-b where R_1-a and R_1-b are as defined above,

(38) —

(CH₂)_0-4—

N(—

H or R_N-5)—

SO₂—

R_N-2 where R_N-5 and R_N-2 can be the same of different and are as described above, or

(39) —

(CH₂)_0-4—

C₃-C₇ cycloalkyl,

(B) —

R_N-heteroaryl, where R_N-heteroaryl is selected from the group as defined above in R_1-heteroaryl and where the R_N-heteroaryl group is bonded by any atom of the parent R_N-heteroaryl group substituted by hydrogen such that the new bond to the R_N-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is optionally substituted with one, two, three, or four of the groups (1)-(39) defined above as optional substituents on R_N-aryl;

(C) R_N-aryl-W-R_N-aryl,

(D) R_N-aryl-W-R_N-heteroaryl,

(E) R_N-aryl-W-R_{N-1-heterocycle}, where R_{n-1-heterocycle} is the same as R_{1-heterocycle} as defined above,

(F) R_N-heteroaryl-W-R_N-aryl,

(G) R_N-heteroaryl-W-R_N-heteroaryl,

(H) R_N-heteroaryl-W-R_{1-heterocycle},

(I) R_1-heteroaryl-W-R_N-aryl,

(J) R_{1-heterocycle}-W-R_N-heteroaryl, and

(K) R_{1-heterocycle}-W-R_{1-heterocycle},

where W is

—

(CH₂)_0-4—

,

—

O—

,

—

S(O)_0-2—

,

—

N(R_N-5)—

where R_N-5 is as defined above, or

—

CO—

;

R_N-A is selected from the group consisting of H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl and alkynyl, phenyl, C₁-C₄ alkyl-R_N-aryl, C₁-C₄ alkyl-R_N-heteroaryl, C₁-C₄ alkyl-C₃-C₇ cycloalkyl and C₁-C₄ alkyl-R_{1-heterocycle}, wherein each multi-atom group may be optionally substituted with one, two, or three substituents independently selected from the group consisting of —

F, —

Cl, —

OH, —

SH, —

C≡

N, —

CF₃, C₁-C₃ alkoxy, —

C(O)O—

R_1-a, and —

NR_1-aR_1-b where R_1-a and R_1-b are —

H, C₁-C₆ alkyl or phenyl.

2. A compound of claim 1, wherein R₁ is substituted with two —

F.

3. A compound of claim 2, wherein the —

F substitutions are on the −

3 and −

5 positions.

4. A compound of claim 1, wherein R₂ and R₃ are both —

H.

5. A compound according to claim 1, wherein R_p is C₁-C₈ alkyl.

6. A compound of claim 1, where R_N-1 is phenyl and the phenyl is attached to the carbonyl at the 1-position and substituted with one —

CO—

NR_N-2R_N-3 group.

7. A compound according to claim 1, where R_N-1 is phenyl and the phenyl is (a) attached to the carbonyl at the 1-position, (b) substituted with one —

CO—

NR_N-2R_N-3 group in the 3-position, and (c) substituted with methyl at the 5-position.

8. A compound according to claim 6, wherein R_N-2 and R_N-3 are the same and are C₃ alkyl.

9. A compound according to claim 8, wherein R_N-2 and R_N-3 are the same and are C₃ alkyl.

10. A compound according to claim 1, which is

N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(4-methyl-1-piperazinyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide;

N¹-{(1S,2R)-1-benzyl-3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxypropyl}-N³,N³-dipropylisophthalamide;

or

a pharmaceutically acceptable salt thereof.

11. A method for treating a patient who has Alzheimer'"'"'s disease, delaying development of Alzheimer'"'"'s disease in a patient of predisposed to development of the disease, preventing a patient from developing Alzheimer'"'"'s disease, treating a patient with mild cognitive impairment (MCI), preventing or delaying the onset of Alzheimer'"'"'s disease in those who would progress from MCI to AD, treating Down'"'"'s syndrome, treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, treating other degenerative dementias, including 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 and who is in need of such treatment, the method comprising administration of a therapeutically effective amount of a compound according to claim 1.

12. A method of treatment according to claim 11, wherein the disease is Alzheimer'"'"'s disease.

13. A method of treatment according to claim 11, wherein the method is preventing a disease from developing.

14. A method of treatment according to claim 11, wherein the therapeutically effective amount for oral administration is from about 0.1 mg/day to about 1,000 mg/day;

for parenteral, sublingual, intranasal, intrathecal administration is from about 0.5 to about 100 mg/day;

for depo administration and implants is from about 0.5 mg/day to about 50 mg/day;

for topical administration is from about 0.5 mg/day to about 200 mg/day;

for rectal administration is from about 0.5 mg to about 500 mg.

15. A method of treatment according to claim 14, wherein the therapeutically effective amount for oral administration is from about 1 mg/day to about 100 mg/day and for parenteral administration is from about 5 to about 50 mg daily.

16. A method of treatment according to claim 14 where the therapeutically effective amount for oral administration is from about 5 mg/day to about 50 mg/day.

17. A method according to claim 11, wherein R₁ is substituted with two —

F.

18. A method according to claim 11, wherein the —

F substitutions are on the −

3 and −

5 positions.

19. A method according to claim 11, wherein R₂ and R₃ are both —

H.

20. A method according to claim 11, wherein R_p is C₁-C₈ alkyl.

21. A method according to claim 11, where R_N-1 is phenyl and the phenyl is attached to the carbonyl at the 1-position and substituted with one —

CO—

NR_N-2R_N-3 group.

22. A method according to claim 11, where R_N-1 is phenyl and the phenyl is (a) attached to the carbonyl at the 1-position, (b) substituted with one —

CO—

NR_N-2R_N-3 group in the 3-position, and (c) substituted with methyl at the 5-position.

23. A method according to claim 22, wherein R_N-2 and R_N-3 are the same and are C₃ alkyl.

24. A compound according to claim 23, wherein R_N-2 and R_N-3 are the same and are C₃ alkyl.

25. A method according to claim 11 where the pharmaceutically acceptable salt is selected from the group consisting of salts of the following acids:

acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic, pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, phthalic, polygalactouronic, propionic, salicylic, stearic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic.

26. A method according to claim 11, where the compound is

N¹-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-(4-methyl-1-piperazinyl)propyl]-5-methyl-N³,N³-dipropylisophthalamide;

N¹-{(1S,2R)-1-benzyl-3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxypropyl}-N³,N³-dipropylisophthalatmide;

or

a pharmaceutically acceptable salt thereof.

27. A method for inhibiting cleavage of amyloid precursor protein (APP), in a reaction mixture, at a site between Met596 and Asp597, numbered for the APP-695 amino acid isotype;

or at a corresponding site of an isotype or mutant thereof, comprising exposing said reaction mixture to an effective inhibitory amount of a compound according to claim 1.

28. The method of claim 27, wherein said cleavage site is between Met652 and Asp653, numbered for the APP-751 isotype;

between Met 671 and Asp 672, numbered for the APP-770 isotype;

between Leu596 and Asp597 of the APP-695 Swedish Mutation;

between Leu652 and Asp653 of the APP-751 Swedish Mutation;

or between Leu671 and Asp672 of the APP-770 Swedish Mutation.

29. The method of claim 27, wherein said reaction mixture is exposed in vitro.

30. The method of claim 27, wherein said reaction mixture is exposed in a cell.

31. The method of claim 30, wherein said cell is an animal cell.

32. The method of claim 31, wherein said cell is a human cell.

33. A method for inhibiting cleavage of amyloid precursor protein (APP), in a reaction mixture, at a site between Met596 and Asp597, numbered for the APP-695 amino acid isotype;

or at a corresponding site of an isotype or mutant thereof, comprising exposing said reaction mixture to an effective inhibitory amount of a compound according to claim 1.

34. The method of claim 33, wherein said cleavage site is between Met652 and Asp653, numbered for the APP-751 isotype;

between Met 671 and Asp 672, numbered for the APP-770 isotype;

between Leu596 and Asp597 of the APP-695 Swedish Mutation;

between Leu652 and Asp653 of the APP-751 Swedish Mutation;

or between Leu671 and Asp672 of the APP-770 Swedish Mutation.

35. The method of claim 33, wherein said reaction mixture is exposed in vitro.

36. The method of claim 33, wherein said reaction mixture is exposed in a cell.

37. The method of claim 35, wherein said cell is an animal cell.

38. The method of claim 37, wherein said cell is a human cell.

39. A method for inhibiting production of amyloid beta peptide (A beta) in a cell, comprising administering to said cell an effective inhibitory amount of a compound according to claim 1.

40. The method of claim 39, wherein said administering is to an animal.

41. The method of claim 40, wherein said administering is to a human.

42. A method for inhibiting the production of beta-amyloid plaque in an animal, comprising administering to said animal an effective inhibitory amount of a compound according to claim 1.

43. The method of claim 42, wherein said animal is a human.

44. A method for treating or preventing a disease characterized by beta-amyloid deposits in the brain comprising administering to a patient an effective therapeutic amount of a compound according to claim 1.

45. The method of claim 44, wherein said therapeutic amount is in the range of from about 0.1 to about 1500 mg/day.

46. The method of claim 44, wherein said therapeutic amount is in the range of from about 15 to about 1000 mg/day.

47. The method of claim 45, wherein said therapeutic amount is in the range of from about 1 to about 100 mg/day.

48. The method of claim 47, wherein said therapeutic amount is in the range of from about 5 to about 50 mg/day.

49. The method of claim 45, wherein said disease is Alzheimer'"'"'s disease.

50. The method of claim 44, wherein said disease is Mild Cognitive Impairment, Down'"'"'s Syndrome, or Hereditary Cerebral Hemmorrhage with Amyloidosis of the Dutch Type.

51. Beta-secretase complexed with a compound according to claim 1.

52. A method for producing a beta-secretase complex comprising:

exposing beta-secretase to a compound according to claim 1, or a pharmaceutically acceptable salt thereof in a reaction mixture under conditions suitable for the production of said complex.

53. The method of claim 52, where said exposing is in vitro.

54. The method of claim 53, wherein said reaction mixture is a cell.

55. A kit comprising a plurality of containers, each container comprising one or more unit dose of a compound according to claim 1.

56. The kit of claim 55, wherein each container is adapted for oral delivery and comprises a tablet, gel, or capsule.

57. The kit of claim 55, wherein each container is adapted for parenteral delivery and comprises a depot product, syringe, ampoule, or vial.

58. The kit of claim 55, wherein each container is adapted for topical delivery and comprises a patch, medipad, ointment, or cream.

59. A composition comprising a compound according to claim 1;

and an inert diluent or edible carrier.

60. The composition of claim 59, wherein said carrier is an oil.

61. A composition comprising a compound according to claim 1;

and an inert diluent or edible carrier.

62. The composition of claim 61, wherein said carrier is an oil.

63. A method for inhibiting beta-secretase activity, comprising exposing said beta-secretase to an effective inhibitory amount of a compound according to claim 1.

64. The method of claim 63, wherein said beta-secretase is exposed to said compound in vitro.

65. The method of claim 63, wherein said beta-secretase is exposed to said compound in a cell.

66. The method of claim 65, wherein said cell is in an animal.

67. The method of claim 66, wherein said animal is a human.

68. A method for inhibiting beta-secretase activity, comprising exposing said beta-secretase to an effective inhibitory amount of a compound according to claim 1.

69. The method of claim 68, wherein said beta-secretase is exposed to said compound in vitro.

70. The method of claim 68, wherein said beta-secretase is exposed to said compound in a cell.

71. The method of claim 70, wherein said cell is in an animal.

72. The method of claim 71, wherein said animal is a human.