Compounds to treat Alzheimer's disease

• US 20060276642A1
• Filed: 04/17/2006
• Published: 12/07/2006
• Est. Priority Date: 03/23/2000
• Status: Abandoned Application

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Tung, Jay, John, Varghese, Gailunas, Andrea, Fang, Lawrence Y., Hom, Roy, Mamo, Shumeye S.
• Application Number:
  US11/405,705
• Publication Number:
  US 20060276642A1
• Time in Patent Office: Days
• US Class Current: 540/575
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/07 Optical isomers
• 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: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07C 271/14 to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 271/18 to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/33 in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07K 5/0207 containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

Abstract

The present invention is directed toward substituted hydroxyethylene compounds of formula (XII) useful in treating Alzheimer'"'"'s disease and other similar diseases.

Claims

1. A hydroxyethylene compound of the formula

Where R₁ is:

(I) C₁-C₆ alkyl, unsubstituted or substituted with one, two or three C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

NH₂, —

C≡

N, —

CF₃, or —

N₃,

(II) —

(CH₂)_1-2—

S—

CH₃,

(III) —

CH₂—

CH₂—

S—

CH₃,

(IV) —

CH₂—

(C₂-C₆ alkenyl) unsubstituted or substituted by one —

F,

(V) —

(CH₂)_0-3—

(R_1-aryl) where R_1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br and —

I,

(D) C₁-C₃ alkoxy,

(E) —

O—

CF₃,

(F) —

NH₂,

(G) —

OH, or

(H) —

C≡

N,

(VI) —

(CH₂)_{n1-(R1-heteroaryl}) where n₁ is 0, 1, 2, or 3 and R_1-heteroaryl is;

(A) pyridinyl,

(B) pyrimidinyl,

(C) quinolinyl,

(D) indenyl,

(E) indanyl,

(F) benzothiophenyl,

(G) indolyl,

(H) indolinyl,

(I) pyridazinyl,

(J) pyrazinyl,

(K) isoindolyl,

(L) isoquinolyl,

(M) quinazolinyl,

(N) quinoxalinyl,

(O) phthalazinyl,

(P) imidazolyl,

(Q) isoxazolyl,

(R) pyrazolyl,

(S) oxazolyl,

(T) thiazolyl,

(U) indolizinyl,

(V) indazolyl,

(W) benzothiazolyl,

(X) benzimidazolyl,

(Y) benzofuranyl,

(Z) furanyl,

(AA) thienyl,

(BB) pyrrolyl,

(CC) oxadiazolyl,

(DD) thiadiazolyl,

(EE) triazolyl,

(FF) tetrazolyl,

(GG) 1,4-benzodioxan

(HH) purinyl,

(II) oxazolopyridinyl,

(JJ) imidazopyridinyl,

(KK) isothiazolyl,

(LL) naphthyridinyl,

(MM) cinnolinyl,

(NN) carbazolyl,

(OO) β

-carbolinyl,

(PP) isochromanyl,

(QQ) chromanyl,

(RR) furazanyl,

(SS) tetrahydroisoquinoline,

(TT) isoindolinyl,

(UU) isobenzotetrahydrofuranyl,

(VV) isobenzotetrahydrothienyl,

(WW) isobenzothiophenyl,

(XX) benzoxazolyl, or

(YY) pyridopyridinyl,

 

where the R_1-heteroaryl group is bonded to —

(CH₂)_0-3—

by any ring atom of the parent R_N-heteroaryl group substituted by hydrogen such that the new bond to the R_1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two;

(1) C₁-C₃ alkyl,

(2) —

CF₃,

(3) —

F, Cl, —

Br, or —

I,

(4) C₁-C₃ alkoxy,

(5) —

O—

CF₃,

(6) —

NH₂,

(7) —

OH, or

(8) —

C≡

N,

with the proviso that when n₁ is zero R_1-heteroaryl is not bonded to the carbon chain by nitrogen, or

(VII) —

(CH₂)_n1—

(R_{1-heterocycle}) where n₁ is as defined above and

R_{1-heterocycle} is

(A) morpholinyl,

(B) thiomorpholinyl,

(C) thiomorpholinyl S-oxide,

(D) thiomorpholinyl S,S-dioxide,

(E) piperazinyl,

(F) homopiperazinyl,

(G) pyrrolidinyl,

(H) pyrrolinyl,

(I) tetrahydropyranyl,

(J) piperidinyl,

(K) tetrahydrofuranyl, or

(L) tetrahydrothiophenyl,

 

where the R_{1-heterocycle} group is bonded by any atom of the parent R_{1-heterocycle} group substituted by hydrogen such that the new bond to the R_1-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two;

(1) ═

O,

(2) C₁-C₃ alkyl,

(3) —

CF₃,

(4) —

F, Cl, —

Br and —

I,

(5) C₁-C₃ alkoxy,

(6) —

O—

CF₃,

(7) —

NH₂,

(8) —

OH, or

(9) —

C≡

N,

with the proviso that when n₁ is zero R_{1-heterocycle} is not bonded to the carbon chain by nitrogen;

where R₂ is;

(I) —

H,

(II) C₁-C₆ alkyl, or

(III) —

(CH₂)_0-4—

R_2-1 where R_2-1 is (C₃-C₆)cycloalkyl, R_1-aryl or R_1-heteroaryl where R_1-aryl and R_1-heteroaryl are as defined above,

where R_N is;

(I) R_N-1—

X_N—

where X_N is;

(A) —

CO—

,

(B) —

SO₂—

,

(C) —

(CR′

R″

)_1-6 where R₁ and R″

are the same or different and are —

H or C₁-C₄ alkyl,

(D) —

CO—

(CR′

R″

)_1-6—

X_N-1 where X_N-1 is —

O—

, —

S— and

—

NR′

R″

— and

where R′ and

R″

are as defined above,

(E) a single bond;

where R_N-1 is;

(A) R_N-aryl where R_N-aryl is phenyl, 1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two, three or four of the following substituents which can be the same or different and are;

(1) C₁-C₆ alkyl,

(2) —

F, —

Cl, —

Br, or —

I,

(3) —

OH,

(4) —

NO₂,

(5) —

CO—

OH,

(6) —

C≡

N,

(7) —

CO—

NR_N-2R_N-3 where R_N-2 and R_N-3 are the same or different and are;

(a) —

H,

(b) —

C₁-C₆ alkyl unsubstituted or substituted with one

 

(i) —

OH, or

 

(ii) —

NH₂,

(c) —

C₁-C₆ alkyl unsubstituted or substituted with one to three —

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) —

C₁-C₆ alkenyl with one or two double bonds,

(h) —

C₁-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, or

(k) —

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

(8) —

CO—

(C₃-C₁₂ alkyl),

(9) —

CO—

(C₃-C₆ cycloalkyl),

(10) —

CO—

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

(11) —

CO—

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

(12) —

CO—

R_N-4 where R_N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C₁-C₃ alkyl,

(13) —

CO—

O—

R_N-5 where R_N-5 is;

(a) C₁-C₆ alkyl, or

(b) —

(CH₂)_0-2—

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

(14) —

SO₂—

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

(15) —

SO—

(C₁-C₈ alkyl),

(16) —

SO₂ (C₃-C₁₂ alkyl),

(17) —

NH—

CO—

O—

R_N-5 where R_N-5 is as defined above,

(18) —

NH—

CO—

N(C₁-C₃ alkyl)₂,

(19) —

N—

CS—

N(C₁-C₃ alkyl) 2,

(20) —

N(C₁-C₃ alkyl)-CO—

R_N-5 where R_N-5 is as defined above,

(21) —

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

(22) —

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

(23) —

O—

CO—

(C₁-C₆ alkyl),

(24) —

O—

CO—

N(C₁-C₃ alkyl)₂,

(25) —

O—

CS—

N(C₁-C₃ alkyl) 2,

(26) —

O—

(C₁-C₆ alkyl),

(27) —

O—

(C₂-C₅ alkyl)-COOH,

(28) —

S—

(C₁-C₆ alkyl),

(29) C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —

F,

(30) —

O—

(C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —

F, or

(31) —

O-φ

,

(B) —

R_N-heteroaryl where R_N-heteroaryl is;

(A) pyridinyl,

(B) pyrimidinyl,

(C) quinolinyl,

(D) indenyl,

(E) indanyl,

(F) benzothiophenyl,

(G) indolyl,

(H) indolinyl,

(I) pyridazinyl,

(J) pyrazinyl,

(K) isoindolyl,

(L) isoquinolyl,

(M) quinazolinyl,

(N) quinoxalinyl,

(O) phthalazinyl,

(P) imidazolyl,

(Q) isoxazolyl,

(R) pyrazolyl,

(S) oxazolyl,

(T) thiazolyl,

(U) indolizinyl,

(V) indazolyl,

(W) benzothiazolyl,

(X) benzimidazolyl,

(Y) benzofuranyl,

(Z) furanyl,

(AA) thienyl,

(BB) pyrrolyl,

(CC) oxadiazolyl,

(DD) thiadiazolyl,

(EE) triazolyl,

(FF) tetrazolyl,

(GG) 1,4-benzodioxan

(HH) purinyl,

(II) oxazolopyridinyl,

(JJ) imidazopyridinyl,

(KK) isothiazolyl,

(LL) naphthyridinyl,

(MM) cinnolinyl,

(NN) carbazolyl,

(OO) β

-carbolinyl,

(PP) isochromanyl,

(QQ) chromanyl,

(RR) furazanyl,

(SS) tetrahydroisoquinoline,

(TT) isoindolinyl,

(UU) isobenzotetrahydrofuranyl,

(VV) isobenzotetrahydrothienyl,

(WW) isobenzothiophenyl,

(XX) benzoxazolyl, or

(YY) pyridopyridinyl,

 

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 unsubstituted or substituted with one or two;

(1) C₁-C₆ alkyl,

(2) —

F, —

Cl, —

Br, or —

I,

(3) —

OH,

(4) —

NO₂,

(5) —

CO—

OH,

(6) —

C≡

N,

(7) —

CO—

NR_N-2R_N-3 where R_N-2 and R_N-3 are the same or different and are;

 

(a) —

H,

 

(b) —

C₁-C₆ alkyl unsubstituted or substituted with one

 

(i) —

OH, or

 

(ii) —

NH₂,

(c) —

C₁-C₆ alkyl unsubstituted or substituted with 1, 2, or 3 —

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) —

C₁-C₆ alkenyl with one or two double bonds,

 

(h) —

C₁-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, or

 

(k) —

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

(8) —

CO—

(C₃-C₁₂ alkyl),

(9) —

CO—

(C₃-C₆ cycloalkyl),

(10) —

CO—

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

(11) —

CO—

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

(12) —

CO—

R_N-4 where R_N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C₁-C₃ alkyl,

(13) —

CO—

O—

R_N-5 where R_N-5 is;

 

(a) C₁-C₆ alkyl, or

 

(b) —

(CH₂)_0-2—

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

(14) —

SO₂—

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

(15) —

SO—

(C₁-C₈ alkyl),

(16) —

SO₂—

(C₃-C₁₂ alkyl),

(17) —

NH—

CO—

O—

R_N-5 where R_N-5 is as defined above,

(18) —

NH—

CO—

N(C₁-C₃ alkyl)₂,

(19) —

N—

CS—

N(C₁-C₃ alkyl)₂,

(20) —

N(C₁-C₃ alkyl)-CO—

R_N-5 where R_N-5 is as defined above,

(21) —

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

(22) —

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

(23) —

O—

CO—

(C₁-C₆ alkyl),

(24) —

O—

CO—

N(C₁-C₃ alkyl)₂,

(25) —

O—

CS—

N(C₁-C₃ alkyl)₂,

(26) —

O—

(C₁-C₆ alkyl),

(27) —

O—

(C₂-C₅ alkyl)-COOH, or

(28) —

S—

(C₁-C₆ alkyl),

(C) —

R_N-aryl—

R_N-aryl where —

R_N-aryl is as defined above,

(D) —

R_N-aryl—

R_N-heteroaryl where —

R_N-aryl and R_N-heteroaryl are as defined above,

(E) —

R_N-heteroaryl—

R_N-aryl where —

R_N-aryl and —

R_N-heteroaryl are as defined above,

(F) —

R_N-heteroaryl—

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

(G) —

R_N-aryl—

O—

R_N-aryl where —

R_N-aryl is as defined above,

(H) —

R_N-aryl—

S—

R_N-aryl where —

R_N-aryl is as defined above,

(I) —

R_N-heteroaryl—

O—

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

(J) —

R_N-heteroaryl—

S—

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

(K) —

R_N-aryl—

CO—

R_N-aryl where —

R_N-aryl is as defined above,

(L) —

R_N-aryl—

CO—

R_N-heteroaryl where —

R_N-aryl and R_N-heteroaryl are as defined above,

(M) —

R_N-aryl—

SO₂—

R_N-aryl where —

R_N-aryl is as defined above,

(N) —

R_N-heteroaryl—

CO—

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

(O) —

R_N-heteroaryl—

SO₂—

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

(P) —

R_N-aryl—

O(C₁-C₈ alkyl)-φ

where R_N-aryl is as defined above,

(Q) —

R_N-aryl—

S(C₁-C₈ alkyl)-φ

where R_N-aryl is as defined above,

(R) —

R_N-heteroaryl—

O—

(C₁-C₈ alkyl)-φ

where R_N-heteroaryl is as defined above, or

(S) —

R_N-heteroaryl—

S(C₁-C₈ alkyl)-φ

where R_N-heteroaryl is as defined above,

(II) A-X_N—

where X_N is —

CO—

,

wherein A is

(A) -T-E-(Q)_m′

,

(1) where -T is

 

where

(a) x=1 when y=1 and x=2 when y=0,

(b) m is 0, 1, 2 or 3,

(c) the values of x and y vary independently on each carbon when m is 2 and 3, and

(d) R′

″

varies independently on each carbon and is H, (C₁-C₂)alkyl, phenyl, or phenyl(C₁-C₃)alkyl;

(2) -E is

(a) C₁-C₅ alkyl, but only if m′

does not equal 0,

(b) methylthioxy(C₂-C₄)alkyl,

(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,

(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,

(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,

(f) biphenyl,

(g) diphenyl ether,

(h) diphenylketone,

(i) phenyl(C₁-C₈)alkyloxyphenyl, or

(j) C₁-C₆ alkoxy;

(3) -Q is

(a) C₁-C₃ alkyl,

(b) C₁-C₃ alkoxy,

(c) C₁-C₃ alkylthioxy,

(d) C₁-C₆ alkylacylamino,

(e) C₁-C₆ alkylacyloxy,

(f) amido (including primary, C₁-C₆ alkyl and phenyl secondary and tertiary amino moieties),

(g) C₁-C₆ alkylamino

(h) phenylamino,

(i) carbamyl (including C₁-C₆alkyl and phenyl amides and esters),

(j) carboxyl (including C₁-C₆alkyl and phenyl esters),

(k) carboxy(C₂-C₅)alkoxy,

(l) carboxy(C₂-C₅)alkylthioxy,

(m) heterocyclylacyl,

(n) heteroarylacyl, or

(o) hydroxyl;

(4) m′

is 0, 1, 2 or 3;

(B) -E(Q)_m″

wherein E and -Q are as defined as above and m″

is 0, 1, 2, or 3;

(C) -T-E wherein -E and -Q are as defined as above;

or

(D) -E wherein -E is as defined as above;

(III) —

CO—

(C₁-C₆alkyl) where alkyl is unsubstituted or substituted with one or two;

(A) —

OH,

(B) —

C₁-C₆ alkoxy,

(C) —

C₁-C₆ thioalkoxy,

(D) —

CO—

O—

R_N-8 where R_N-8 is —

H, C₁-C₆ alkyl or -φ

,

(E) —

CO—

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

(F) —

CO—

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

(G) —

SO₂—

(C₁-C₈ alkyl),

(H) —

SO₂—

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

(I) —

NH—

CO—

(C₁-C₆ alkyl),

(J) —

NH—

CO—

O—

R_N-8 where R_N-8 is as defined above,

(K) —

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

(L) —

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

(M) —

O—

CO—

(C₁-C₆ alkyl),

(N) —

O—

CO—

NR_N-8R_N-8 where the R_N-8 is the same or different and are as defined above, or

(O) —

O—

(C₁-C₅ alkyl)-COOH,

(IV) —

CO—

(C₁-C₃ alkyl)-O—

(C₁-C₃ alkyl) where alkyl is unsubstituted or substituted with one or two

(A) —

OH,

(B) —

C₁-C₆ alkoxy,

(C) —

C₁-C₆ thioalkoxy,

(D) —

CO—

O—

R_N-8 where R_N-8 is —

H, C₁-C₆ alkyl or -φ

,—

(P,

(E) —

CO—

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

(F) —

CO—

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

(G) —

SO₂—

(C₁-C₈ alkyl),

(H) —

SO₂—

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

(I) —

NH—

CO—

(C₁-C₆ alkyl),

(J) —

NH—

CO—

O—

R_N-8 where R_N-8 is as defined above,

(K) —

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

(L) —

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

(M) —

O—

CO—

(C₁-C₆ alkyl),

(N) —

O—

CO—

NR_N-8R_N-8 where the R_N-8 are the same or different and are as defined above, or

(O) —

O—

(C₁-C₅ alkyl)-COOH,

(V) —

CO—

(C₁-C₃ alkyl)-S—

(C₁-C₃ alkyl) where alkyl is unsubstituted or substituted with one or two

(A) —

OH,

(B) —

C₁-C₆ alkoxy,

(C) —

C₁-C₆ thioalkoxy,

(D) —

CO—

O—

R_N-8 where R_N-8 is —

H, C₁-C₆ alkyl or -φ

,—

(P,

(E) —

CO—

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

(F) —

CO—

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

(G) —

SO₂—

(C₁-C₈ alkyl),

(H) —

SO₂—

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

(I) —

NH—

CO—

(C₁-C₆ alkyl),

(J) —

NH—

CO—

O—

R_N-8 where R_N-8 is as defined above,

(K) —

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

(L) —

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

(M) —

O—

CO—

(C₁-C₆ alkyl),

(N) —

O—

CO—

NR_N-8R_N-8 where the R_N-8 are the same or different and are as defined above, or

(O) —

O—

(C₁-C₅ alkyl)-COOH,

(VI) —

CO—

CH(—

(CH₂)_0-2—

O—

R_N-0)—

(CH₂)_0-2—

R_N-aryl/R_N-heteroaryl) where R_N-aryl and R_N-heteroaryl are as defined above, where R_N-10 is;

(A) —

H,

(B) C₁-C₆ alkyl,

(C) C₃-C₇ cycloalkyl,

(D) C₂-C₆ alkenyl with one double bond,

(E) C₂-C₆ alkynyl with one triple bond,

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

(G) R_N-heteroaryl where R_N-heteroaryl is as defined above;

where B is —

O—

, —

NH—

, or —

N(C₁-C₆ alkyl)-;

where R_C is;

(I) —

(C₁-C₁₀)alkyl-K_1-3 in which;

(A) the alkyl chain is unsubstituted or substituted with one —

OH,

(B) the alkyl chain is unsubstituted or substituted with one C₁-C₆ alkoxy unsubstituted or substituted with 1-5 —

F,

(C) the alkyl chain is unsubstituted or substituted with one —

O-φ

(D) the alkyl chain is unsubstituted or substituted with 1-5 —

F,

(E) the alkyl chain is unsubstituted or substituted with a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,

(F) each K is;

(1) H,

(2) C₁-C₃ alkyl,

(3) C₁-C₃ alkoxy,

(4) C₁-C₃ alkylthioxy,

(5) C₁-C₆ alkylacylamino,

(6) C₁-C₆ alkylacyloxy,

(7) amido

(8) C₁-C₆ alkylamino

(9) phenylamino,

(10) carbamyl

(11) carboxyl

(12) carboxy(C₂-C₅)alkoxy,

(13) carboxy(C₂-C₅)alkylthioxy,

(14) heterocyclylacyl,

(15) heteroarylacyl,

(16) amino unsubstituted or substituted with C₁-C₆ alkyl,

(17) hydroxyl, or

(18) carboxylmethyl ester;

(II) —

(CH₂)_0-3-J-[(—

(CH₂)_0-3—

K]_1-3 where K is as defined above and J is;

(A) a 5 to 7 atom monocyclic aryl group,

(B) a 8 to 12 atom multicyclic aryl group,

(C) a 5 to 7 atom heterocyclic group,

(D) a 8 to 12 atom multicyclic heterocyclic group, or

(E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group;

(III) —

(CH₂)_0-3—

(C₃-C₇)cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three

(A) C₁-C₃ alkyl unsubstituted or substituted with 1, 2, 3, or 4 —

F,

—

Cl, —

Br, or —

I,

(B) —

CO—

OH,

(C) —

CO—

O—

(C₁-C₄ alkyl),

(D) —

OH, or

(E) C₁-C₆ alkoxy,

(IV) —

(CH₂)_2-6—

OH,

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl where R_C-x and R_C-y are —

H, C₁-C₄ alkyl and φ

- and R_C-aryl is the same as R_N-aryl,

(VI) —

(CH₂)_0-4—

R_C-heteroaryl where R_C-heteroaryl is;

(A) pyridinyl,

(B) pyrimidinyl,

(C) quinolinyl,

(D) indenyl,

(E) indanyl,

(F) benzothiophenyl,

(G) indolyl,

(H) indolinyl,

(I) pyridazinyl,

(J) pyrazinyl,

(K) isoindolyl,

(L) isoquinolyl,

(M) quinazolinyl,

(N) quinoxalinyl,

(O) phthalazinyl,

(P) isoxazolyl,

(Q) pyrazolyl,

(R) indolizinyl,

(S) indazolyl,

(T) benzothiazolyl,

(U) benzimidazolyl,

(V) benzofuranyl,

(W) furanyl,

(X) thienyl,

(Y) pyrrolyl,

(Z) oxadiazolyl,

(AA) thiadiazolyl,

(BB) triazolyl,

(CC) tetrazolyl,

(DD) 1,4-benzodioxan

(EE) purinyl,

(FF) oxazolopyridinyl,

(GG) imidazopyridinyl,

(HH) isothiazolyl,

(II) naphthyridinyl,

(JJ) cinnolinyl,

(KK) carbazolyl,

(LL) β

-carbolinyl,

(MM) isochromanyl,

(NN) chromanyl,

(OO) furazanyl,

(PP) tetrahydroisoquinoline,

(QQ) isoindolinyl,

(RR) isobenzotetrahydrofuranyl,

(SS) isobenzotetrahydrothienyl,

(TT) isobenzothiophenyl,

(UU) benzoxazolyl, or

(VV) pyridopyridinyl,

(VII) —

(CH₂)_0-4—

R_{C-heterocycle} where R_{C-heterocycle} is the same as R_{1-heterocycle},

(VIII) —

C(R_C-1)(R_C-2)—

CO—

NH—

R_C-3 where R_C-1 and R_C-2 are the same or different and are;

(A) —

H,

(B) —

C₁-C₆ alkyl,

(C) —

(C₁-C₄ alkyl)-R<sub>C′

-aryl</sub> where R<sub>C′

-aryl</sub> is as defined above for

R_1-aryl i

(D) —

(C₁-C₄ alkyl)-R_C-heteroaryl where R_C-heteroaryl is as defined above,

(E) —

(C₁-C₄ alkyl)-R_{C-heterocycle} where R_{C-heterocycle} is as defined above,

(F) —

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

(G) —

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

(H) —

(CH₂)_1-4—

OH,

(I) —

(CH₂)_1-4—

R_C-4—

(CH₂)_1-4—

R_C-aryl where R_C-4 is —

O—

, S—

, —

NH—

or

—

NHR_C-5—

where R_C-5 is C₁-C₆ alkyl, and where R<sub>C′

-aryl</sub> is as defined above,

(J) —

(CH₂)_1-4—

R_C-4—

(CH₂)_1-4—

R_C-heteroaryl where R_C-4 and R_C-heteroaryl are as defined above, or

(K) —

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

and where R_C-3 is;

(A) —

H,

(B) —

C₁-C₆ alkyl,

(C) —

R<sub>C′

-aryl</sub> where R<sub>C′

-aryl</sub> is as defined above,

(D) —

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

(E) —

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

(F) —

(C₁-C₄ alkyl)-R<sub>C′

-aryl</sub> where R<sub>C′

-aryl</sub> is as defined above,

(G) —

(C₁-C₄ alkyl)-R_C-heteroaryl where R_C-heteroaryl is as defined above, or

(H) —

(C₁-C₄ alkyl)-R_{C-heterocycle} where R_{C-heterocycle} is as defined above,

(IX) —

CH(φ

)₂,

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one, two or three;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br and —

I,

(D) C₁-C₃ alkoxy,

(E) —

OCF₃,

(F) —

NH₂,

(G) —

OH, or

(H) —

C≡

N,

(XI) —

CH₂—

C≡

CH;

(XII) —

(CH₂)_0-1—

CHR_C-5—

(CH₂)_0-1-φ

where R_C-5 is;

(A) —

OH, or

(B) —

CH₂—

OH;

(XIII) —

CH(-φ

) —

CO—

O(C₁-C₃ alkyl);

(XIV) —

CH(—

CH₂—

OH)—

CH(—

OH)-φ

-NO₂;

(XV) —

(CH₂)₂—

O—

(CH₂)₂—

OH;

(XVI) —

CH₂—

NH—

CH₂—

CH(—

O—

CH₂—

CH₃) 2;

(XVII) —

(C₂-C₈)alkynyl;

or

(XVIII) —

H;

or a pharmaceutically acceptable salt thereof.

44. A compound of formula

where R₁ is:

(V) —

CH₂-phenyl, where phenyl is substituted with two —

F in the 3- and 5-positions giving 3,5-difluorophenyl, or

(VI) —

(CH₂)_n1—

(R_1-heteroaryl), where n1 and R_1-heteroaryl are as defined above;

where R₂ is as defined in claim 1;

and

PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl, -phenyl-C(═

N)—

H, or 1-piperidyloxycarbonyl.

51. A compound of formula

where R₁ is:

(V) —

CH₂-phenyl, where phenyl is substituted with two —

F in the 3- and 5-positions giving 3,5-difluorophenyl, or

(VI) —

(CH₂)_n1—

(R_1-heteroaryl), where n1 and R_1-heteroaryl are as defined above; and

where R₂ is as defined in claim 1.

58. A compound of formula

where R₁, R₂ and R_N are as defined in claim 1.

2-29. -29. (canceled)

30. A compound of the formula

where R₁ is:

(V) —

CH₂-phenyl, where phenyl is substituted with two —

F in the 3- and 5-positions giving 3,5-difluorophenyl, or

(VI) —

(CH₂)_n1—

(R_1-heteroaryl), where n1 and R_1-heteroaryl are as defined above; and

PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl, -phenyl-C(═

N)—

H, or 1-piperidyloxycarbonyl.

31-34. -34. (canceled)

35. An epoxide compound of the formula

where R₁ is:

(A) —

CH₂-φ

where -φ

is substituted with two —

F,

(B) —

(CH₂)_n1—

R_1-heteroaryl where n₁ is 0, 1, 2, or 3 and R_1-heteroaryl is;

(A) pyridinyl,

(B) pyrimidinyl,

(C) quinolinyl,

(D) indenyl,

(E) indanyl,

(F) benzothiophenyl,

(G) indolyl,

(H) indolinyl,

(I) pyridazinyl,

(J) pyrazinyl,

(K) isoindolyl,

(L) isoquinolyl,

(M) quinazolinyl,

(N) quinoxalinyl,

(O) phthalazinyl,

(P) imidazolyl,

(Q) isoxazolyl,

(R) pyrazolyl,

(S) oxazolyl,

(T) thiazolyl,

(U) indolizinyl,

(V) indazolyl,

(W) benzothiazolyl,

(X) benzimidazolyl,

(Y) benzofuranyl,

(Z) furanyl,

(AA) thienyl,

(BB) pyrrolyl,

(CC) oxadiazolyl,

(DD) thiadiazolyl,

(EE) triazolyl,

(FF) tetrazolyl,

(GG) 1,4-benzodioxan

(HH) purinyl,

(II) oxazolopyridinyl,

(JJ) imidazopyridinyl,

(KK) isothiazolyl,

(LL) naphthyridinyl,

(MM) cinnolinyl,

(NN) carbazolyl,

(OO) β

-carbolinyl,

(PP) isochromanyl,

(QQ) chromanyl,

(RR) furazanyl,

(SS) tetrahydroisoquinoline,

(TT) isoindolinyl,

(UU) isobenzotetrahydrofuranyl,

(VV) isobenzotetrahydrothienyl,

(WW) isobenzothiophenyl,

(XX) benzoxazolyl, or

(YY) pyridopyridinyl,

(C) —

(CH₂)_n1—

R_{1-heterocycle} where n, is 0, 1, 2, or 3 and R₁ heterocycle is;

(A) morpholinyl,

(B) thiomorpholinyl,

(C) thiomorpholinyl S-oxide,

(D) thiomorpholinyl S,S-dioxide,

(E) piperazinyl,

(F) homopiperazinyl,

(G) pyrrolidinyl,

(H) pyrrolinyl,

(I) tetrahydropyranyl,

(J) piperidinyl,

(K) tetrahydrofuranyl, or

(L) tetrahydrothiophenyl, and

PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl, -phenyl-C(═

N)—

H, or 1-piperidyloxycarbonyl.

36-43. -43. (canceled)

45-50. -50. (canceled)

52-57. -57. (canceled)

59-72. -72. (canceled)

73. A method of treating or preventing a disease or condition selected from Alzheimer'"'"'s disease, mild cognitive impairment, Down'"'"'s syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer'"'"'s disease or central or preipheral amyloid diseases in a patient who is in need of such treatment which comprises administration to said patient a therapeutically effective amount of a hydroxyethylene compound of the formula

where R₁ is:

(I) C₁-C₆ alkyl, unsubstituted or substituted with one, two or three C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, —

OH, —

NH₂, —

C≡

N, —

CF₃, or —

N₃,

(II) —

(CH₂)_1-2—

S—

CH₃,

(III) —

CH₂—

CH₂—

S—

CH₃,

(IV) —

CH₂—

(C₂-C₆ alkenyl) unsubstituted or substituted by one —

F,

(V) —

(CH₂)_0-3—

(R_1-aryl) where R_1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br and —

I,

(D) C₁-C₃ alkoxy,

(E) —

O—

CF₃,

(F) —

NH₂,

(G) —

OH, or

(H) —

C≡

N,

(VI) —

(CH₂)_n1—

(R_1-heteroaryl) where n₁ is 0, 1, 2, or 3 and R_1-heteroaryl is;

(A) pyridinyl,

(B) pyrimidinyl,

(C) quinolinyl,

(D) indenyl,

(E) indanyl,

(F) benzothiophenyl,

(G) indolyl,

(H) indolinyl,

(I) pyridazinyl,

(J) pyrazinyl,

(K) isoindolyl,

(L) isoquinolyl,

(M) quinazolinyl,

(N) quinoxalinyl,

(O) phthalazinyl,

(P) imidazolyl,

(Q) isoxazolyl,

(R) pyrazolyl,

(S) oxazolyl,

(T) thiazolyl,

(U) indolizinyl,

(V) indazolyl,

(W) benzothiazolyl,

(X) benzimidazolyl,

(Y) benzofuranyl,

(Z) furanyl,

(AA) thienyl,

(BB) pyrrolyl,

(CC) oxadiazolyl,

(DD) thiadiazolyl,

(EE) triazolyl,

(FF) tetrazolyl,

(GG) 1,4-benzodioxan

(HH) purinyl,

(II) oxazolopyridinyl,

(JJ) imidazopyridinyl,

(KK) isothiazolyl,

(LL) naphthyridinyl,

(MM) cinnolinyl,

(NN) carbazolyl,

(OO) β

-carbolinyl,

(PP) isochromanyl,

(QQ) chromanyl,

(RR) furazanyl,

(SS) tetrahydroisoquinoline,

(TT) isoindolinyl,

(UU) isobenzotetrahydrofuranyl,

(VV) isobenzotetrahydrothienyl,

(WW) isobenzothiophenyl,

(XX) benzoxazolyl, or

(YY) pyridopyridinyl,

 

where the R_1-heteroaryl group is bonded to —

(CH₂)_0-3—

by any ring atom of the parent R_N-heteroaryl group substituted by hydrogen such that the new bond to the R_1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two;

(1) C₁-C₃ alkyl,

(2) —

CF₃,

(3) —

F, Cl, —

Br, or —

I,

(4) C₁-C₃ alkoxy,

(5) —

O—

CF₃,

(6) —

NH₂,

(7) —

OH, or

(8) —

C≡

N,

with the proviso that when n₁ is zero R_1-heteroaryl is not bonded to the carbon chain by nitrogen, or

(VII) —

(CH₂)_n1—

(R_{1-heterocycle}) where n₁ is as defined above and

R_{1-heterocycle} is

(A) morpholinyl,

(B) thiomorpholinyl,

(C) thiomorpholinyl S-oxide,

(D) thiomorpholinyl S,S-dioxide,

(E) piperazinyl,

(F) homopiperazinyl,

(G) pyrrolidinyl,

(H) pyrrolinyl,

(I) tetrahydropyranyl,

(J) piperidinyl,

(K) tetrahydrofuranyl, or

(L) tetrahydrothiophenyl,

 

where the R_{1-heterocycle} group is bonded by any atom of the parent R_{1-heterocycle} group substituted by hydrogen such that the new bond to the R_1-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two;

(1) ═

O,

(2) C₁-C₃ alkyl,

(3) —

CF₃,

(4) —

F, Cl, —

Br and —

I,

(5) C₁-C₃ alkoxy,

(6) —

O—

CF₃,

(7) —

NH₂,

(8) —

OH, or

(9) —

C≡

N,

with the proviso that when n₁ is zero R_{1-heterocycle} is not bonded to the carbon chain by nitrogen;

where R₂ is;

(I) —

H,

(II) C₁-C₆ alkyl, or

(III) —

(CH₂)_0-4—

R_2-1 where R_2-1 is (C₃-C₆)cycloalkyl, R_{1-aryl or R1-heteroaryl} where R_1-aryl and R_1-heteroaryl are as defined above,

where R_N is;

(I) R_N-1—

X_N—

where X_N is;

(A) —

CO—

,

(B) —

SO₂—

,

(C) —

(CR′

R″

)_1-6 where R′ and

R″

are the same or different and are —

H or C₁-C₄ alkyl,

(D) —

CO—

(CR′

R″

)_1-6—

X_N-1 where X_N-1 is —

O—

, —

S— and

—

NR′

R″

— and

where R′ and

R″

are as defined above,

(E) a single bond;

where R_N-1 is;

(A) R_N-aryl where R_N-aryl is phenyl, 1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two, three or four of the following substituents which can be the same or different and are;

(1) C₁-C₆ alkyl,

(2) —

F, —

Cl, —

Br, or —

I,

(3) —

OH,

(4) —

NO₂,

(5) —

CO—

OH,

(6) —

C≡

N,

(7) —

CO—

NR_N-2R_N-3 where R_N-2 and R_N-3 are the same or different and are;

(a) —

H,

(b) —

C₁-C₆ alkyl unsubstituted or substituted with one

 

(i) —

OH, or

 

(ii) —

NH₂,

(c) —

C₁-C₆ alkyl unsubstituted or substituted with one to three —

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) —

C₁-C₆ alkenyl with one or two double bonds,

(h) —

C₁-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, or

(k) —

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

(8) —

CO—

(C₃-C₁₂ alkyl),

(9) —

CO—

(C₃-C₆ cycloalkyl),

(10) —

CO—

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

(11) —

CO—

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

(12) —

CO—

R_N-4 where R_N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C₁-C₃ alkyl,

(13) —

CO—

O—

R_N-5 where R_N-5 is;

(a) C₁-C₆ alkyl, or

(b) —

(CH₂)_0-2—

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

(14) —

SO₂—

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

(15) —

SO—

(C₁-C₈ alkyl),

(16) —

SO₂—

(C₃-C₁₂ alkyl),

(17) —

NH—

CO—

O—

R_N-5 where R_N-5 is as defined above,

(18) —

NH—

CO—

N(C₁-C₃ alkyl)₂,

(19) —

N—

CS—

N(C₁-C₃ alkyl)₂,

(20) —

N(C₁-C₃ alkyl)-CO—

R_N-5 where R_N-5 is as defined above,

(21) —

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

(22) —

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

(23) —

O—

CO—

(C₁-C₆ alkyl),

(24) —

O—

CO—

N(C₁-C₃ alkyl)₂,

(25) —

O—

CS—

N(C₁-C₃ alkyl) 2,

(26) —

O—

(C₁-C₆ alkyl),

(27) —

O—

(C₂-C₅ alkyl)-COOH,

(28) —

S—

(C₁-C₆ alkyl),

(29) C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —

F,

(30) —

O—

(C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —

F, or

(31) —

O-T,

(B) —

R_N-heteroaryl where R_N-heteroaryl is

(A) pyridinyl,

(B) pyrimidinyl,

(C) quinolinyl,

(D) indenyl,

(E) indanyl,

(F) benzothiophenyl,

(G) indolyl,

(H) indolinyl,

(I) pyridazinyl,

(J) pyrazinyl,

(K) isoindolyl,

(L) isoquinolyl,

(M) quinazolinyl,

(N) quinoxalinyl,

(O) phthalazinyl,

(P) imidazolyl,

(Q) isoxazolyl,

(R) pyrazolyl,

(S) oxazolyl,

(T) thiazolyl,

(U) indolizinyl,

(V) indazolyl,

(W) benzothiazolyl,

(X) benzimidazolyl,

(Y) benzofuranyl,

(Z) furanyl,

(AA) thienyl,

(BB) pyrrolyl,

(CC) oxadiazolyl,

(DD) thiadiazolyl,

(EE) triazolyl,

(FF) tetrazolyl,

(GG) 1,4-benzodioxan

(HH) purinyl,

(II) oxazolopyridinyl,

(JJ) imidazopyridinyl,

(KK) isothiazolyl,

(LL) naphthyridinyl,

(MM) cinnolinyl,

(NN) carbazolyl,

(OO) β

-carbolinyl,

(PP) isochromanyl,

(QQ) chromanyl,

(RR) furazanyl,

(SS) tetrahydroisoquinoline,

(TT) isoindolinyl,

(UU) isobenzotetrahydrofuranyl,

(VV) isobenzotetrahydrothienyl,

(WW) isobenzothiophenyl,

(XX) benzoxazolyl, or

(YY) pyridopyridinyl,

 

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 unsubstituted or substituted with one or two;

(1) C₁-C₆ alkyl,

(2) —

F, —

Cl, —

Br, or —

I,

(3) —

OH,

(4) —

NO₂,

(5) —

CO—

OH,

(6) —

C≡

N,

(7) —

CO—

NR_N-2R_N-3 where R_N-2 and R_N-3 are the same or different and are;

 

(a) —

H,

 

(b) —

C₁-C₆ alkyl unsubstituted or substituted with one

 

(i) —

OH, or

 

(ii) —

NH₂,

 

(c) —

C₁-C₆ alkyl unsubstituted or substituted with 1, 2, or 3 —

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) —

C₁-C₆ alkenyl with one or two double bonds,

 

(h) —

C₁-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, or

 

(k) —

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

(8) —

CO—

(C₃-C₁₂ alkyl),

(9) —

CO—

(C₃-C₆ cycloalkyl),

(10) —

CO—

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

(11) —

CO—

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

(12) —

CO—

R_N-4 where R_N-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C₁-C₃ alkyl,

(13) —

CO—

O—

R_N-5 where R_N-5 is;

 

(a) C₁-C₆ alkyl, or

 

(b) —

(CH₂)_0-2—

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

(14) —

SO₂—

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

(15) —

SO—

(C₁-C₈ alkyl),

(16) —

SO₂ (C₃-C₁₂ alkyl),

(17) —

NH—

CO—

O—

R_N-5 where R_N-5 is as defined above,

(18) —

NH—

CO—

N(C₁-C₃ alkyl)₂,

(19) —

N—

CS—

N(C₁-C₃ alkyl)₂,

(20) —

N(C₁-C₃ alkyl)-CO—

R_N-5 where R_N-5 is as defined above,

(21) —

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

(22) —

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

(23) —

O—

CO—

(C₁-C₆ alkyl),

(24) —

O—

CO—

N(C₁-C₃ alkyl)₂,

(25) —

O—

CS—

N(C₁-C₃ alkyl)₂,

(26) —

O—

(C₁-C₆ alkyl),

(27) —

O—

(C₂-C₅ alkyl)-COOH, or

(28) —

S—

(C₁-C₆ alkyl),

(C) —

R_N-aryl—

R_N-aryl where —

R_N-aryl is as defined above,

(D) —

R_N-aryl—

R_N-heteroaryl where —

R_N-aryl and —

R_N-heteroaryl are as defined above,

(E) —

R_N-heteroaryl—

R_N-aryl where —

R_N-aryl and —

R_N-heteroaryl are as defined above,

(F) —

R_N-heteroaryl—

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

(G) —

R_N-aryl—

O—

R_N-aryl where —

R_N-aryl is as defined above,

(H) —

R_N-aryl—

S—

R_N-aryl where —

R_N-aryl is as defined above,

(I) —

R_N-heteroaryl—

O—

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

(J) —

R_N-heteroaryl—

S—

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

(K) —

R_N-aryl—

CO—

R_N-aryl where —

R_N-aryl is as defined above,

(L) —

R_N-aryl—

CO—

R_N-heteroaryl where —

R_N-aryl and R_N-heteroaryl are as defined above,

(M) —

R_N-aryl—

SO₂—

R_N-aryl where —

R_N-aryl is as defined above,

(N) —

R_N-heteroaryl—

CO—

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

(O) —

R_N-heteroaryl—

SO₂—

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

(P) —

R_N-aryl—

O—

(C₁-C₈ alkyl)-φ

where R_N-aryl is as defined above,

(Q) —

R_N-aryl—

S—

(C₁-C₈ alkyl)-φ

where R_N-aryl is as defined above,

(R) —

R_N-heteroaryl—

O(C₁-C₈ alkyl)-φ

where R_N-heteroaryl is as defined above, or

(S) —

R_N-heteroaryl—

S—

(C₁-C₈ alkyl)-φ

where R_N-heteroaryl is as defined above,

(II) A-X_N—

where X_N is —

CO—

,

wherein A is

(A) -T-E-(Q)_m′

,

(1) where -T is

 

where

(a) x=1 when y=1 and x=2 when y=0,

(b) m is 0, 1, 2 or 3,

(c) the values of x and y vary independently on each carbon when m is 2 and 3, and

(d) R′

″

varies independently on each carbon and is H, (C₁-C₂)alkyl, phenyl, or phenyl(C₁-C₃)alkyl;

(2) -E is

(a) C₁-C₅ alkyl, but only if m′

does not equal 0,

(b) methylthioxy(C₂-C₄)alkyl,

(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,

(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,

(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,

(f) biphenyl,

(g) diphenyl ether,

(h) diphenylketone,

(i) phenyl(C₁-C₈)alkyloxyphenyl, or

(j) C₁-C₆ alkoxy;

(3) -Q is

(a) C₁-C₃ alkyl,

(b) C₁-C₃ alkoxy,

(c) C₁-C₃ alkylthioxy,

(d) C₁-C₆ alkylacylamino,

(e) C₁-C₆ alkylacyloxy,

(f) amido (including primary, C₁-C₆ alkyl and phenyl secondary and tertiary amino moieties),

(g) C₁-C₆ alkylamino

(h) phenylamino,

(i) carbamyl (including C₁-C₆ alkyl and phenyl amides and esters),

(j) carboxyl (including C₁-C₆ alkyl and phenyl esters),

(k) carboxy(C₂-C₅)alkoxy,

(l) carboxy(C₂-C₅)alkylthioxy,

(m) heterocyclylacyl,

(n) heteroarylacyl, or

(o) hydroxyl;

(4) m′

is 0, 1, 2 or 3;

(B) -E(Q)_m″

wherein E and -Q are as defined as above and m″

is 0, 1, 2, or 3;

(C) -T-E wherein -E and -Q are as defined as above;

or

(D) -E wherein -E is as defined as above;

(III) —

CO—

(C₁-C₆alkyl) where alkyl is unsubstituted or substituted with one or two;

(A) —

OH,

(B) —

C₁-C₆ alkoxy,

(C) —

C₁-C₆ thioalkoxy,

(D) —

CO—

O—

R_N-8 where R_N-8 is —

H, C₁-C₆ alkyl or -φ

,

(E) —

CO—

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

(F) —

CO—

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

(G) —

SO₂—

(C₁-C₈ alkyl),

(H) —

SO₂—

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

(I) —

NH—

CO—

(C₁-C₆ alkyl),

(J) —

NH—

CO—

O—

R_N-8 where R_N-8 is as defined above,

(K) —

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

(L) —

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

(M) —

O—

CO—

(C₁-C₆ alkyl)I

(N) —

O—

CO—

NR_N-8R_N-8 where the R_N-8 is the same or different and are as defined above, or

(O) —

O—

(C₁-C₅ alkyl)-COOH,

(IV) —

CO—

(C₁-C₃ alkyl)-O—

(C₁-C₃ alkyl) where alkyl is unsubstituted or substituted with one or two

(A) —

OH,

(B) —

C₁-C₆ alkoxy,

(C) —

C₁-C₆ thioalkoxy,

(D) —

CO—

O—

R_N-8 where R_N-8 is —

H, C₁-C₆ alkyl or -φ

,—

(P,

(E) —

CO—

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

(F) —

CO—

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

(G) —

SO₂—

(C₁-C₈ alkyl),

(H) —

SO₂—

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

(I) —

NH—

CO—

(C₁-C₆ alkyl),

(J) —

NH—

CO—

O—

R_N-8 where R_N-8 is as defined above,

(K) —

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

(L) —

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

(M) —

O—

CO—

(C₁-C₆ alkyl),

(N) —

O—

CO—

NR_N-8R_N-8 where the R_N-8 are the same or different and are as defined above, or

(O) —

O—

(C₁-C₅ alkyl)-COOH,

(V) —

CO—

(C₁-C₃ alkyl)-S—

(C₁-C₃ alkyl) where alkyl is unsubstituted or substituted with one or two

(A) —

OH,

(B) —

C₁-C₆ alkoxy,

(C) —

C₁-C₆ thioalkoxy,

(D) —

CO—

O—

R_N-8 where R_N-8 is —

H, C₁-C₆ alkyl or -φ

,

(E) —

CO—

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

(F) —

CO—

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

(G) —

SO₂—

(C₁-C₈ alkyl),

(H) —

SO₂—

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

(I) —

NH—

CO—

(C₁-C₆ alkyl),

(J) —

NH—

CO—

O—

R_N-8 where R_N-8 is as defined above,

(K) —

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

(L) —

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

(M) —

O—

CO—

(C₁-C₆ alkyl),

(N) —

O—

CO—

NR_N-8R_N-8 where the R_N-8 are the same or different and are as defined above, or

(O) —

O—

(C₁-C₅ alkyl)-COOH,

(VI) —

CO—

CH(—

(CH₂)_0-2—

O—

R_N-0)—

(CH₂)_0-2—

R_N-aryl/R_N-heteroaryl) where R_N-aryl and R_N-heteroaryl are as defined above, where R_N-10 is;

(A) —

H,

(B) C₁-C₆ alkyl,

(C) C₃-C₇ cycloalkyl,

(D) C₂-C₆ alkenyl with one double bond,

(E) C₂-C₆ alkynyl with one triple bond,

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

(G) R_N-heteroaryl where R_N-heteroaryl is as defined above;

where B is —

O—

, —

NH—

, or —

N(C₁-C₆ alkyl)-;

where R_C is;

(I) —

(C₁-C₁₀)alkyl-K_1-3 in which;

(A) the alkyl chain is unsubstituted or substituted with one —

OH,

(B) the alkyl chain is unsubstituted or substituted with one C₁-C₆ alkoxy unsubstituted or substituted with 1-5 —

F,

(C) the alkyl chain is unsubstituted or substituted with one —

O-φ

,

(D) the alkyl chain is unsubstituted or substituted with 1-5 —

F,

(E) the alkyl chain is unsubstituted or substituted with a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,

(F) each K is;

(1) H,

(2) C₁-C₃ alkyl,

(3) C₁-C₃ alkoxy,

(4) C₁-C₃ alkylthioxy,

(5) C₁-C₆ alkylacylamino,

(6) C₁-C₆ alkylacyloxy,

(7) amido

(8) C₁-C₆ alkylamino

(9) phenylamino,

(10) carbamyl

(11) carboxyl

(12) carboxy(C₂-C₅)alkoxy,

(13) carboxy(C₂-C₅)alkylthioxy,

(14) heterocyclylacyl,

(15) heteroarylacyl,

(16) amino unsubstituted or substituted with C₁-C₆ alkyl,

(17) hydroxyl, or

(18) carboxylmethyl ester;

(II) —

(CH₂)_0-3-J-[(—

(CH₂)_0-3—

K]_1-3 where K is as defined above and J is;

(A) a 5 to 7 atom monocyclic aryl group,

(B) a 8 to 12 atom multicyclic aryl group,

(C) a 5 to 7 atom heterocyclic group,

(D) a 8 to 12 atom multicyclic heterocyclic group, or

(E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group;

(III) —

(CH₂)_0-3—

(C₃-C₇)cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three

(A) C₁-C₃ alkyl unsubstituted or substituted with 1, 2, 3, or 4 —

F,

—

Cl, —

Br, or —

I,

(B) —

CO—

OH,

(C) —

CO—

O—

(C₁-C₄ alkyl),

(D) —

OH, or

(E) C₁-C₆ alkoxy,

(IV) —

(CH₂)_2-6—

OH,

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl where R_C-1 and R_C-y are —

H, C₁-C₄ alkyl and φ

- and R_C-aryl is the same as R_N-aryl,

(VI) —

(CH₂)_0-4—

R_C-heteroaryl where R_C-heteroaryl is;

(A) pyridinyl,

(B) pyrimidinyl,

(C) quinolinyl,

(D) indenyl,

(E) indanyl,

(F) benzothiophenyl,

(G) indolyl,

(H) indolinyl,

(I) pyridazinyl,

(J) pyrazinyl,

(K) isoindolyl,

(L) isoquinolyl,

(M) quinazolinyl,

(N) quinoxalinyl,

(O) phthalazinyl,

(P) isoxazolyl,

(Q) pyrazolyl,

(R) indolizinyl,

(S) indazolyl,

(T) benzothiazolyl,

(U) benzimidazolyl,

(V) benzofuranyl,

(W) furanyl,

(X) thienyl,

(Y) pyrrolyl,

(Z) oxadiazolyl,

(AA) thiadiazolyl,

(BB) triazolyl,

(CC) tetrazolyl,

(DD) 1,4-benzodioxan

(EE) purinyl,

(FF) oxazolopyridinyl,

(GG) imidazopyridinyl,

(HH) isothiazolyl,

(II) naphthyridinyl,

(JJ) cinnolinyl,

(KK) carbazolyl,

(LL) β

-carbolinyl,

(MM) isochromanyl,

(NN) chromanyl,

(OO) furazanyl,

(PP) tetrahydroisoquinoline,

(QQ) isoindolinyl,

(RR) isobenzotetrahydrofuranyl,

(SS) isobenzotetrahydrothienyl,

(TT) isobenzothiophenyl,

(UU) benzoxazolyl, or

(VV) pyridopyridinyl,

(VII) —

(CH₂)_0-4—

R_{C-heterocycle} where R_{C-heterocycle} is the same as R_{1-heterocycle},

(VIII) —

C(R_C-1)(R_C-2)—

CO—

NH—

R_C-3 where R_C-1 and R_C-2 are the same or different and are;

(A) —

H,

(B) —

C₁-C₆ alkyl,

(C) —

(C₁-C₄ alkyl)-R<sub>C′

-aryl</sub> where R<sub>C′

-aryl</sub> is as defined above for R_1-aryl,

(D) —

(C₁-C₄ alkyl)-R_C-heteroaryl where R_C-heteroaryl is as defined above,

(E) —

(C₁-C₄ alkyl)-R_{C-heterocycle} where R_{C-heterocycle} is as defined above,

(F) —

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

(G) —

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

(H) —

(CH₂)_1-4—

OH,

(I) —

(CH₂)_1-4—

R_C-4—

(CH₂)_1-4—

R<sub>C′

-aryl</sub> where R_C-4 is —

O—

, S—

, —

NH—

or

—

NHR_C-5—

where R_C-5 is C₁-C₆ alkyl, and where R<sub>C′

-aryl</sub> is as defined above,

(J) —

(CH₂)_1-4—

R_C-4—

(CH₂)_1-4—

R_C-heteroaryl where R_C-4 and R_C-heteroaryl are as defined above, or

(K) —

R<sub>C′

-aryl</sub> where R<sub>C′

-aryl</sub> is as defined above, and where R_C-3 is;

(A) —

H,

(B) —

C₁-C₆ alkyl,

(C) —

R<sub>C′

-aryl</sub> where R<sub>C′

-aryl</sub> is as defined above,

(D) —

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

(E) —

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

(F) —

(C₁-C₄ alkyl)-R<sub>C′

-aryl</sub> where R<sub>C′

-aryl</sub> is as defined above,

(G) —

(C₁-C₄ alkyl)-R_C-heteroaryl where R_C-heteroaryl is as defined above, or

(H) —

(C₁-C₄ alkyl)-R_{C-heterocycle} where R_{C-heterocycle} is as defined above,

(IX) —

CH(φ

)₂,

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one, two or three;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br and —

I,

(D) C₁-C₃ alkoxy,

(E) —

OCF₃,

(F) —

NH₂,

(G) —

OH, or

(H) —

C≡

N,

(XI) —

CH₂—

C≡

CH;

(XII) —

(CH₂)_0-1—

CHR_C-5—

(CH₂)_0-1-φ

where R_C-5 is;

(A) —

OH, or

(B) —

CH₂—

OH;

(XIII) —

CH(-φ

)-CO—

O(C₁-C₃ alkyl);

(XIV) —

CH(—

CH₂—

OH)—

CH(—

OH)-φ

-NO₂;

(XV) —

(CH₂)₂—

O—

(CH₂)₂—

OH;

(XVI) —

CH₂—

NH—

CH₂—

CH(—

O—

CH₂—

CH₃) 2;

(XVII) —

(C₂-C₈)alkynyl;

or

(XVIII) —

H;

or a pharmaceutically acceptable salt thereof.

74-141. -141. (canceled)