Compounds to treat Alzheimer's disease

• US 20040214846A1
• Filed: 05/18/2004
• Published: 10/28/2004
• Est. Priority Date: 03/23/2000
• Status: Active Grant

• 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.
• Granted Patent: US 7,030,239 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• 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

2. A compound according to claim 1

where R₁ is:

(V) —

(CH₂)_0-3—

(R_1-aryl), or

(VI) —

(CH₂)_n1—

(R_1-heteroaryl)

where RN is;

(I) R_N-1—

X_N—

where X_N is;

(A) —

CO—

, or

(B) —

SO₂—

,

where R_N-1 is;

(A) R_N-aryl, or

(B) —

R_N-heteroaryl,

(VI) —

CO—

CH(—

(CH₂)_0-2—

O—

R_N-10)—

(CH₂)_0-2—

R_N-aryl/R_N-heteroaryl)

where R_C is;

(I) —

C₁-C₈ alkyl,

(III) —

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

(IV) —

(CH₂)_0-3—

OH,

(V) —

(CR_C-xR_C-y)_0-4R_C-aryl,

(VII) —

(CH₂)_0-4—

R_C-heteroaryl,

(VIII) —

(CH₂)_0-4—

R_{C-heterocycle},

(VI) —

C(R_C-1)(R_C-2)—

CO—

NH—

R_C-3, or

(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 or two;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br or —

I,

(D) C₁-C₃ alkoxy, or

(E) —

OCF_3.

3. A compound according to claim 2

where R₁ is:

(V) —

CH₂—

(R_1-aryl), or

(VI) —

CH₂—

(R_1-heteroaryl);

where R₂ is —

H;

where R_N is;

(I) R_N-1—

X_N—

where X_N is;

(A) —

CO—

,

where R_N-1 is;

(A) R_N-aryl, or

(B) —

R_N-heteroaryl,

where R_C is;

(III) —

(CH₂)_0-3-(C₃-C₇) cycloalkyl,

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_{C-heteroaryl,}

(VII) —

(CH₂)_0-4—

R_{C-heterocycle},

(VIII) —

C(R_C-1)(R_C-2)—

CO—

NH—

R_C-3, or

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.

4. A compound according to claim 3 where R_C is:

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_C-heteroaryl, or

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.

5. A compound according to claim 1 where R₁ is

—

CH₂—

(R_1-aryl) where R_1-aryl is phenyl.

6. A compound according to claim 1 where R₁ is

—

CH₂—

(R_1-aryl) where R_1-aryl is phenyl substituted with two —

F.

7. A compound according to claim 6 where phenyl is substituted with two —

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

8. A compound according to claim 1 where R₂ is:

(1) —

H,

(II) C₁-C₆ alkyl, or

(III) —

(CH₂)_0-4—

R_2-1 where R_2-1 is R_1-aryl.

9. A compound according to claim 1 where R₂ is:

(II) C₁-C₆ alkyl, or

(III) benzyl.

10. A compound according to claim 1 where RN is:

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl where R_N-aryl is phenyl substituted with one —

CO—

NR_N-2R_N-3 where the substitution on phenyl is 1,3-.

11. A compound according to claim 10 where R_N-2 and R_N-3 are the same and are C₃ alkyl.

12. A compound according to claim 1 where R_N is:

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl where R_N-aryl is phenyl substituted with one C₁ alkyl and with one —

CO—

NR_N-2R_N-3 where the substitution on the phenyl is 1,3,5-.

13. A compound according to claim 12 where R_N-2 and R_N-3 are the same and are C₃ alkyl.

14. A compound according to claim 1 where R_N is R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-heteroaryl where R_N-heteroaryl is substituted with one —

CO—

NR_N-2R_N-3.

15. A compound according to claim 14 where R_N-2 and R_N-3 are the same and are —

C₃ alkyl.

16. A compound according to claim 1 where R_N is:

A-X_N—

where X_N is —

CO—

, where A is;

(C) C₁₀H₇—

CH(OH)—

, or

(D) t-butoxy.

17. A compound according to claim 1 where R_C is:

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_C-heteroaryl,

(VII) —

(CH₂)_0-4—

R_{C-heterocycle},

(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 or two;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br or —

I,

(D) C₁-C₃ alkoxy,

(E) —

OCF₃, or

(XVIII) —

H.

18. A compound according to claim 17 where R_C is:

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl where R_C-aryl is phenyl.

19. A compound according to claim 18 where phenyl substituted in the 3-position or 3,5-positions.

20. A compound according to claim 17 where R_C is:

(VI) —

CH₂—

R_C-heteroaryl,

21. A compound according to claim 17 where R_C is:

(VII) —

CH₂—

R_{C-heterocycle.}

22. A compound according to claim 17 where R_C is:

(X) -cyclohexyl ring fused to a phenyl ring.

23. A compound according to claim 1 where R_C is:

(I) —

(C₁-C₁₀)alkyl-K_1-3 where each K is;

(1) H,

(11) carboxyl,

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

or

(18) carboxyl methyl ester;

(II) —

(CH₂)_0-3-J-[—

K]_1-3, where J is;

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

(B) a 5 to 10 atom multicyclic cycloalkyl group,

and each K is;

(1) H,

(3) C₁-C₃ alkoxy, or

(11) carboxyl,

(III) —

(CH₂)_0-3—

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

(B) —

CO—

OH,

(C) —

CO—

O—

(C₁-C₄ alkyl), or

(E) C₁-C₆ alkoxy,

(IV) —

(CH₂)_2-6—

OH,

(V) —

(CH₂)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_C-heteroaryl,

(VII) —

(CH₂)_0-4—

R_{C-heterocycle}, or

(XVIII) —

(C₂-C₈) alkynyl.

24. A compound according to claim 23 where R_C is:

(I) —

(C₁-C₁₀)alkyl-K where K is H, carboxyl, carboxyl methyl ester, amino unsubstituted or substituted with C₁-C₆ alkyl,

(II) a benzyl or phenylpropyl group substituted with a carboxyl group,

(III) —

(CH₂)_0-3—

(C₃-C₇) cycloalkyl where cycloalkyl is cyclohexyl, cyclohexyl substituted with 1 or 2 carboxyl groups, or cyclohexyl substituted with 1 or 2 alkoxy groups,

(V) —

(CH₂)_0-4-phenyl substituted or unsubstituted with F,

(VI) —

(CH₂)_0-4-heteroaryl, or

(VII) selected from —

(CH₂)_0-4-morpholinyl and —

(CH₂)_0-4-tetrahydrofuryl.

25. A compound according to claim 24 where R_C is:

(I) C₅H₁₀—

K or C₇H₁₄—

K where K is carboxyl or carboxyl methyl ester,

(II) a benzyl or phenylpropyl group substituted with a carboxyl group at the 5-position, or

(III) a cyclohexyl ring substituted at the 3- and 5-positions or at the 4-position with a carboxyl group.

26. A compound according to claim 1

where R₁ is:

(I) C₁-C₅ alkyl,

(II) —

(CH₂)_1-2—

S—

CH₃,

(IV) C₁-C₅ alkenyl,

(V) —

(CH₂)_0-3—

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

(VI) —

(CH₂)_0-3—

(R_1-heteroaryl) where R_1-heteroaryl is as defined above, wherein any of the above are unsubstituted or substituted with up to two C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, or —

CF₃;

where R₂ is;

(I) —

H

(II) C₁-C₆ alkyl, or

(III) —

(CH₂)_0-3—

R_2-1 where R_2-1 is (C₃-C₆)cycloalkyl, R_1-aryl or R_1-heteroaryl where R_1-aryl is a 5 or 6-membered aryl group and R_1-heteroaryl is as defined above;

where R_N is;

(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;

where R_C is;

(I) —

(C₁-C₁₀)alkyl-K_1-3

(E) the alkyl chain optionally contains a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,

(F) each K is;

(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) carboxyl methyl ester;

(II) —

(CH₂)_0-3-J-[(—

(CH₂)_0-3—

K]_1-3 where K is;

(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;

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 monocyclic heterocyclic group,

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

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

where B is O or NH.

27. A compound according to claim 1 where the pharmaceutically acceptable salt is a salt of hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic, CH₃—

(CH₂)_n—

COOH where n is 0 thru 4, HOOC—

(CH₂)_n—

COOH where n is as defined above, HOOC—

CH═

CH—

COOH and φ

-COOH acid or triethanolamine, N-methylglucamine, diethanolamine, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, or carbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali or alkaline earth metal.

28. A compound according to claim 1 which is:

N-[(1S, 2S, 4R)-1-(3,5-Difluorobenzyl)-4-(syn, syn)-(3,5-dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide,

6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid,

5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-pentanoic acid,

4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyric acid,

3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionic acid,

8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S) hydroxyhexanoylamino]-octanoic acid,

8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester,

N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide,

4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbanoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(5)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbanoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, or

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide.

29. A compound according to claim 1 which is:

44. A compound of formula

45. A compound according to claim 44 where where R₁ is —

CH₂-phenyl, where phenyl is substituted with two —

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

46. A compound according to claim 44 where PROTECTING GROUP is 1-butoxycarbonyl.

47. A compound according to claim 44 where PROTECTING GROUP is benzyloxycarbonyl.

48. A compound according to claim 44 where R₂ is —

H.

49. A compound according to claim 44 where R₂ is C₁-C₆ alkyl.

50. A compound according to claim 44 which is:

(1S,2S, 4R)-[1-(3,5-Difluorobenzyl)-4-((3aS, 8aR)-2,2-dimethyl-8,8α

-dihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamic acid tert-butyl ester,

[2-(3,5-Difluorophenyl)-1-(S)-(4-(R)-ethyl-5-oxo-tetrahydrofuran-2-(S)-yl)-ethyl]-carbamic acid tert-butyl ester,

(1S,2S, 4R)-[1-(3,5-Difluorobenzyl)-4-((3aS, 8aR)-2,2-dimethyl-8,8α

-dihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamic acid benzyl ester, or

[2-(3,5-Difluorophenyl)-1-(S)-(4-(R)-ethyl-5-oxo-tetrahydrofuran-2-(S)-yl)-ethyl]-carbamic acid benzyl ester.

51. A compound of formula

52. A compound according to claim 51 where where R₁ is —

CH₂-phenyl, where phenyl is substituted with two —

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

53. A compound according to claim 51 where PROTECTING GROUP is t-butoxycarbonyl.

54. A compound according to claim 51 where PROTECTING GROUP is benzyloxycarbonyl.

55. A compound according to claim 51 where R₂ is —

H.

56. A compound according to claim 51 where R₂ is C₁-C₆ alkyl.

57. A compound according to claim 51 which is 5S-[1S-Amino-2-(3,5-difluorophenyl)ethyl]-3R-ethyldihydrofuran-2-one.

58. A compound of formula

59. A compound according to claim 58 where R₁ is:

(I) C₁-C₆ alkyl

(V) —

(CH₂)_0-1—

(R_1-aryl), or

(VI) —

(CH₂)_n1—

(R_1-heteroaryl).

60. A compound according to claim 59 where R₁ is

—

(CH₂)—

(R_1-aryl) where R_1-aryl is phenyl.

61. A compound according to claim 60 where phenyl is substituted with one, two or three —

F, —

Cl, —

Br and —

I.

62. A compound according to claim 61 where phenyl is substituted with two —

F.

63. A compound according to claim 62 where phenyl is substituted with two —

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

64. A compound according to claim 58 where R₂ is —

H.

65. A compound according to claim 58 where R₂ is C₁-C₆ alkyl.

66. A compound according to claim 58 where R₂ is —

(CH₂)—

R_1-aryl where R_1-aryl is phenyl.

67. A compound according to claim 58 where PROTECTING GROUP is t-butoxycarbonyl.

68. A compound according to claim 58 where PROTECTING GROUP is benzyloxycarbonyl.

69. A compound according to claim 58 where RN is:

(I) R_N-1—

X_N—

where X_N is;

(A) —

O—

, or

(B) —

SO₂—

,

where R_N-1 is;

(A) R_N-aryl, or

(B) —

R_N-heteroaryl,

(V) —

CO—

CH(—

(CH₂)_0-2—

O—

R_N-10)—

(CH₂)_0-2—

R_N-aryl/R_N-heteroaryl).

70. A compound according to claim 69 where R_N is:

(I) R_N-1—

X_N—

where X_N is

(A) —

CO—

,

where R_N-1 is;

(A) R_N-aryl, and

(B) —

R_N-heteroaryl.

71. A compound according to claim 70 where R_N is:

(a) R_N-1X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl where R_N-aryl is phenyl substituted with one —

CO—

NR_N-2R_N-3 where the substitution on phenyl is 1,3- and where R_N-2 and R_N-3 are the same and are C₃ alkyl

(b) R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl where R_N-aryl is phenyl substituted with one C₁ alkyl and with one —

CO—

NR_N-2R_N-3 where the substitution on the phenyl is 1,3,5- and where R_N-2 and R_N-3 are the same and are C₃ alkyl.

72. A compound according to claim 58 which is N-{2-(3,5-Difluorophenyl)-(1S, 2S, 4R)-[1-(4-ethyl-5-oxotetrahydrofuran-2-yl)]ethyl}-N′

,N′

-dipropylisophthalamide.

30. A compound of the formula

31. A compound according to claim 30 where where R₁ is —

CH₂-phenyl, where phenyl is substituted with two —

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

32. A compound according to claim 30 where PROTECTING GROUP is t-butoxycarbonyl.

33. A compound according to claim 30 where PROTECTING GROUP is benzyloxycarbonyl.

34. A compound according to claim 30 which is:

(L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester,

(L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acid tert-butyl ester,

(L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acid tert-butyl ester,

(L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)-ethyl]-carbamic acid benzyl ester,

(L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acid benzyl ester, or

(L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acid benzyl ester.

35. An epoxide compound of the formula

36. An epoxide compound of formula (VI) according to claim 35 where R₁ is:

(B) —

(CH₂)_n1—

(R_1-heteroaryl).

37. An epoxide compound of formula (VI) according to claim 36 where n₁ is 1.

38. An epoxide compound of formula (VI) according to claim 35 where R₁ is:

(C) —

(CH₂)_n1—

(R_{1-heterocycle}).

39. An epoxide compound of formula (VI) according to claim 38 where n₁ is 1.

40. An epoxide compound of formula (VI) according to claim 35 where phenyl is substituted in the 3- and 5-positions giving 3,5-difluorophenyl.

41. An epoxide compound of formula (VI) according to claim 35 where PROTECTING GROUP is t-butoxycarbonyl.

42. An epoxide compound of formula (VI) according to claim 35 where PROTECTING GROUP is benzyloxycarbonyl.

43. An epoxide compound of formula (VI) according to claim 35 which is

(1S, 2R)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic acid tert-butyl ester,

or (1S, 2R)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic acid benzyl ester.

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

74. A method of treatment according to claim 73 where the disease is Alzheimer'"'"'s disease.

75. A method of treatment according to claim 73 where the disease is Down'"'"'s syndrome.

76. A method of treatment according to claim 73 where the disease is Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.

77. A method of treatment according to claim 73 where the disease is cerebral amyloid angiopathy,

78. A method of treatment according to claim 73 where the disease is degenerative dementias.

79. A method of treatment according to claim 73 where the disease is dementia associated with Parkinson'"'"'s disease.

80. A method of treatment according to claim 73 where the method is treating a disease or condition that already exists.

81. A method of treatment according to claim 73 where the method is preventing a disease or condition from developing.

82. A method of treatment according to claim 73 where 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.

83. A method of treatment according to claim 73 where the therapeutically effective amount is 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.

84. A method of treatment according to claim 73 where the therapeutically effective amount for oral administration is from about 5 mg/day to about 50 mg/day.

88. A method of treatment according to claim 73 where R₁ is:

—

CH₂—

(R_1-aryl) where R_1-aryl is phenyl.

89. A method of treatment according to claim 88 where R₁ is:

—

CH₂—

(R_1-aryl) where R_1-aryl is phenyl substituted with two —

F.

90. A method of treatment according to claim 89 where phenyl is substituted with two —

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

91. A method of treatment according to claim 73 where R₂ is:

(I) —

H,

(II) C₁-C₆ alkyl, or

(III) —

(CH₂)_0-4—

R_2-1 where R_2-1 is R_1-aryl.

92. A method of treatment according to claim 73 where R₂ is:

(I) C₁-C₆ alkyl, or

(III) benzyl.

93. A method of treatment according to claim 73 where R_N is

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl where R_N-aryl is phenyl substituted with one —

CO—

NR_N-2R_N-3 where the substitution on phenyl is 1,3-.

94. A method of treatment according to claim 73 where R_N-2 and R_N-3 are the same and are C₃ alkyl.

95. A method of treatment according to claim 73 where R_N is

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl where R_N-aryl is phenyl substituted with one C₁ alkyl and with one —

CO—

NR_N-2R_N-3 where the substitution on the phenyl is 1,3,5-.

96. A method of treatment according to claim 95 where R_N-2 and R_N-3 are the same and are C₃ alkyl.

97. A method of treatment according to claim 73 where R_N is

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-heteroaryl where R_N-heteroaryl is substituted with one —

CO—

NR_N-2R_N-3.

98. A method of treatment according to claim 73 where R_N-2 and R_N-3 are the same and are —

C₃ alkyl.

99. A method of treatment according to claim 73 where R_N is:

A-X_N—

where X_N is —

CO—

, where A is;

(C) C₁₀H₇—

CH(OH)—

, or

(D) t-butoxy.

100. A method of treatment according to claim 73 where R_C is:

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_C-heteroaryl,

(VII) —

(CH₂)_0-4—

R_{C-heterocycle},

(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 or two;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br or —

I,

(D) C₁-C₃ alkoxy,

(E) —

OCF₃, or

(XVIII) —

H.

101. A method of treatment according to claim 100 where R_C is:

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl where R_C-aryl is phenyl.

102. A method of treatment according to claim 101 where phenyl substituted in the 3-position or 3,5-positions.

103. A method of treatment according to claim 100 where R_C is:

(VI) —

CH₂—

R_C-heteroaryl,

104. A method of treatment according to claim 100 where R_C is:

(VII) —

CH₂—

R_{C-heterocycle.}

105. A method of treatment according to claim 100 where R_C is:

(X) -cyclohexyl ring fused to a phenyl ring.

106. A method of treatment according to claim 73 where R_C is:

(I) —

(C₁-C₁₀)alkyl-K_1-3 where each K is;

(1) H,

(11) carboxyl,

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

or

(18) carboxyl methyl ester;

(II) —

(CH₂)_0-3-J-[—

K]_1-3, where J is;

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

(B) a 5 to 10 atom multicyclic cycloalkyl group,

and each K is;

(1) H,

(3) C₁-C₃ alkoxy, or

(11) carboxyl,

(III) —

(CH₂)_0-3—

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

(B) —

CO—

OH,

(C) —

CO—

O—

(C₁-C₄ alkyl), or

(E) C₁-C₆ alkoxy,

(IV) —

(CH₂)_2-6—

OH,

(V) —

(CH₂)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4R_C-heteroaryl,

(VII) —

(CH₂)_0-4—

R_{C-heterocycle}, or

(XVIII) —

(C₂-C₈) alkynyl.

107. A method of treatment according to claim 73 where R_C is:

(I) —

(C₁-C₁₀)alkyl-K where K is H, carboxyl, carboxyl methyl ester, amino unsubstituted or substituted with C₁-C₆ alkyl,

(II) a benzyl or phenylpropyl group substituted with a carboxyl group,

(III) —

(CH₂)_0-3—

(C₃-C₇) cycloalkyl where cycloalkyl is cyclohexyl, cyclohexyl substituted with 1 or 2 carboxyl groups, or cyclohexyl substituted with 1 or 2 alkoxy groups,

(V) —

(CH₂)_0-4-phenyl substituted or unsubstituted with F,

(VI) —

(CH₂)_0-4-heteroaryl, or

(VII) selected from —

(CH₂)_0-4-morpholinyl and —

(CH₂)_0-4-tetrahydrofuryl.

108. A method of treatment according to claim 73 where R_C is:

(I) C₅H₁₀—

K or C₇H₁₄—

K where K is carboxyl or carboxyl methyl ester,

(II) a benzyl or phenylpropyl group substituted with a carboxyl group at the 5-position, or

(III) a cyclohexyl ring substituted at the 3- and 5-positions or at the 4-position with a carboxyl group.

109. A method of treatment according to claim 73

where R₁ is:

(1) C₁-C₅ alkyl,

(II) —

(CH₂)_1-2—

S—

CH₃,

(IV) C₁-C₅ alkenyl,

(V) —

(CH₂)_0-3—

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

(VI) —

(CH₂)_0-3—

(R_1-heteroaryl) where R_1-heteroaryl is as defined above, wherein any of the above are unsubstituted or substituted with up to two C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, or —

CF₃;

where R₂ is;

(I) —

H,

(II) C₁-C₆ alkyl, or

(III) —

(CH₂)_0-3—

R_2-1 where R_2-1 is (C₃-C₆)cycloalkyl, R_1-aryl or R_1-heteroaryl where R_1-aryl is a 5 or 6-membered aryl group and R_1-heteroaryl is as defined above;

where R_N is;

(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;

where R_C is;

(I) —

(C₁-C₁₀)alkyl-K_1-3

(E) the alkyl chain optionally contains a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,

(F) each K is;

(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) carboxyl methyl ester;

(II) —

(CH₂)_0-3-J-[(—

(CH₂)_0-3—

K]_1-3 where K is;

(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) carboxyl methyl ester;

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 monocyclic heterocyclic group,

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

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

where B is O or NH.

110. A method of treatment according to claim 73 where the pharmaceutically acceptable salt is a salt of hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic, CH₃—

(CH₂)_n—

COOH where n is 0 thru 4, HOOC—

(CH₂)n—

COOH where n is as defined above, HOOC—

CH═

CH—

COOH and φ

-COOH acid or triethanolamine, N-methylglucamine, diethanolamine, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, or carbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali or alkaline earth metal.

111. A method of treatment according to claim 73 wherein said compound is:

N-[(1S, 25, 4R)-1-(3,5-Difluorobenzyl)-4-(syn, syn)-(3,5-dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide,

6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid,

5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-pentanoic acid,

4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyric acid,

3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionic acid,

8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoic acid,

8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester,

N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)₄—

(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide,

4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(5)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, or

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methy-N,N-dipropyl-isophthalamide.

112. A method of treatment according to claim 73 wherein said compound is:

85. A method of treatment according to 73

where R₁ is:

(V) —

(CH₂)_0-3—

(R_1-aryl), or

(VI) —

(CH₂)_n1—

R_1-heteroaryl)

where R_N is;

(I) R_N-1—

X_N—

where X_N is;

(A) —

CO—

, or

(B) —

SO₂—

,

where R_N-1 is;

(A) R_N-aryl, or

(B) —

R_N-heteroaryl,

(VI) —

CO—

CH(—

(CH₂)_0-2—

O—

R_N-10)—

(CH₂)_0-2—

R_N-aryl/R_N-heteroaryl)

where R_C is;

(I) —

C₁-C₈ alkyl,

(III) —

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

(IV) —

(CH₂)_0-3—

OH,

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_{C-heteroaryl,}

(VII) —

(CH₂)_0-4—

R_{C-heterocycle},

(VIII) —

C(R_C-1)(R_C-2)—

CO—

NH—

R_C-3, or

(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 or two;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br or —

I,

(D) C₁-C₃ alkoxy, or

(E) —

OCF_3.

86. A method of treatment according to claim 85

where R₁ is:

(V) —

CH₂—

(R_1-aryl), or

(VI) —

CH₂—

(R_1-heteroaryl);

where R₂ is —

H;

where R_N is;

(I) R_N-1—

X_N—

where X_N is;

(A) —

CO—

,

where R_N-1 is;

(A) R_N-aryl, or

(B) —

R_N-heteroaryl,

where R_C is;

(III) —

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_{C-heteroaryl,}

(VII) —

(CH₂)_0-4—

R_{C-heterocycle},

(VIII) —

C(R_C-1)(R_C-2)—

CO—

NH—

R_C-3, or

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.

87. A method of treatment according to claim 86 where R_C is:

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_C-heteroaryl, or

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.

113. A pharmaceutical composition which comprises a compound of formula

114. The pharmaceutical composition of claim 113

where R₁ is:

(V) —

(CH₂)_0-3—

(R_1-aryl), or

(VI) —

(CH₂)_n1—

(R_1-heteroaryl)

where R_N is;

(I) R_N-1—

X_N—

where X_N is;

(A) —

CO—

, or

(B) —

SO₂—

,

where R_N-1 is;

(A) R_N-aryl, or

(B) —

R_N-heteroaryl,

(VI) —

CO—

CH(—

(CH₂)_0-2—

O—

R_N-10)—

(CH₂)_0-2—

R_N-aryl/R_N-heteroaryl)

where R_C is;

(I) —

C₁-C₈ alkyl,

(III) —

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

(IV) —

(CH₂)_0-3—

OH,

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_{C-heteroaryl,}

(VII) —

(CH₂)_0-4—

R_{C-heterocycle},

(VIII) —

C(R_C-1)(R_C-2)—

CO—

NH—

R_C-3, or

(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 or two;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br or —

I,

(D) C₁-C₃ alkoxy, or

(E) —

OCF_3.

115. The pharmaceutical composition of claim 113

where R₁ is:

(V) —

CH₂—

(R_1-aryl), or

(VI) —

CH₂—

(R_1-heteroaryl);

where R₂ is —

H;

where R_N is;

(I) R_N-1—

X_N—

where X_N is;

(A) —

CO—

,

where R_N-1 is;

(A) R_N-aryl, or

(B) —

R_N-heteroaryl,

where R_C is;

(III) —

(CH₂)_0-3—

(C₃-C₇) cycloalkyl,

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_{C-heteroaryl,}

(VII) —

(CH₂)_0-4—

R_{C-heterocycle},

(VIII) —

C(R_C-1)(R_C-2)—

CO—

NH—

R_C-3, or

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.

116. The pharmaceutical composition of claim 113 where R_C is:

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_C-heteroaryl, or

(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.

117. The pharmaceutical composition of claim 113 where R₁ is:

—

CH₂—

(R_1-aryl) where R_1-aryl is phenyl.

118. The pharmaceutical composition of claim 113 where R₁ is:

—

CH₂—

(R_1-aryl) where R_1-aryl is phenyl substituted with two —

F.

119. The pharmaceutical composition of claim 113 where phenyl is substituted with two —

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

120. The pharmaceutical composition of claim 113 where R₂ is:

(I) —

H,

(II) C₁-C₆ alkyl, or

(III) —

(CH₂)_0-4—

R_2-1 where R_2-1 is R_1-aryl.

121. The pharmaceutical composition of claim 113 where R₂ is:

(II) C₁-C₆ alkyl, or

(III) benzyl.

122. The pharmaceutical composition of claim 113 where R_N is

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl where R_N-aryl is phenyl substituted with one —

CO—

NR_N-2R_N-3 where the substitution on phenyl is 1,3-.

123. The pharmaceutical composition of claim 113 where R_N-2 and R_N-3 are the same and are C₃ alkyl.

124. The pharmaceutical composition of claim 113 where R_N is

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-aryl where R_N-aryl is phenyl substituted with one C₁ alkyl and with one —

CO—

NR_N-2R_N-3 where the substitution on the phenyl is 1,3,5-.

125. The pharmaceutical composition of claim 113 where R_N-2 and R_N-3 are the same and are C₃ alkyl.

126. The pharmaceutical composition of claim 113 where R_N is

R_N-1—

X_N—

where X_N is —

CO—

, where R_N-1 is R_N-heteroaryl where R_N-heteroaryl is substituted with one —

CO—

NR_N-2R_N-3.

127. The pharmaceutical composition of claim 113 where R_N-2 and R_N-3 are the same and are —

C₃ alkyl.

128. The pharmaceutical composition of claim 113 where R_N is:

A-X_N—

where X_N is —

CO—

, where A is;

(C) C₁₀H₇—

CH(OH)—

, or

(D) t-butoxy.

129. The pharmaceutical composition of claim 113 where R_C is:

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_C-heteroaryl,

(VII) —

(CH₂)_0-4—

R_{C-heterocycle},

(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 or two;

(A) C₁-C₃ alkyl,

(B) —

CF₃,

(C) —

F, Cl, —

Br or —

I,

(D) C₁-C₃ alkoxy,

(E) —

OCF₃, or

(XVIII) —

H.

130. The pharmaceutical composition of claim 113 where R_C is:

(V) —

(CR_C-xR_C-y)_0-4—

R_C-aryl where R_C-aryl is phenyl.

131. The pharmaceutical composition of claim 113 where phenyl substituted in the 3-position or 3,5-positions.

132. The pharmaceutical composition of claim 113 where R_C is:

(VI) —

CH₂—

R_C-heteroaryl,

133. The pharmaceutical composition of claim 113 where R_C is:

(VII) —

CH₂—

R_{C-heterocycle.}

134. The pharmaceutical composition of claim 113 where R_C is:

(X) -cyclohexyl ring fused to a phenyl ring.

135. The pharmaceutical composition of claim 113 where R_C is:

(I) —

(C₁-C₁₀)alkyl-K_1-3 where each K is;

(1) H,

(11) carboxyl,

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

or

(18) carboxyl methyl ester;

(II) —

(CH₂)_0-3-J-[—

K]_1-3, where J is;

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

(B) a 5 to 10 atom multicyclic cycloalkyl group,

and each K is;

(1) H,

(3) C₁-C₃ alkoxy, or

(11) carboxyl,

(III) —

(CH₂)_0-3—

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

(B) —

CO—

OH,

(C) —

CO—

O—

(C₁-C₄ alkyl), or

(E) C₁-C₆ alkoxy,

(IV) —

(CH₂)_2-6—

OH,

(V) —

(CH₂)_0-4—

R_C-aryl,

(VI) —

(CH₂)_0-4—

R_C-heteroaryl,

(VII) —

(CH₂)_0-4—

R_{C-heterocycle}, or

(XVIII) —

(C₂-C₈) alkynyl.

136. The pharmaceutical composition of claim 113 where R_C is:

(I) —

(C₁-C₁₀)alkyl-K where K is H, carboxyl, carboxyl methyl ester, amino unsubstituted or substituted with C₁-C₆ alkyl,

(II) a benzyl or phenylpropyl group substituted with a carboxyl group,

(III) —

(CH₂)_0-3—

(C₃-C₇) cycloalkyl where cycloalkyl is cyclohexyl, cyclohexyl substituted with 1 or 2 carboxyl groups, or cyclohexyl substituted with 1 or 2 alkoxy groups,

(V) —

(CH₂)_0-4-phenyl substituted or unsubstituted with F,

(VI) —

(CH₂)_0-4-heteroaryl, or

(VII) selected from —

(CH₂)_0-4-morpholinyl and —

(CH₂)_0-4-tetrahydrofuryl.

137. The pharmaceutical composition of claim 113 where R_c is:

(I) C₅H₁₀—

K or C₇H₁₄—

K where K is carboxyl or carboxyl methyl ester,

(II) a benzyl or phenylpropyl group substituted with a carboxyl group at the 5-position, or

(III) a cyclohexyl ring substituted at the 3- and 5-positions or at the 4-position with a carboxyl group.

138. The pharmaceutical composition of claim 113

where R₁ is:

(I) C₁-C₅ alkyl,

(II) —

(CH₂)_1-2—

S—

CH₃,

(IV) C₁-C₅ alkenyl,

(V) —

(CH₂)_0-3—

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

(VI) —

(CH₂)_0-3—

(R_1-heteroaryl) where R₁ heteroaryl is as defined above, wherein any of the above are unsubstituted or substituted with up to two C₁-C₃ alkyl, —

F, —

Cl, —

Br, —

I, or —

CF₃;

where R₂ is;

(I) —

H

(II) C₁-C₆ alkyl, or

(III) —

(CH₂)_0-3—

R_2-1 where R_2-1 is (C₃-C₆)cycloalkyl, R_1-aryl or R_1-heteroaryl where R_1-aryl is a 5 or 6-membered aryl group and R_1-heteroaryl is as defined above;

where R_N is;

(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;

where R_C is;

(I) —

(C₁-C₁₀)alkyl-K_1-3

(E) the alkyl chain optionally contains a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,

(F) each K is;

(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) carboxyl methyl ester;

(II) —

(CH₂)_0-3-J-[(—

(CH₂)_0-3—

K]_1-3 where K is;

(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) carboxyl methyl ester;

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 monocyclic heterocyclic group,

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

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

where B is O or NH.

139. The pharmaceutical composition of claim 113 where the pharmaceutically acceptable salt is a salt of hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic, CH₃—

(CH₂), —

COOH where n is 0 thru 4, HOOC—

(CH₂)_n—

COOH where n is as defined above, HOOC—

CH═

CH—

COOH and φ

-COOH acid or triethanolamine, N-methylglucamine, diethanolamine, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, or carbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali or alkaline earth metal.

140. The pharmaceutical composition of claim 113 wherein said compound is:

N-[(1S, 2S, 4R)-1-(3,5-Difluorobenzyl)-4-(syn, syn)-(3,5-dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide,

6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid,

5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S-hydroxyhexanoylamino]-pentanoic acid,

4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyric acid,

3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionic acid,

8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoic acid,

8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester,

N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide,

4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid,

4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-(2-Diethylamino-ethylcarbamoyl) 1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, or

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methy-N,N-dipropyl-isophthalamide.

141. The pharmaceutical composition of claim 113 wherein said compound is: