Alzheimer's Disease (AD) is characterised by the abnormal deposition of amyloid in the brain in the form of extra-cellular plaques and intra-cellular neurofibrillary tangles. The rate of amyloid accumulation is a combination of the rates of formation, aggregation and egress from the brain. It is generally accepted that the main constituent of amyloid plaques is the 4kD amyloid protein (pA4, also referred to as AD, 0-protein and (3AP) which is a proteolytic product of a precursor protein of much larger size. The ragged NH2-and COOH-termini of the native AP amyloid indicates that a complex mechanism of proteolysis is involved in its biogenesis.

The amyloid precursor protein (APP or AßPP) has a receptor-like structure with a large ectodomain, a membrane spanning region and a short cytoplasmic tail. Different isoforms of APP result from the alternative splicing of three exons in a single gene and have 695, 751 and 770 amino acids respectively.

The Ap domain encompasses parts of both extra-cellular and transmembrane domains of APP, thus its release implies the existence of two distinct proteolytic events to generate its NH2-and COOH-termini. At least two secretory mechanisms exist which release APP from the membrane and generate the soluble, COOH-truncated forms of APP (APPs). Proteases which release APP and its fragments from the membrane are termed"secretases". Most APPs is released by a putative a- secretase which cleaves within the A (3 domain (between residues Lysl6 and Leul7) to release a-APPs and precludes the release of intact AP. A minor portion of APPs is released by a (3-secretase, which cleaves near the NH2-

terminus of AD and produces COOH-terminal fragments (CTFs) which contain the whole AD domain. Finding these fragments in the extracellular compartment suggests that another proteolytic activity (y- secretase) exists under normal conditions which can generate the COOH- terminus of AD.

It is believed that y-secretase itself depends for its activity on the presence of presenilin-1. In a manner that is not fully understood presenilin-1 appears to undergo autocleavage.

The compounds of the present invention are useful for treating AD by inhibiting the activity of the putative y-secretase thus preventing the formation of insoluble Ap and arresting the production of A (3. Further, some of the present compounds also stabilise full-length presenilin-1.

In a further aspect some of the compounds of the present application are useful as inhibitors of presenilin-1 cleavage.

The compounds of the present invention are related to HIV protease inhibitors described in EP-A-337 714 and EP-A-356 223, both in the name of Merck & Co., Inc.. These compounds are aspartyl protease inhibitors.

Specifically, a subset of the compounds of the present invention differ from those previously described by the stereochemistry of a hydroxyl group which is a particularly preferred feature of the present invention and has not previously been disclosed for these particular compounds. This is a surprising feature giving rise to the present invention.

The present invention, in one aspect, provides a compound comprising the group : wherein R2 and R3 are as defined below, which compound is a diastereoisomer of a known protease inhibitor comprising the group

wherein R2 and R3 are as defined below.

The present invention accordingly provides a compound of formula I or a pharmaceutically acceptable salt thereof : (I) wherein : R1 is (1) C1-10alkyl, C2-10alkenyl or C2-loalkynyl optionally substituted with one to three substituents independently chosen from : (i) hydroxy ; (ii) carboxy ; (iii) halogen ; (iv) Ci-4alkoxy ; (v) Cl-4alkoxycarbonyl ; (vi)-NR6R7 wherein R6 and R7 are independently chosen from hydrogen, C1 alkyl and Cl-salkoxyCl-5alkyl ; (vii)-CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above ; (viii)-N (R8) QR9 wherein : Q is C (O), C (S), S02 or C (NH2) ;

R8 is hydrogen or Ci-4alkyl ; and R9 is hydrogen, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino di (C1-4alkyl) amino wherein each alkyl group is independently chosen ; (ix) C3 7cycloalkyl ; (x) phenyl or naphthyl ; a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S ; a six-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms ; each of which is optionally substituted by one to three groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) C1 4alkyl, C2 4alkenyl and C2-4alkynyl, (d) C1 4alkoxy, (e) NR6R7 wherein R6 and R7 are independently as defined above, (f) CO2R8 wherein R8 is independently as defined above, (g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above, (h) SO2NR6R7 wherein R6 and R7 are independently as defined above, (i) CH2NR6R7 wherein R6 and R7 are independently as defined above, (j) N (RS) CORS wherein Rs is independently as defined above and R8 is independently as defined for R8, and (k) NR8SO2R8 wherein R8 and R8 are independently as defined above ; or (2) phenyl or naphthyl ; a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S ; a six-membered

heterocyclic ring containing 1, 2 or 3 nitrogen atoms ; each of which is optionally substituted by one to three groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) Cl 4alkyl, C2 4alkenyl and C2-4alkynyl, (d) C1-4alkoxy, (e) NR6R7 wherein R6 and R7 are independently as defined above, (f) COzRS wherein R8 is independently as defined above, (g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above, (h) S02NR6R7 wherein R6 and R7 are independently as defined above, (i) CH2NR6R7 wherein R6 and R7 are independently as defined above, (j) N (R8) COR8' wherein R8 and R8 are independently as defined above, and (k) NR8SO2R8 wherein R8 and R8 are independently as defined above ; R2 and R3 are independently chosen from Ci-loalkyl, Ci-ioalkoxy, C2-loalkenyl, C2-ioalkenyloxy, C2-loalkynyl or C2-loalkynyloxy ; phenyl ; naphthyl ; a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S ; a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms ; and a group (CH2) pQl wherein Q1 is phenyl, naphthyl, a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S, and a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms ; and wherein each of R2 and R3 is

independently optionally substituted by one to three groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) C1-3alkyl, C2-s alkenyl and C2-3alkynyl, (d) C1 3alkoxy, (e) NR6R7 wherein R6 and R7 are independently as defined above, (f) CO2R8 wherein R8 is independently as defined above, (g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above, (h) SOzNR6R7 wherein R6 and R7 are independently as defined above, (i) CH2NR6R7 wherein R6 and R7 are independently as defined above, (j) N (R8) COR8 wherein R8 and R8 are independently as defined above, (k) NR8SO2R8 where R8 and R8 are independently as defined above ; alternatively R3 may be hydrogen ; R4 and R5 are independently chosen from hydrogen, Cl 6alkyl optionally substituted by halogen, hydroxy, thiol, amino, C1-4alkoxy, C1-4 alkylthio, carboxy, C1-4 alkoxycarbonyl and (CH2) qQ2 wherein Q2 is a five- membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatom optionally chosen from O, N, and S providing that not more than one heteroatom is O or S, a six-membered unsaturated heterocycle containing 1, 2 or 3 N atoms and phenyl and naphthyl, or a fused ring which is indolyl, each of the foregoing rings being optionally substituted with one to three groups independently chosen from hydroxy, C1-4alkyl, C1-4alkoxy, thiol, C1 4alkylthio, halogen, amino, carboxy, amido, CO2H and

-NHC (NH2) 2 and wherein each of the foregoing rings is optionally fused to a benzene ring ; and A is : (1) hydrogen ; (2) Ci-loalkyl, C2-loalkenyl or C2-loalkynyl optionally substituted with one to three substituents independently chosen from : (i) hydroxy ; (ii) carboxy ; (iii) halogen ; (iv) Cl 4alkoxy ; (v) Cl 4alkoxycarbonyl ; (vi)-NR6R7 wherein R6 and R7 are independently chosen from hydrogen, C1 alkyl and C1-salkoxyCl-salkyl ; (vii)-CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above ; (viii)-N (R8) QR9 wherein : Q is C (O), C (S), SO2 or C (NH2) ; R8 is hydrogen or C1 4alkyl ; and R9 is hydrogen, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino di (Ci-4alkyl) amino wherein each alkyl group is independently chosen ; (ix) Cs-7cycloalkyl ; (x) phenyl or naphthyl ; a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S ; a six-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms ; each of which is optionally substituted by one to three groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,

(d) C1 4alkoxy, (e) NR6R7 wherein R6 and R7 are independently as defined above, (f) CO2R8 wherein R8 is independently as defined above, (g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above, (h) SO2NR6R7 wherein R6 and R7 are independently as defined above, (i) CH2NR6R7 wherein R6 and R7 are independently as defined above, (j) N (R8) COR8 wherein R8 is independently as defined above and R8 is independently as defined for R8, and (k) NR8SO2R8 wherein R8 and R8 are independently as defined above ; or (3) a seven-membered heterocycle -having an otherwise unsubstituted carbon atom at the point of attachment to the rest of the compound of formula I, -having at a first atom alpha to the point of attachment a carbon atom which is unsubstituted or substituted by an oxygen or sulphur atom, -having at a first atom beta to the point of attachment, which atom is alpha to the foregoing first atom alpha, a carbon atom or a nitrogen atom, -having at a second atom alpha to the point of attachment a carbon atom, which is optionally substituted by oxygen, or a nitrogen atom, -having at a second atom beta to the point of attachment, which atom is alpha to the foregoing second atom alpha, a carbon atom or a nitrogen atom, and having at the two remaining atoms carbon atoms ;

-a double bond may be present between the second atom alpha and the second atom beta ; -the seven-membered heterocycle may be fused to one or two aromatic rings via any adjacent pair of atoms other than the point of attachment and the first atom alpha alone or in combination ; -the aromatic ring may be benzene or a five-membered heterocycle containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S providing that not more than one heteroatom is O or S or a six-membered heterocycle containing 1, 2 or 3 nitrogen atoms ; -alternatively a pair of adjacent carbon atoms in the seven- membered heterocycle, other than the point of attachment and the first atom alpha alone or in combination, may form part of a fused cyclopropyl or cyclopentyl ring ; -one to three substitutable atoms of the seven-membered heterocycle are optionally substituted by : an aromatic ring as defined above optionally substituted by hydroxy, halogen, methoxy or alkyl having one to four carbon atoms ; an alkyl group having one to four carbon atoms optionally substituted by a halogen atom, hydroxy, an aromatic ring as defined above optionally substituted by hydroxy, halogen, methoxy or alkyl having one to four carbon atoms, cycloalkyl having three to seven carbon atoms, methoxy, bicycloalkyl having seven to twelve carbon atoms, heterocycle having five to seven atoms one of which is oxygen, nitrogen or sulphur which is optionally oxidized ; a heterocycle having five to seven atoms one of which is oxygen, nitrogen or sulphur which is optionally oxidized ; cycloalkyl having three to seven carbon atoms ; or bicycloalkyl having seven to twelve carbon atoms ;

or the two groups A attached to the same nitrogen atom, together with that atom, form : a five-membered heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms chosen from O, N and S, not more than one of the heteroatoms being O or S ; or a six-membered heterocyclic ring optionally containing 1 or 2 further nitrogen atoms ; each of which is optionally substituted by one to three groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) C1 4alkyl, C2 4alkenyl and C2-4alkynyl, (d) C1-4alkoxy, (e) NR6R7 wherein R6 and R7 are independently as defined above, (f) COzRS wherein R8 is independently as defined above, (g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above, (h) S02NR6R7 wherein R6 and R7 are independently as defined above, (i) CH2NR6R7 wherein R6 and R7 are independently as defined above, (j) N (R8) COR8 wherein R8 is independently as defined above and R8 is independently as defined for R8, and (k) NR8SO2R8 wherein R8 and R8 are independently as defined above ; B is C=O or CHOH in the R configuration ; X is oxygen or a bond ; n is zero or one, and p is zero, one, two or three ; and q is zero, one, two or three ;

with the proviso that no carbon atom is substituted by more than one hydroxy group.

In an embodiment the compounds of the present invention are of formula I :

(I') where R1, R2, R3, R4, R5, A and n are as defined above.

In one embodiment the compounds of the present invention are of formula I":

where R1, R2, R3, R4, R5, A and n are as defined above.

In another embodiment there are provided compounds of formula I"':

where R1, R2, R3, R4 and R5 are as defined above.

The following preferred definitions of substituents apply to each of the formulae I, I', I"and I"'which refer to those substituents.

Preferably RI is (1) C1-10alkyl, C2-10alkenyl or C2-10alkynyl optionally substituted with one to three substituents independently chosen from : (i) hydroxy ; (ii) halogen ; (iii) amino ; (iv) C1 4alkoxy ; and (v) phenyl which is optionally substituted by one or two groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) C1-4alkyl, C2-4alkenyl and C2-4alkenyl, (d) C1-4alkoxy, and (e) amino ; or (2) phenyl which is optionally substituted by one or two groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) C1 4alkyl, C2 4alkenyl and C2 4alkynyl, (d) C1 4alkoxy and (e) amino.

When Rl is a heterocyclic ring it may be saturated, partially saturated or unsaturated. Preferably the heterocyclic ring is a heteroaromatic ring.

More preferably R1 is C1 loalkyl optionally substituted with up to three substituents as defined above. Even more preferably R1 is C1-ealkyl optionally substituted by one to three substituents as defined above. Most preferably RI is C1 6alkyl optionally substituted by halogen, phenyl, hydroxy or C1 4alkoxy. In particular RI may be tertiary butyl or benzyl.

R2 and R3 may be independently chosen from phenyl ; naphthyl ; a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S ; a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms ; and a group (CH2) pQ' wherein Q1 is phenyl ; naphthyl ; a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S ; and a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms ; and wherein each of R2 and R3 is independently optionally substituted by one to three groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) Cl 3alkyl, C2 3alkenyl and C2-3alkynyl, (d) Cl 3alkoxy, (e) NR6R7 wherein R6 and R7 are independently as defined above, (f) CO2R3 wherein R8 is independently as defined above, (g) CONR6R7 wherein R6 and R7 are independently as defined above, (h) SO2NR6R7 wherein R6 and R7 are independently as defined above, (i) CH2NR6R7 wherein R6 and R7 are independently as defined above,

(j) N (RS) CORS wherein Rs and R8' are independently as defined above, (k) NR8SO2R3 where R8 and R8' are independently as defined above ; More preferably R2 and R3 are (CH2) pQl.

Preferably p is one.

Preferably Q1 is phenyl optionally substituted by one or two groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl, (d) C1 4alkoxy and (e) amino.

In one embodiment R2 and R3 are both benzyl.

More preferably Q1 is phenyl.

Preferably R4 and R5 are independently chosen from optionally substituted Cl 6alkyl and (CH2) qQ2. More preferably R4 and R5 are independently chosen from C1 6alkyl and (CH2) qQ2.

Preferably Q2 is optionally substituted phenyl. More preferably Q2 is phenyl.

In particular R4 and R5 are independently chosen from methyl, benzyl, phenyl, 2-methylpropyl, 1-hydroxyethyl, isopropyl and isobutyl.

A is preferably hydrogen or a group

wherein R7 is phenyl, Cl 6alkyl or C3 7cycloalkyl and Y is hydrogen or C1 6 alkyl. More preferably A is hydrogen or a group as defined above wherein R7 is a cyclohexyl group.

X is preferably oxygen. n may be zero. n may be one. p is preferably one. q is preferably zero or one.

Thus a subclass of compounds of formula I and I'is provided wherein : R1 is (1) C1-10alkyl C2-10alkenyl or C2-loalkynyl optionally substituted with one or more substituents independently chosen from : (i) hydroxy ; (ii) halogen ; (iii) amino ; (iv) Cl 4alkoxy ; and (v) phenyl which is optionally substituted by one or two groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) Cl 4alkyl, C2 4alkenyl and C2-4alkynyl, (d) Cl 4alkoxy and (e) amino ; or (2) phenyl which is optionally substituted by one or two groups independently chosen from : (a) halogen, cyano and nitro, (b) hydroxy, (c) C1 4alkyl, C2 4alkenyl and C2 4alkynyl, (d) C1-4 alkoxy and (e) amino ;

R2 and R3 are both (CH2) pQl wherein Ql is phenyl optionally substituted by one or two groups independently chosen from : (a) halogen, (b) hydroxy, (c) Cl 4alkyl, C2 4alkenyl and C2-4alkynyl, (d) C1-4alkoxy, and (e) amino ; R4 and R5 are independently chosen from Cl 6alkyl optionally substituted by halogen, hydroxy, amino or C1-4alkoxy, and (CH2) qQ2 wherein Q2 is phenyl optionally substituted by hydroxy, Cl 4alkyl, C1- 4alkoxy, thiol, C1 4alkylthio, halogen, amino, carboxy, amido, CO2H and- NHC (NH2) 2 ; A is hydrogen or wherein R7 is phenyl, C1-6alkyl or C3 7cycloalkyl ; Y is hydrogen or Cl-6 alkyl ; n is zero or one ; p is one ; and q is zero or one.

For the avoidance of doubt each time the moieties A, R6, R7, R8, R8' and R9 occur more than once in the definition of the compounds of formula (I) they are chosen independently.

As used herein, the expression"Ci-loalkyl"includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl,

isopropyl and t-butyl. Derived expressions such as"Ci-6alkyl","C1-4alkyl", "C2-ioalkenyl","C2-4alkenyl","C2-io alkynyl and"C2-4alkynyl"are to be construed in an analogous manner.

The expression"C3-7cycloalkyl"as used herein includes cyclic propyl, butyl, pentyl, hexyl and heptyl groups such as cyclopropyl and cyclohexyl.

The term"heterocyclic"includes rings which are saturated, partially saturated or unsaturated. Unsaturated heterocyclic rings are also known as heteroaromatic rings.

Suitable 5-and 6-membered heteroaromatic rings include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl and thiadiazolyl groups. A suitable 5-membered heteroaromatic ring containing four nitrogen atoms is tetrazolyl. Suitable 6-membered heteroaromatic rings containing three nitrogen atoms include 1, 2, 4-triazine and 1, 3, 5-triazine.

Suitable saturated heterocyclic rings include piperazine, morpholine, piperidine, tetrahydrofuran and tetrahydrothiophene. Tetrahydrofuran is preferred.

The term"halogen"as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.

As used herein the term"Ci-4alkoxy"includes methoxy and ethoxy groups, and straight-chained, branched and cyclic propoxy and butoxy groups, including cyclopropylmethoxy.

Specific Examples according to the present invention include : {lS-benzyl-4R- [1-(lS-carbamoyl-2-(R)-hydroxypropylcarbamoyl)-(S)- ethylcarbamoyl]-2R-hydroxy-5-phenylpentyl}-carbamic acid, tert-butyl ester ; {lS-benzyl-4R- [l- (lS-carbamoyl-2- (S)-methylbutylcarbamoyl)-lS-2- methylpropylcarbamoyl]-2R-hydroxy-5-phenylpentyl}-carbamic acid, tert- butyl ester ;

{lS-benzyl-4- [l- (5-cyclohexyl-2-oxo-2, 3-dihydro-lH-benzo [e] [1, 4] diazepin- 3 (R, S)-ylcarbamoyl)-(S)-ethylcarbamoyl]-2R-hydroxybutyl}-carbami c acid, tert-butyl ester ; {1S-benzyl-4R- [1- (5-cyclohexyl-2-oxo-2, 3-dihydro-lH-benzo [e] [l, 4] diazepin- 3 (R, S)-ylcarbamoyl)-(S)-ethylcarbamoyl]-2R-hydroxy-5-phenylpenty l}- carbamic acid, tert-butyl ester ; {lS-benzyl-4R- [1-(lS-carbamoyl-2-phenylethylcarbamoyl)-1S-3- methylbutylcarbamoyl]-2R-hydroxy-5-phenylpentyl}-carbamic acid, benzyl ester ; {lS-benzyl-4R- [1- (lS-carbamoyl-2-phenylethylcarbamoyl)-lS-3- methylbutylcarbamoyl]-2-oxo-5-phenylpentyl}-carbamic acid tert-butyl ester ; {lS-benzyl-4R- [1-(lS-carbamoyl-2-phenylethylcarbamoyl)-lS-3-methyl- butylcarbamoyl]-2R-hydroxy-5-phenylpentyl} carbamic acid tert-butyl ester ; {lS-benzyl-4R- [1-(lS-carbamoyl-2-phenylethylcarbamoyl)-S- ethylcarbamoyl]-2R-hydroxy-5-phenylpentyl} carbamic acid tert-butyl ester ; (lS-benzyl-4R-{1S- [(carbamoylphenylmethyl) carbamoyl]-S- ethylcarbamoyl}-2R-hydroxy-5-phenylpentyl) carbamic acid tert-butyl ester ; and the pharmaceutically acceptable salts thereof.

Examples of pharmaceutically acceptable salts are hydrochlorides, sulfates, citrates, tartrates, acetates, methanesulfonates, phosphates, oxalates and benzoates.

The compounds of the present invention have an activity as inhibitors of y secretase. In a preferred embodiment the compounds of the invention inhibit proteolysis of PS-1.

The invention also provides pharmaceutical compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid

sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories ; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e. g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums or surfactants such as sorbitan monooleate, polyethylene glycel, and other pharmaceutical diluents, e. g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0. 1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The present invention also provides a compound of the invention or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human body. Preferably the treatment is for a condition associated with the deposition of P-amyloid. Preferably the condition is a neurological disease having associated P-amyloid deposition such as Alzheimer's disease.

The present invention further provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Alzheimer's disease.

Also disclosed is a method of treatment of a subject suffering from or prone to Alzheimer's disease which comprises administering to that subject an effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

For treating or preventing Alzheimer's Disease, a suitable dosage level is about 0. 01 to 250 mg/kg per day, preferably about 0. 01 to 100 mg/kg per day, and especially about 0. 01 to 5 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, dosage outside these limits may be used.

There is also provided a process for producing a compound of formula I or a pharmaceutically acceptable salt thereof which comprises reacting a compound of formula II with a compound of formula III :

(11) (111) wherein R1, R2, R3, R4, R5, A, X and n are as defined above and P is hydrogen or a protecting group such as a trialkylsilane group, for example t-butyl dimethylsilyl, followed, if necessary, by deprotection of the resulting compound to produce a compound of formula I. The reaction is generally carried out in the presence of coupling agents such as 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1- hydroxybenzotriazole in a solvent such as DMF, generally at about room temperature for six to twelve hours. Any necessary deprotection is achieved by conventional means.

The compound of formula II is produced by reacting a compound of formula IV : (IV) wherein R1, R2, R3 and X are as defined above in a solvent such as dioxane, with a base such as lithium hydroxide in a polar solvent such as water generally at room temperature for above five hours. If desired the resulting compound of formula II in which P is hydrogen is protected by conventional means.

The compound of formula IV is produced by reacting a compound of formula V with a compound of formula VI or a compound of formula VII :

wherein R1, R2 and X are as defined above, R3'is the acyl derivative of a group R3 as defined above and R3"is a group R3 bound to an oxo group at the portion of R3 which connects to the compound of formula V. The reaction is generally carried out in the presence of a base such as lithium diisopropylamide in a solvent such as THF generally cooled to-78°C for about thirty minutes. The reaction mixture is subsequently dehydrated without purification and then hydrogenated with, for example, hydrogen over 5% Pd/C catalyst at about 50 psi for about 2h.

The compound of formula V in which R1 is tertiary butyl and R2 is benzyl can be prepared as described by J. Litera et al., Collect. Czech.

Chem. Commun. 1998, 63, 23 if. Compounds of formula V in which R1 is other than tertiary butyl and R2 is other than benzyl can be made by analogous methods.

Compounds of formulae III and VI are commercially available or known in the prior art or can be made from commercially available or known compounds by standard methods.

Alternatively the compounds of the present invention can be made by the following typical experimental procedure or by methods analogous thereto : TBS FMOC Chemistry m ? (PyBOP couplings) R...// HN-0 10 TBSO Fe R6 0 H) H N R"0, -n O R'O R'i O PyBOP I HOBT Hunig's base NMP B 1-ATFA/DCM 6x10m ! n 6 x iO ml ! n (filtered into NH, MOOH) H H R° TBS Rs \/H BAF/THF R" N-, iw J. N fL H-flr N 1H ORz OR'O ORz OR \O D

in which R1, R2, R3, R4, R5 and n are as defined above and A is hydrogen.

A. 50 mg (0. 030 mmol) of FMOC-Sieber amide resin is placed in a Quest 210 solid phase reactor and treated with Piperidine/DMF (0. 5 mL ; 1 : 1 mixture) with mixing for 30 minutes. The reactor is drained and washed with DMA (10 x 1 mL). 1 mL of a 0. 1 M solution of FMOC- amino acid 1 in DMA is added followed by 0. 2 mL of a DMA mixed solution of HOBT and Hunig's base (0. 5 M in both) and 0. 5 mL of a 0. 2 M solution of PyBOP in DMA. The reactor is mixed for 60 minutes, drained, and washed with DMA (10 x 1 mL). The reactor is treated with Piperidine/DMF (0. 5 mL ; 1 : 1 mixture) and mixed for 30 minutes. The reactor is drained and washed with DMA (10 x 1 mL). 1 mL of a 0. 1 M solution of FMOC-amino acid 2 in DMA is added followed by 0. 2 mL of a DMA mixed solution of HOBT and Hunig's base (0. 5 M in both) and 0. 5 mL of a 0. 2 M solution of PyBOP in DMA. The reactor is mixed for 60 minutes, drained, and washed with DMA (10 x 1 mL). The reactor is treated with Piperidine/DMF (0. 5 mL ; 1 : 1 mixture) and mixed for 30 minutes. The reactor is drained and washed with DMA (10 x 1 mL).

B. 21 mg (0. 04 mmol) of the TBS-protected isostere and 5 mg HOBT in 0. 5 mL NMP is added to the reactor, followed by Hunig's base (50 ! 1L) and 0. 5 M PyBOP in NMP (0. 5 mL). The reactor is mixed for 16 h,

filtered, and washed with DMA (5 x 1 mL), MeOH (2 x 1 mL) and DCE (10 x 1 mL).

C. The reactor is treated with 0. 5 mL of a 1% solution of TFA in DCM and stood for 10 minutes. The reactor is drained into a test tube containing 2 M NH3 in MeOH (1 mL) and the cleavage repeated a further 5 times (identical conditions). The product is concentrated (SpeedVac), dissolved in 1 mL DCM and washed with water (1 mL) using a phase separation CombiTube. The DCM layer is concentrated (SpeedVac) to give essentially pure TBS-protected product.

D. The product is dissolved in 1 M TBAF in THF (0. 5 mL), stood for 7 h, water (2 mL) is added and the product is extracted out with DCM (3 x 1 mL). The product is purified by flash chromatography (5% MeOH/ DCM).

All products are analyzed by analytical LC-MS utilizing diode array detection (210-250 nm) and APcI detection (150-850 amu) using a full 5%- 95% MeCN gradient with 0. 1% aqueous TFA. A strong M+Na+ peak is oberved in the mass spectrum.

It will be understood that any compound of formula I initially obtained from the above process may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art.

It will also be appreciated that where more than one isomer can be obtained from a reaction then the resulting mixture of isomers can be separated by conventional means.

Where the above-described process for the preparation of the compounds according to the invention gives rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973 ; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

A typical assay which can be used to determine the level of activity of compounds of the present invention is as follows : (1) Mouse neuroblastoma neuro 2a cells expressing human app695 are cultured at 50-70% confluency in the presence of sterile lOmM sodium butyrate.

(2) Cells are placed in 96-well plates at 30, 000/well/1001lL in minimal essential medium (MEM) (phenol red-free) + 10% foetal bovine serum (FBS), 50mM HEPES buffer (pH7. 3), 1% glutamin, 0. 2mg/mL G418 antibiotic, lOmM sodium butyrate.

(3) Make dilutions of the compound plate. Dilute stock solution to 5. 5% DMSO/IIOAM compound. Mix compounds vigorously and store at 4°C until use.

(4) Add 10, uL compound/well. Mix plate briefly, and leave for 18h in 37°C incubator.

(5) Remove 90gel of culture supernatant and dilute 1 : 1 with ice-cold 25mM HEPES (pH. 3), 0. 1% BSA, l. OmM EDTA (+ broad spectrum protease inhibitor cocktail ; pre-aliquotted into a 96-well plate). Mix and keep on ice or freeze at-80°C.

(6) Add back 100, uL of warm MEM + 10% FBS, 50mM HEPES (pH7. 3), 1% glutamine, 0. 2mg/mL G418, 10mM sodium butyrate to each well, and return plate to 37°C incubator.

(7) Prepare reagents necessary to determine amyloid peptide levels, for example by ELISA assay (8) To determine if compounds are cytotoxic cell viability following compound administration is assessed by the use of redox dye reduction. A typical example is a combination of redox dye MTS (Promega) and the electron coupling reagent PES. This mixture is made up according to the manufacturer's instructions and left at room temperature.

(9) Quantitate amyloid beta 40 and 42 peptides using an appropriate volume of diluted culture medium by standard ELISA techniques.

(10) Add 15, uL/well MTS/PES solution to the cells ; mix and leave at 37°C.

(11) Read plate when the absorbance values are approximately 1. 0 (mix briefly before reading to disperse the reduced formazan product).

The Examples of the present invention all had an ED5o of less than 500nM, preferably less than 200nM and most preferably less than 100nM in the above assay.

The following examples illustrate the present invention.

EXAMPLE 1 {1S-Benzyl-4R-[1-(1S-carbamoyl-2-(R)-hydroxypropylcarbamoyl) -(S)- ethvlcarbamoyll-2R-hydroxv-5-phenylpentyl}-carbamic acid ter-butyl ester Step 1 : f 1S- (4R-Benzvl-5-oxo-tetrahvdrofuran-2R-vl)-2-phenvlethYll- carbamic acid, tert-butvl ester A solution of [1S- (5-oxo-tetrahydrofuran-2R-yl)-2-phenylethyl]-carbamic acid, tert-butyl ester (prepared as described in J. Litera et al., Collect.

Czech. Chem. Commun. 1998, 63, 231) (3. 0 g, 0. 99 mmol) in THF (10 ml) was added to a solution of lithium diisopropylamide [made from n- butyllithium (8. 64 ml of a 2. 5 M solution in hexane) and diisopropylamine

(3. 06 ml)] in THF (10 ml) at-78 °C. The reaction mixture was stirred for 40 minutes at-78 °C, then treated with benzaldehyde. After 30 minutes, the reaction mixture was quenched by the addition of aqueous NH4Cl (5 ml) and water. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with aqueous citric acid, aqueous NaHCOs solution and brine. The combined extracts were dried (MgSO4), filtered and evaporated in vacuo to give a thick oil. This crude reaction product was treated with acetic anhydride (5 ml), triethylamine (5 ml) and heated at 120 °C for lh. The reaction mixture was cooled to room temperature, diluted with ether and washed with aqueous citric acid, aqueous NaHCOs solution and brine. The ethereal extracts were dried (MgS04) and evaporated in vacuo to give the reaction product as a crude solid which was used without further purification. This crude reaction product was dissolved in ethyl acetate (25 ml) and methanol (5 ml), treated with 5% Pd/C catalyst and hydrogenated at 50 psi for 2h. The reaction mixture was filtered and evaporated in vacuo to give the title compound, which was either purified by flash column chromatography, or by trituration with ether, (yield 3. 9g, 78%). 1H NMR (250 MHz, CDCl3) 7. 38-7. 15 (10 H, m) ; 4. 38-4. 11 (2 H, m), 3. 90 (1 H, brs) ; 3. 27 (1 H, dd, J = 13. 7, 4. 0) ; 2. 95-2. 67 (4 H, m), 2. 28-2. 17 (1 H, m) ; 1. 86-1. 70 (1 H, m) ; 1. 34 (9 H, s).

Step 2 : 2R-Benzyl-5S-tert-butoxvcarbonylamino-4R- (tert- butyldimethvlsilanvloxv)-6-phenvl-hexanoic acid The compound obtained in Step 1 (2. 0g, 5. 1 mmol) was dissolved in 1, 2- dimethoxyethane (36 mL) and treated with a solution of sodium hydroxide in water (1. 0 M, 36mL, 1. 1 equiv.) and stirred at room temperature for 0. 5h. The reaction mixture was carefully acidified to pH 4 with citric acid, then extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgS04), filtered and evaporated in vacuo. The crude hydroxyacid was dissolved in DMF (20mL) and treated with tert-

butyldimethylsilyl chloride (7. 8g, 5 equiv.) and imidazole (4. 2g, 10 equiv.) and stirred overnight. The reaction mixture was treated with methanol and stirred for 2h, then evaporated in vacuo. The reaction mixture was partitioned between aqueous citric acid and ethyl acetate. The organic layer was washed with brine, dried (MgS04), filtered and evaporated in vacuo. Purification by flash column chromatography gave the title compound (2. 55g, 95%) 1H NMR (400 MHz, d6-DMSO) 12. 08 (1 H, s) ; 7. 25- 7. 04 (10 H, m) ; 6. 45 (1 H, d, J = 8. 9) ; 3. 74-3. 53 (2 H, m) ; 2. 76-2. 50 (5 H, m) ; 1. 8-1. 5 (2 H, m) ; 1. 22 (9 H, s) ; 0. 80 (9 H, s) ; 0. 07 (3 H, s) ; 0. 05 (3H, s).

Step 3 : {lS-Benzyl-4R-rl-(lS-carbamovl-2-(R)-hvdroxypropvlcarbamovl) - (S)-ethvlcarbamovll-2R-hydroxv-5-phenvlpentvll-carbamic acid. tert-butyl ester The compound obtained in Step 2 (50 mg), H2N-L-ala-L-thr-CONH2 (20 mg), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22 mg) and 1-hydroxybenzotriazole (15 mg) in DMF was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed with aqueous citric acid, aqueous NaHCOs, brine, dried (MgS04), filtered and evaporated in vacuo.

Purification by flash column chromatography gave the product (40 mg, 60%). This material was dissolved in a solution of tetrabutylammonium fluoride in THF (1. 0 M, 2 ml) and stirred at room temperature overnight.

The reaction mixture was diluted with citric acid and ether and the resulting precipitate was collected by filtration, washed and dried in vacuo to give the title compound. (19 mg, 57%) 1H NMR (360 MHz, d6-DMSO) 8. 02 (1 H, d, J = 6. 8) ; 7. 44 (1 H, d, J = 7. 9) ; 7. 26-7. 08 (12 H, m) ; 6. 51 (1 H, d, J = 8. 9) ; 4. 89 (1 H, brs) ; 4. 67 (1 H, brs) ; 4. 27-4. 23 (2 H, brm) ; 4. 04 (2 H, m) ; 3. 4 (2 H, m) ; 2. 9-2. 4 (4 H, m) ; 1. 60-1. 56 (2 H, m) ; 1. 24-0. 99 (15 H, m).

In the same way as for Step 3 using the appropriate amine the following compounds were also made :

EXAMPLE 2 {1S-Benzyl-4R-[1-(1S-carbamoyl-2-(S)-methylbutylcarbamoyl)-( S)-2- methyl-1-2R-hydroL-5-phenylpentyl)-carbamic acid, tert- butyl ester H NMR (360 MHz, d6-DMSO) 7. 53 (1 H, d, J = 8. 7) ; 7. 42 (1 H, d, J = 8. 7) ; 7. 23-7. 10 (12 H, m) ; 6. 2 (1 H, vbrs) ; 4. 48 (1H, brs) ; 4. 19-4. 09 (2 H, m) ; 3. 56- 3. 52 (2 H, m) ; 2. 91-2. 54 (5 H, m) ; 2. 00-1. 95 (1 H, m) ; 1. 74-1. 61 (3 H, m) ; 1. 46-0. 80 (23 H, m).

EXAMPLE 3 {1S-Benzyl-4-[1-(5-cyclochexyl-2-oxo-2,3-dihydro-1H-benzo[e] [1,4]diazepin- 3 (R, S)-ylcarbamovl)- (S)-ethylcarbamoyll-2R-hvdroxvll-carbamic acid. tert-butyl ester 1H NMR (400 MHz, d6-DMSO) 10. 63 (0. 5 H, s) ; 10. 58 (0. 5 H, s) ; 8. 78 (0. 5 H, d, J = 8. 2) ; 8. 68 (0. 5 H, d, J = 8. 2) ; 7. 96 (1 H, m) ; 7. 73 (1 H, m) ; 7. 55- 7. 51 (1 H, m) ; 7. 28-7. 12 (7 H, m) ; 6. 53-6. 51 (1 H, m) ; 5. 03-5. 00 (1 H, m) ; 4. 77-4. 75 (1 H, m) ; 4. 50-4. 46 (1 H, m) ; 3. 50-3. 40 (1H, m) ; 3. 00-2. 85 (2 H, m) ; 2. 40-0. 80 (28 H, m).

EXAMPLE 4 {1S-Benzyl-4R-[1-(5-cyclochexyl-2-oxo-2,3-dihydro-1H-benzo[e ][1,4]diazepin- 3 3(R,S)-ylcarbamoyl)-(s)-ethylcarbamoyl]-2R-hydroxy-5-phenylp entyl}- carbamic acid tert-butyl ester 1H NMR (400 MHz, d6-DMSO) 10. 65 (0. 5 H, s) ; 10. 60 (0. 5 H, s) ; 8. 62 (0. 5 H, d, J = 8. 2) ; 8. 53 (0. 5 H, d, J = 7. 8) ; 7. 92-7. 88 (1 H, m) ; 7. 76-7. 74 (1 H,

m) ; 7. 54-7. 51 (1 H, m) ; 7. 29-7. 09 (12 H, m) ; 6. 52-6. 48 (1 H, m) ; 5. 00-4. 98 (1 H, m) ; 4. 65-4. 60 (1 H, m) ; 4. 50-4. 40 (1 H, m) ; 3. 51-3. 38 (2 H, m) ; 3. 0-2. 4 (5 H, m) ; 2. 0-1. 1 (25 H, m).

EXAMPLE 5 {1S-Benzyl-4R-[1-(1S-carbamoyl-2-phenylethylcarbamoyl)-1S-3- <BR> <BR> <BR> <BR> methylbutylcarbamovll-2R-hyphenylpentyl}-carbamic acid, benzyl ester 7. 89 (1 H, d, J = 7. 2) ; 7. 65 (1 H, d, J = 7. 2) ; 7. 35-7. 02 (23 H, m) ; 4. 98-4. 78 (3 H, m) ; 4. 44-4. 37 (1 H, m) ; 4. 22-4. 10 (1 H, m) ; 3. 60-3. 52 (1 H, m) ; 3. 52- 3. 42 (1 H, m) ; 3. 02-2. 98 (1 H, m) ; 2. 90-2. 40 (6 H, m) ; 1. 70-1. 20 (5 H, m) ; 0. 81 (3 H, d, J = 6. 5) ; 0. 75 (3 H, d, J = 6. 5).

EXAMPLE 6 {1S-Benzyl-4R-[1-(1S-carbamoyl-2-phenylethylcarbamoyl)-1S-3- methylbutylcarbamovll-2-oxo-5-phenylpentyll-carbamic acid ter-butyl ester {lS-benzyl-4R- [1-(lS-carbamoyl-2-phenylethylcarbamoyl)-lS-3- methylbutylcarbamoyl]-2S-hydroxy-5-phenylpentyl}-carbamic acid tert- butyl ester (S. J. deSolms et al, J. Med. Chem., 1991, 34, 2852) (68. 9 mg, 0. 10 mmol) was dissolved in glacial acetic acid (3 mL) and treated with pyridinium dichromate (92 mg, 0. 25 mmol) and stirred for 3h at room temperature. The reaction mixture was carefully neutralized with NaHC03 solution and extracted with ethyl acetate. The combined organic extracts were washed with NaHC03 solution, dried (MgS04), filtered and evaporated in vacuo. Trituration with ethyl acetate gave the title compound, (49. 6 mg, 72%).

The following three compounds were made by methods described herein using FMOC-Sieber amide resin : EXAMPLE 7 {1S-Benzyl-4R-[1-(1S-carbamoyl-2-phenylethylcarbamoyl)-1S-3- methyl- butylcarbamoyll-2R-hydroxphenylpentyllcarbamic acid tert-butyl ester 1H NMR (d6-DMSO, 360 MHz) 8 7. 88 (1H, d, J = 8 Hz), 7. 63 (1 H, d, J = 8 Hz), 7. 28-7. 06 (17 H, m), 6. 47 (1 H, d, J = 9. 3 Hz), 4. 71 (1 H, d, J = 5. 3 Hz), 4. 40 (1 H, m), 4. 16 (1 H, m), 3. 50-2. 30 (7 H, m), 1. 70-1. 30 (5 H, m), 1. 24 (9 H, s), 1. 10 (1 H, s), 0. 82 (3 H, d, J = 6. 6 Hz), 0. 76 (3 H, d, J = 6. 6 Hz). LC-MS (APcI) 673 (M+H+), 695 (M+Na+).

EXAMPLE 8 {1S-Benzyl-4R-[1-(1S-carbamoyl-2-phenylethylcarbamoyl)-S- ethylcarbamoyl]-2R-hydroxy-5-phenylpentyl}carbamic acid tert-butyl ester 1H NMR (d-DMSO, 360 MHZ) # 7. 90 (1H, d, J = 8 Hz), 7. 66 (1H, d, J = 8 Hz), 7. 28-7. 06 (17 H, m), 6. 49 (1 H, d, J=9. 3Hz), 4. 82 (1 H, d, J = 5. 3 Hz), 4. 43 (1 H, m), 4. 18 (1 H, m), 3. 50-2. 30 (7 H, m), 1. 70-0. 90 (15 H, m). LC-MS (APcI) 631 (M+H+), 653 (M+Na+).

EXAMPLE 9 (lS-Benzyl-4R-i 1S-f (-carbamoylphenylmethvl) carbamoyll-S- ethylcarbamoyll-2R-hydroxv-5-phenlpentvl) carbamic acid ter-butyl ester 1H NMR (d6-DMSO, 360 MHz) 8 8. 11 (1H, d, J = 8 Hz), 7. 74 (1 H, d, J = 8 Hz), 7. 28-7. 06 (17 H, m), 6. 45 (1 H, d, J = 9. 3 Hz), 4. 75 (1 H, d, J = 5. 3

Hz), 4. 41 (1 H, m), 4. 17 (1 H, m), 3. 50-2. 30 (5 H, m), 1. 70-0. 90 (15 H, m). LC-MS (APcI) 617 (M+H+), 639 (M+Na+).

For the avoidance of doubt the structures of the specific Examples of the present invention are as follows. In the case of ambiguity in the names given herein the structures below are to be taken as correct. Structure Example Number HO OU H I N N NNz Fui 0 Exam le 1 oh 0 OU Fui N NHC O N N N NH2 N-__ Example 2 H PH 0 H NU N 0 0 H O O Example 3 V | >, Na J X oH OH O NU H OU H i" NU _ H LU O \ Example 4 oh ( H _ _ Fi N NHC p N N H 0 0 0 Y Example 5 N XNH w oh H 0 H 0 1 N NH, N NHC H p \ N N 0 O Iw Exam le 6 Oh H 2H 0 _ _ H N NH2 p N N mu O O 0 Y Example 7 -OH o H N N u NH2 Fui N NH, lez Example 8 oh Oh N NHC H g O-O O Example 9