DD247683A5 - PROCESS FOR THE PREPARATION OF PEPTIDE DERIVATIVES - Google Patents

Abstract

The invention relates to processes for the preparation of certain trifluoromethylketone-substituted peptide derivatives which can be used as research aids in pharmacological and diagnostic studies. The invention provides a process for the preparation of novel trifluoromethyl ketone-substituted peptide derivatives which inhibit human leukocyte elastase and thus act as elastase inhibitors. The object of the invention is to provide a process for the preparation of novel compounds which are applicable as elastase inhibitors. According to the invention, the object is achieved by preparing, for example, peptide derivatives of the formula Ia in which the substituents which have the meaning given in the description are prepared, by the process comprising the oxidation of a compound VII a. Formulas I a and VII a

Description

Field of application of the invention

The present invention relates to methods of preparing certain trifluoromethyl ketone-substituted peptide derivatives which in turn inhibit human leukocyte elastase (HLE), thereby always being useful when such inhibition is desired, such as research tools in pharmacological, diagnostic and related studies and in the treatment of degenerative tissue diseases such as pulmonary emphysema, atherosclerosis, rheumatoid arthritis and osteoarithritis in warm-blooded animals. The invention further includes intermediates which serve to synthesize these peptide derivatives. Process for their preparation, pharmaceutical compositions containing such peptide derivatives and methods of their use.

Characteristic of the known technical solutions

The most obvious prior art is the European patent application, publication no. No. 124317, published November 7, 1984, which contains the production of a related series of peptide inhibitors to human leukocyte elastase, but which contains one ardehyde group at the terminal C atom instead of the trifluoroacetyl group from the current compound of formula I:

R ¹ ι

go, M _# CH, CO, CF ₃

Ia

β:

έγ ο

.UX ₃

Ic

wherein the substituents have the meaning given in the following description.

Object of the invention

The invention provides a process for the preparation of novel trifluoromethyl ketone-substituted peptide derivatives which inhibit human leukocyte elastase and thus act as elastase inhibitors.

Explanation of the essence of the invention

The object of the invention is to provide processes for the preparation of novel compounds which are applicable as elastase inhibitors.

The substituted peptides of the present invention can be represented by the following formulas Ia, Ib and Ic:

\ CO _# NH »CH.CO _# CF_

Ia

ib

B ¹ ""

CO.IH.CH.CO "

where is true

R ^{1 is} alkyl;

R ² and R ⁵ are alkyl, substituted alkyl, aryl, aralkyl, substituted aralkyl or substituted aryl;

R ³ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, aryl, substituted

Aryl, aralkyl, substituted aralkyl, an aliphatic heterocyclic compound, a substituted aliphatic heterocyclic compound, an aromatic heterocyclic compound or a substituted aromatic heterocyclic compound;

R ^{4 and} R ⁶ are hydrogen or methyl;

Il

A is selected from among those group; which from - C -,

O O O

Il U Μ

-N-C-, - O - C - and - S -

a ι

consists; and

η is O, 1 or 2;

and optionally their acid and base addition salts.

Compounds of the formulas I a, I b or I c are referred to below as dipeptides, tripeptides or tetrapeptides.

The compounds of the invention include those in which

R ^{1 is} an alkyl group of 1 to 5 carbon atoms, more preferably 2 to 5 carbon atoms;

(r) alkanoyloxy of 1 to 6 carbon atoms;

(s) aroyloxy, wherein the aryl moiety contains 6.10 or 12 carbon atoms;

(t) aralkanoyloxy of 8 to 14 carbon atoms;

(u) alkylsulfonamido wherein the alkyl group contains from 1 to 6 carbon atoms;

(v) aralkylsulfonamido wherein the aralykl group contains 7 to 13 carbon atoms;

(w) arylsulfonamido wherein the aryl group contains 6, 10 or 12 carbon atoms;

(x) acylsulfonamido (i.e., acylaminosulfonyl and sulfonylaminocarbonyl) including acylsulfonamido wherein the

Acyl group contains 1 to 7 carbon atoms when it represents the terminal portion of the acylsulfonamide and provided that, in the presence of an aryl in the acylsulfonamide, this aryl is further substituted by fluorine,

Chlorine, iodine and nitro selected member may be substituted;

(y) alkoxycarbonyl wherein the alkoxy group contains from 1 to 6 carbon atoms;

(ζ) aralkoxycarbonylamino, wherein the aralkoxy group has 8 to 13 carbon atoms (ζB.benzyloxycarbonylamino)

contains;

(aa) aryloxycarbonylamino, wherein the aryloxy group contains 6, 10 or 12 carbon atoms;

(bb) alkoxycarbonylamino, wherein the alkyloxy group contains 1 to 6 carbon atoms;

(cc) aryl of 6, 10 or 12 carbon atoms (ζB., phenyl, biphenyl, naphthyl);

(dd) aryl having 6, 10 or 12 carbon atoms and substituted by 1 to 3 members selected from chlorine, bromine, iodine,

Fluorine, trifluoromethyl, hydroxy, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (1 to 6 carbon atoms), carboxy, 5-tetrazolo and acylsulfonamido (i.e., acylaminosulfonyl and

Sulfonylaminocarbonyl) (1 to 15 carbon atoms) R ² and R ⁵ are each independently selected from the group consisting of:

(I) an alkyl group having 1 to 10 carbon atoms;

(II) an alkyl group having 1 to 6 carbon atoms which is substituted by at least one member selected from the group consisting of:

(a) hydroxy;

(b) amino;

(c) alkylamino amide to 6 carbon atoms;

(d) dialkylamino, wherein each alkyl group contains 1 to 6 carbon atoms;

(e) alkanoyl of 1 to 6 carbon atoms;

(f) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbon atoms;

(g) aralkanoyl of 8 to 13 carbon atoms;

(h) Amido attached via either one of its nitrogen atoms or one of its carbon atoms to the alkyl group

can be attached;

(i) alkylcarbonylamino wherein the alkyl group contains from 1 to 6 carbon atoms;

(j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 6 carbon atoms;

(k) arylcarbonylamino, wherein the aryl group contains 6, 10 or 12 carbon atoms;

(I) aralkylcarbonylamino, wherein the aralkyl group contains 7 to 13 carbon atoms;

(m) arylaminocarbonyl wherein the aryl group contains 6, 10 or 12 carbon atoms;

(n) aralkylaminocarbonyl wherein the aralkyl group contains from 7 to 13 carbon atoms;

(0) carboxy;

(ρ) aryloxycarbonyl wherein the aryl group contains 6, 10 or 12 carbon atoms;

(q) aralkoxycarbonyl wherein the aralkoxy group contains 7 to 13 carbon atoms;

and with the proviso that when the acylsulfonamido contains an aryl, the aryl further by a

Fluorine, chlorine, bromine, iodine and nitro selected member can be substituted; (ee) cycloalkyl of 3 to 15 carbon atoms (eg, cyclohexyl, adamantyl, norbornyl);

(ff) alkylureido, wherein the alkyl group contains 1 to 6 carbon atoms;

(gg) aralkylureido, wherein the aralkyl group contains from 8 to 13 carbon atoms;

(hh) arylureido, wherein the aryl group contains 6, 10 or 12 carbon atoms; and

(III) an aryl group having 6 carbon atoms such. As phenyl.

R ^{3 is} selected from the group which consists of:

(1) an alkyl group having 1 to 4 carbon atoms;

(II) an aryl group having from 1 to 12 carbon atoms and from 1 to 4 heteroatoms, each of which is independently selected from nitrogen and oxygen;

(III) an alkyl group having 1 to 12 carbon atoms and optionally 1 to 4 heteroatoms, each of which is independently selected from nitrogen and oxygen and which is substituted on at least one of the carbon or nitrogen atoms by 1 to 3 members which are independently be selected from the group consisting of:

For carbon:

(a) hydroxy, provided that it may not be located on a carbon atom directly attached to A;

(b) amino, provided that it may not be located on a carbon atom directly attached to A;

(c) alkylamino of 1 to 6 carbon atoms, provided that it may not be located on a carbon atom directly attached to A;

(d) dialkylamino, wherein each alkyl group contains from 1 to 6 carbon atoms, and provided that it may not be located on a carbon atom directly attached to A;

(e) alkanoyl of 1 to 6 carbon atoms;

(f) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbon atoms;

(g) aralkanoyl of 8 to 13 carbon atoms;

(h) Amido attached to the alkyl group via either one of its nitrogen atoms or one of its carbon atoms

can be attached;

(i) alkylcarbonylamino wherein the alkyl group contains from 1 to 6 carbon atoms;

(j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 6 carbon atoms;

(k) arylcarbonylamino, wherein the aryl group contains 6, 10 or 12 carbon atoms;

(k) - (1) arylcarbonylamino wherein the aryl group contains 6, 10 or 12 carbon atoms and is represented by carboxy, alkoxycarbonyl of 1 to 3 alkoxy carbon atoms, 5-tetrazolo and acylsulfonamido (ie acylaminosulfonyl and sulfonylaminocarbonyl) of 1 to 15 carbon atoms selected member being substituted, and provided that in the presence of an aryl in the acylsulfonamide, the aryl may be further substituted by a member selected from fluorine, chlorine, bromine, iodine and nitro;

(I) aralkylcarbonylamino, wherein the aralkyl group contains 7 to 13 carbon atoms;

(I) - (I) Aralkylcarbonylamino, wherein the aralkyl group contains 7 to 13 carbon atoms and is represented by carboxy, alkoxycarbonyl of 1 to 3 alkoxy carbon atoms, 5-tetrazolo and acylsulfonamido (ie, acylaminosulfonyl and sulfonylaminocarbonyl) of 1 to 15 carbon atoms selected member being substituted, and provided that in the presence of an aryl in the acylsulfonamide, the aryl may be further substituted by a member selected from fluorine, chlorine, bromine, iodine and nitro;

(m) arylaminocarbonyl wherein the aryl group contains 6, 10 or 12 carbon atoms;

(n) aralkylaminocarbonyl, wherein the aralkyl group contains 7 to 13 carbon atoms;

(o) carboxy;

(ρ) aryloxycarbonyl wherein the aryl group contains 6, 10 or 12 carbon atoms;

(q) aralkoxycarbonyl, wherein the aralkoxy group contains 7 to 13 carbon atoms;

(r) alkanoyloxy of 1 to 6 carbon atoms;

(s) aroyloxy, wherein the aryl moiety contains 6.10 or 12 carbon atoms;

(t) aralkanoyloxymit8 to 13 carbon atoms;

(u) alkylsulfonamido wherein the alkyl group contains from 1 to 6 carbon atoms;

(u) - (1) cycloalkylsulfonamido wherein the cycloalkyl moiety contains 3 to 15 carbon atoms (eg, cyclohexyl, adamantyl, norbornyl);

(v) aralkylsulfonamido wherein the aralkyl group contains 7 to 13 carbon atoms;

(w) arylsulfonamido wherein the aryl group contains 6, 10 or 12 carbon atoms;

(x) acylsulfonamide (i.e., acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbon atoms) inclusive

Acylsulfonamido wherein the acyl group contains from 1 to 7 carbon atoms when it is the terminal portion of the acylsulfonamide and provided that in the presence of an aryl in the acylsulfonamide the aryl is further substituted by a member selected from fluoro, chloro, bromo, iodo and nitro can;

(y) alkoxycarbonyl wherein the alkoxy group contains up to 6 carbon atoms;

(z) aralkoxycarbonylamino wherein the aralkoxy group contains from 8 to 13 carbon atoms

(eg, benzyloxycarbonylamino);

(z) - (1) aralkylaminocarbonyloxy wherein the aralkyl group contains 8 to 13 carbon atoms; (z) - (2) aryloxy wherein the aryl contains 6, 10 or 12 carbon atoms;

(z) - (3) aryloxy wherein the aryl contains 6, 10 or 12 carbon atoms and is substituted by a member selected from aminocarbonyl, aminocarbonylalkyl of 1 to 3 alkyl carbon atoms, alkoxycarbonyl of 1 to 3 carbon atoms and carboxy;

(aa) aryloxycarbonylamino, wherein the aryloxy group contains 6, 10 or 12 carbon atoms;

(aa) - (1) arylaminocarbonyloxy wherein the aryl group contains 6, 10 or 12 carbon atoms;

(bb) alkoxycarbonylamino wherein the alkyloxy group contains up to 6 carbon atoms;

(bb) - (1) alkoxycarbonylamino wherein the alkoxy groupi contains up to 6 carbon atoms and is optionally bonded via carbon to a carbon of an aromatic heterocyclic group as described in (gg) under R ³ ;

(bb) - (2) alkoxycarbonylamino wherein the alkoxy group contains up to 6 carbon atoms substituted by an aliphatic heterocyclic group according to the description given in (ff) under R ³ ;

(bb) - (3) aryloxycarbonylamino wherein the aryl contains 6 or 10 carbon atoms and the alkyl has 1 to 6 carbon atoms;

(bb) - (4) alkylaminocarbonyloxy wherein the alkyl group contains 1 to 6 carbon atoms;

(cc) aryl having 6, 10 or 12 carbon atoms (eg, phenyl, naphthyl, biphenyl);

(cc) - (D aryloxy with 6,10 or 12 carbon atoms;

(dd) aryl having 6, 10 or 12 carbon atoms and substituted by 1 to 3 members independently of one another

Chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, aminocarbonylalkyl (2 to 6 carbon atoms), aminocarbonyl, 5- Tetrazolo and acylsulfonamido (ie, acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbon atoms), and provided that when the acylsulfonamide contains an aryl, then that aryl is further selected from fluoro, chloro, bromo, iodo, and nitro can be substituted;

(dd) - (1) Aryloxy having 6, 10 or 12 carbon atoms and substituted on carbon by 1 to 3 members independently selected from chlorine, bromine iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, aminocarbonylalkyl (2 to 6 carbon atoms), aminocarbonyl, 5-tetrazolo, acylsulfonamido (ie acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbon atoms), and provided that in the presence of an aryl in the acylsulfonamide, the aryl may be further substituted by a member selected from fluorine, chlorine, bromine, iodine and nitro;

(ee) cycloalkyl of 3 to 15 carbon atoms (eg, cyclohexyl, adamantyl, norbornyl);

(ee) - (1) cycloalkyloxy of 3 to 15 carbon atoms;

(ff) an aliphatic heterocyclic group of at least 4 atoms having 1 to 5 carbon atoms and 1 to 4

Heteroatoms, each independently selected from nitrogen and oxygen (eg, morpholine, piperazine), wherein the aliphatic heterocyclic group may optionally contain one or two double bonds and wherein the aliphatic heterocyclic group on any nitrogen with an alkyl group having 1 to 6 Carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, an aryloxycarbonyl group having 6, 10 or 12 aryl carbon atoms, an aralkyloxycarbonyl group having 7 to 13 aralkyl carbon atoms or an alkoxycarbonyl group having 1 to 6 carbon atoms;

-I / - <ΆΙ DoO

(ff) - (1) an aliphatic heterocyclic oxy group wherein the oxy bond is connected directly to a carbon atom of the aliphatic heterocyclic group, said aliphatic heterocyclic group consisting of at least 5 atoms having 1 to 5 carbon atoms and 1 to 4 heteroatoms each of which was independently selected from nitrogen and oxygen (eg, morpholine, piperazine), wherein the aliphatic heterocyclic group may optionally contain 1 or 2 double bonds, and wherein the aliphatic heterocyclic group is on each nitrogen atom having an alkyl group 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, an aryloxycarbonyl group having 6, 10 or ^ aryl carbon atoms ^ in an aralkyloxycarabonyl group may be substituted to bisAralkyl carbon atoms or an alkyloxycarbonyl group to 6 alkyl carbon atoms;

(gg) an aromatic heterocyclic group having (1) 1 to 15 carbon atoms and 1 to 4 heteroatoms, of which

each independently selected from sulfur, nitrogen and oxygen, and having (2) 1 to 3 five- or 6-membered rings, at least one of which is aromatic, and optionally up to

3 carbon atoms of the aromatic ring (s) may be substituted with one member of the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, carboxy, aminocarbonylalkyl (2 to 6 carbon atoms) and aminocarbonyl, and further provided that any nitrogen atom may be substituted by an alkyl group having 1 to 6 carbon atoms;

(gg) - (1) an aromatic heterocyclic oxy group, wherein the oxy bond is connected directly to a carbon atom of an aromatic heterocyclic group having (1) 1 to 15 carbon atoms and 1 to 4 heteroatoms, each independently selected from sulfur , Nitrogen and oxygen and with (2) 1 to 3 five- or 6-membered rings, at least one of which is aromatic, and optionally-up to 3 carbon atoms of the aromatic ring (s) may be substituted with one member of that group compound composed of fluorine, chlorine, bromine, iodine, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, carboxy, aminocarbabonylalkyl (2 to 6 carbon atoms) and aminocarbonyl, and further provided in that any nitrogen atom may be substituted by an alkyl group of 1 to 6 carbon atoms;

(hh) alkylureido wherein the alkyl group contains up to 6 carbon atoms;

(hh) - (1) cycloalkylureido wherein the alkyl group contains 3 to 15 carbon atoms;

(ii) alkylureido wherein the aralkyl group contains 7 to 13 carbon atoms;

(jj) arylureido, wherein the aryl group contains 6, 10 or 12 carbon atoms;

(Jj) -O) arylureido, wherein the aryl group contains 6, 10 or 12 carbon atoms and is substituted by 1 to 3 members independently selected from chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 Carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, aminocarbabonylalkyl (2 to 6 carbon atoms), aminocarbonyl, 5-tetrazolo and acylsulfonamido (ie acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbon atoms) including acylsulfonamide with the acyl group containing 1 to 7 carbon atoms when present in the final portion of the acylsulfonamide and also provided that in the presence of an aryl in the acylsulfonamide, the aryl is further selected from fluoro, chloro, bromo, iodo and nitro may be substituted;

For nitrogen:

(a) alkyl of 1 to 3 carbon atoms;

(b) alkanoyl of 2 to 6 carbon atoms;

(c) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbon atoms;

(d) aralkanoyl of 8 to 14 carbon atoms;

(e) formyl;

(f) an aliphatic heterocyclic group in which the amino bond is directly attached to a carbon of an aliphatic heterocyclic group as defined in (ff) for the carbon substituents;

(g) an aromatic heterocyclic group in which the amino bond is attached directly to a carbon of the aromatic heterocyclic group defined in (gg) for the carbon substituents;

(IV) an aryl group of 6, 10 or 12 carbon atoms;

(V) an aryl group having 6, 10 or 12 carbon atoms, suitably substituted by 1 to 3 members independently selected from fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, alkoxycarbonyl with 2 to

6 carbon atoms, carboxyalkyl, alkylcarbonylamino having 1 to 6 alkyl carbon atoms, 5-tetrazolo and acylsulfonamido (ie acylaminosulfonyl and sulfonylaminocarbonyl) having 1 to 15 carbon atoms, and provided that in the presence of an aryl in the acylsulfonamide, the aryl is further represented by a lower Fluorine, chlorine, bromine, iodine and nitro selected member may be substituted;

(VI) a cycloalkyl group of 3 to 15 carbon atoms (e.g., cyclohexyl, adamantyl, norbornyl);

(VI) - (I) a cycloalkyl group having 3 to 15 carbon atoms (e.g., cyclohexyl, adamantyl, norbornyl) substituted with a member selected from carboxy and alkoxycarbonyl, wherein the alkoxy group contains up to 4 carbon atoms;

(VII) an aliphatic heterocyclic group of at least 5 atoms having 1 to 5 carbon atoms and 1 to

4 heteroatoms, each independently selected from nitrogen and oxygen (eg, morpholine, piperazine), which may be substituted at each nitrogen with a member selected from an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, an aryloxycarbonyl group having 6, 10 or 12 aryl carbon atoms, an aralkoxycarbonyl group having

From 7 to 13 aralkyl carbon atoms and one alkoxycarbonyl group having from 2 to 7 carbon atoms, provided that when A is OCO or NHCO, A must be bonded to a carbon atom of the aliphatic heterocyclic group;

(VIII) an aromatic heterocyclic group having (a) 1 to 15 carbon atoms and 1 to 4 heteroatoms, each independently selected from sulfur, nitrogen and oxygen, and having (b) 1 to 3 five- or six-membered rings, of which is at least one aromatic and optionally having up to 3 carbon atoms of the aromatic ring (s) on any carbon atom containing a member of fluoro, chloro, bromo, iodo, trifluoromethyl. Alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, alkanoyl having 2 to 6 carbon atoms and carboxy group, and further provided that any nitrogen may be substituted by an alkyl group having 1 to 6 carbon atoms, as well with the proviso that A must be bonded to one carbon of the aromatic heterocyclic group when A is OCO or NHCO;

(IX) an alkenyl group of 2 to 10 carbon atoms having at least one double bond; and

(X) an alkenyl group of 2 to 10 carbon atoms having at least one double bond substituted by a member selected from

(a) aryl of 6 or 10 carbon atoms;

(b) aryl of 6 or 10 carbon atoms substituted by 1 to 3 members independently selected from chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, 5-tetrazolo and acylsulfonamido (ie acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbon atoms), and provided that in the presence of an aryl in the acylsulfonamide, the aryl is further selected from fluoro, chloro, Bromine, iodine and nitro selected member may be substituted; and

(c) ureidocarbonyl.

R ⁴ and R ⁶ are independently selected from hydrogen or methyl; η is O, 1 or 2;

A is under

0 0 0. 0

"- * '* *' t η '· -' η '

-0% "'-N-G-, -0-0 * 0, and -S- selected; and

H oo

optionally their acid and base addition salts.

Specific values for compounds of the invention include the following members of the groups defined above:

R ¹ is an alkyl group having 3 carbon atoms;

R ² and R ⁵ are each independently selected from the group consisting of:

(I) an alkyl group having 1 to 4 carbon atoms;

(II) an alkyl group having 1 to 4 carbon atoms substituted by at least one member selected from:

(e) alkanoyl of 1 to 3 carbon atoms;

(f) arylcarbonyl wherein the aryl contains 6 or 10 carbon atoms (eg, phenyl or naphthyl);

(g) aralkanoyl of 8 carbon atoms (e.g., phenylacetyl);

(h) Amido attached to the alkyl group with either one of its nitrogen atoms or one of its carbon atoms

can be connected;

(i) alkylcarbonylamino wherein the alkyl group contains from 1 to 2 carbon atoms;

(j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 2 carbon atoms;

(k) arylcarbonylamino wherein the aryl group contains 6 carbon atoms (eg, phenyl);

(I) aralkylcarbonylamino, wherein the aralkyl group contains 7 carbon atoms;

(m) arylaminocarbonyl wherein the aryl group contains 6 carbon atoms;

(n) aralkylaminocarbonyl wherein the aralkyl group contains 7 carbon atoms;

(o) carboxy;

(ρ) aryloxycarbonyl wherein the aryl group contains 6 carbon atoms;

(q) aralkoxycarbonyl, wherein the aralkoxy group contains 7 carbon atoms;

(r) alkanoyloxy of 1 to 2 carbon atoms;

(s) aroyloxy, wherein the aryl moiety contains 6 carbon atoms;

(t) aralkanoyloxy of 8 carbon atoms;

(u) alkylsulfonamido wherein the alkyl group contains from 1 to 6 carbon atoms;

(v) aralkylsulfonamido, wherein the aralkyl group contains 7 to 13 carbon atoms (eg.

1-Naphthylmethylsulfonylaminooder4-Phenylbutylsulfonylamino);

(w) arylsulfonamido wherein the aryl group contains 6 or 10 carbon atoms;

(x) acylsulfonamidomiti to 15 carbon atoms (eg, phenylsulfonylaminocarbonyl);

(y) alkoxycarbonyl wherein the alkoxy group contains from 1 to 2 carbon atoms;

(z) aralkoxycarbonylamino wherein the aralkoxy group contains 7 carbon atoms (eg, benzyloxycarbonylamino);

(aa) aryloxycarbonylamino, wherein the aryloxy group contains 6 carbon atoms;

(bb) alkoxycarbonylamino, wherein the alkyloxy group contains up to 3 carbon atoms;

(cc) aryl having 6 or 10 carbon atoms (eg, phenyl or naphthyl);

(dd) aryl having 6 or 10 carbon atoms and substituted by 1 to 3 members which are chlorine, bromine, iodine, fluorine,

Trifluoromethyl, hydroxy, alkyl (1 to 2 carbon atoms), alkoxy (1 to 2 carbon atoms), alkoxycarbonyl (2 to 3 carbon atoms), carboxy, 5-tetrazolo and acylsulfonamido (1 to 15 carbon atoms);

(ee) cycloalkyl of 3 to 15 carbon atoms (eg, cyclohexyl, adamantyl, norbornyl).

(ff) alkylureido, wherein the alkyl group contains 1 to 2 carbon atoms;

- 19- £ t * t DOO

(gg) aralkylureido, wherein the aralkyl group contains 7 carbon atoms;

(hh) arylureido, wherein the aryl group contains 6 or 10 carbon atoms; and

(III) an aryl group having 6 carbon atoms.

R ^{3 is} selected from the group consisting of:

(I) an alkyl group having 1 to 12 carbon atoms;

(II) an alkyl group having 1 to 12 carbon atoms and 1 to 4 heteroatoms, each independently selected from nitrogen and oxygen;

(IM) an alkyl group having 1 to 12 carbon atoms and optionally 1 to 4 heteroatoms, each of which

is independently selected from nitrogen and oxygen, and at least one carbon or nitrogen atom substituted by 1 to 3 members independently selected from the group consisting of:

For carbon:

(e) alkanoyl of 1 to 6 carbon atoms;

(f) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbon atoms;

(g) aralkanoyl of 8 to 13 carbon atoms;

(h) amido which may be attached to the alkyl group with either one of its nitrogen or carbon atoms;

(i) alkylcarbonylamino wherein the alkyl group contains from 1 to 6 carbon atoms;

(j) alkylaminocarbonyl wherein the alkyl group contains 1 to 6 carbon atoms;

(k) arylcarbonylamino, wherein the aryl group contains 6 or 10 carbon atoms;

(k) - (1) arylcarbonylamino wherein the aryl group contains 6 or 10 carbon atoms and is substituted by a member selected from carboxy, alkoxycarbonyl having 1 to 3 alkoxy carbon atoms, 5-tetrazol and acylsulfonamido having 1 to 15 carbon atoms;

(I) aralkylcarbonylamino, wherein the aralkyl group contains 7 to 13 carbon atoms;

(I) - (I) aralkylcarbonylamino wherein the aralkyl group contains 7 to 13 carbon atoms and is substituted by a member selected from carboxy, alkoxycarbonyl having 1 to 3 alkoxy carbon atoms, 5-tetrazol and acylsulfonamido having 1 to 15 carbon atoms;

(m) arylaminocarbonyl, wherein the aryl group contains 6 or 10 carbon atoms;

(n) aralkylaminocarbonyl wherein the aralkyl group contains from 7 to 13 carbon atoms;

(o) carboxy;

(ρ) aryloxycarbonyl wherein the aryl group contains 6 or 10 carbon atoms;

(q) aralkoxycarbonyl, wherein the aralkoxy group contains 7 to 13 carbon atoms;

(r) alkanoyloxy of 2 to 3 carbon atoms;

(s) aroyloxy, wherein the aryl moiety contains 6 or 10 carbon atoms;

(t) aralkanoyloxy of 8 to 13 carbon atoms;

(for alkylsulfonamido wherein the alkyl group contains 1 to 6 carbon atoms;

(u) - (1) cycloalkylsulfonamido wherein the cycloalkyl moiety contains from 3 to 15 carbon atoms (e.g., it may be in the

Cycloalkyl to cyclohexyl, adamantyl, norbornyl act), z. For example, 1-adamantylsulfonylamido; (v) aralkylsulfonylido, wherein the aralkyl group contains 7 to 13 carbon atoms;

(w) arylsulfonamido wherein the aryl group contains 6 or 10 carbon atoms;

(x) acylsulfonamido having 1 to 15 carbon atoms; ^

(y) alkoxycarbonyl wherein the alkoxy group contains up to 3 carbon atoms;

(z) aralkoxycarbonylamino, wherein the aralkoxy group contains from 8 to 13 carbon atoms (e.g.

Benzyloxycarbonylamino);

(z) - (1) aralkylaminocarbonyloxy wherein the aralkyl group contains 7 to 13 carbon atoms; (z) - (2) aryloxy wherein the aryl contains 6, 10 or 12 carbon atoms; (z) - (3) aryloxy wherein the aryl contains 6, 10 or 12 carbon atoms and is substituted by a member selected from aminocarbonyl, aminocarbonylalkylmethyl to 3-alkylcarbonates, alkoxycarbonyl of 2 to 4 carbon atoms and carboxy;

(aa) aryloxycarbonylamino, wherein the aryloxy group contains 6 or 10 carbon atoms;

(aa) - (1) arylaminocarbonyloxy wherein the aryl group contains 6 or 10 carbon atoms; (bb) alkoxycarbonylamino, wherein the alkyloxy group contains 1 to 6 carbon atoms;

(bb) - (1) alkoxycarbonylamino wherein the alkoxy group contains from 1 to 6 carbon atoms and optionally to one

Carbon of an aromatic heterocyclic group as described under R ³ is bound in (gg); (bb) - (2) Alkoxycarbonylamino, wherein the alkoxy group contains 1 to 6 carbon atoms, which by an aliphatic

heterocyclic group as described under R ³ in (ff) are substituted; (bb) - (3) aryloxyalkylcarbonylamino wherein the aryl contains 6 or 10 carbon atoms and the alkyl contains 1 to 6 carbon atoms;

(bb) - (4) alkylaminocarbonyloxy wherein the alkyl group contains 1 to 6 carbon atoms; (cc) aryl with 6 or 10 carbon atoms (e.g., phenyl or naphthyl);

(cc) - (1) aryloxy having 6 or 10 carbon atoms; (dd) aryl having 6, 10 or 12 carbon atoms and substituted by 1 to 3 members independently of one another

are selected from chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, aminocarbonylalkyl (2 to

6 carbon atoms), aminocarbonyl, 5-tetrazolo and acylsulfonamido (1 to 15 carbon atoms); (dd) - (1) aryloxy having 6, 10 or 12 carbon atoms and substituted by 1 to 3 members independently selected from chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, acylsulfonamido (1 to

15 carbon atoms), aminocarbonylalkyl (2 to 6 carbon atoms), aminocarbonyl and 6-tetrazolo; (ee) cycloalkyl of 3 to 15 carbon atoms (eg cyclohexyl, adamantyl or norbornyl);

IIGII UMU I UIO

4 heteroatoms, each independently selected from nitrogen and oxygen (e.g., morpholine, piperazine), wherein the aliphatic heterocyclic group may optionally contain 1 or 2 double bond (s) wherein the aliphatic heterocyclic group is attached to any nitrogen with an alkyl Group with

1 to 6 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms, an aryloxycarbonyl group having 6, 10 or 12 aryl carbon atoms, an aralkoxycarbonyl group having 7 to 13 aralkyl carbon atoms or an alkoxycarbonyl group having 1 to 6 Alkyl carbon atoms may be substituted;

(ff) - (1) an aliphatic heterocyclic oxy group in which the oxy bond is connected directly to a carbon of an aliphatic heterocyclic group of at least 5 atoms having 1 to 5 carbon atoms and 1 to 4 heteroatoms, each independently is selected from the group consisting of nitrogen and oxygen, wherein the aliphatic heterocyclic group may optionally contain 1 or 2 double bonds and wherein the aliphatic heterocyclic group is any nitrogen having an alkyl group of 1 to 6 carbon atoms, an alkanoyl group of 2 to 6 Carbon atoms, an aryloxycarbonyl group having 6, 10 or 12 aryl carbon atoms, an aralkoxycarbonyl group having 7 to 13 aralkyl carbon atoms or an alkoxycarbonyl group having 1 to 6 alkyl carbon atoms (e.g., morpholine, piperazine) can;

(gg) an aromatic heterocyclic group having (1) 1 to 15 carbon atoms and 1 to 4 heteroatoms, of which

each independently selected from sulfur, nitrogen and oxygen, and having (2) 1 to 2 five- or 6-membered rings, at least one of which is aromatic and optionally up to

3 carbon atoms of the aromatic ring (s) may be substituted with one member selected from fluoro, chloro, bromo, iodo, trifluoromethyl, methyl containing alkyl, alkoxy of 1 to 2 carbon atoms, alkanoyl with

2 to 3 carbon atoms, carboxy, aminocarbonylalkyl (2 to 6 carbon atoms) and aminocarbonyl, and further provided that any nitrogen atom is replaced by an alkyl group

1 to 6 carbon atoms may be substituted; (gg) - (1) an aromatic heterocyclic oxy group in which the oxy bond is directly connected to a carbon atom of an aromatic heterocyclic group which in turn has (1) 1 to 15 carbon atoms and 1 to 15 carbon atoms

Contains 4 heteroatoms, each of which is independently selected from sulfur, nitrogen and oxygen, and which (2) contains 1 to 2 five- or six-membered rings, at least one of which is aromatic and optionally having up to 3 carbon atoms of the aromatic ring or of the aromatic rings may be substituted with a member selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, alkoxy of 1 to 2 carbon atoms, alkanoyl of 2 to 3 carbon atoms, carboxy, aminocarbonylalkyl (2 to 6 carbon atoms) and aminocarbonyl and further provided that any nitrogen atom may be substituted by an alkyl group of 1 to 6 carbon atoms;

(hh) alkylureido wherein the alkyl group contains from 1 to 6 carbon atoms;

(hh) - (1) cycloalkylureido wherein the alkyl group contains from 3 to 15 carbon atoms;

(ii) aralkylureido wherein the aralkyl group contains 7 to 13 carbon atoms;

(jj) arylureido, wherein the aryl group contains 6 or 10 carbon atoms;

(jj) - (1) arylureido, wherein the aryl group contains 6 or 10 carbon atoms and is substituted by 1 to 3 members, independently of one another, chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms ), Alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, acylsulfonamido (1 to 15 carbon atoms), aminocarbonylalkyl (2 to 6 carbon atoms), aminocarbonyl and 5-tetrazolo were selected;

For nitrogen:

(a) alkyl of 1 to 3 carbon atoms;

(b) alkanoyl of 2 to 6 carbon atoms;

(c) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbon atoms;

(d) aralkanoyl of 8 to 13 carbon atoms;

(e) formyl;

(f) an aliphatic heterocyclic amino group wherein the amino bond is directly attached to a carbon of an aliphatic heterocyclic group as defined in (ff) for the carbon substituents;

(g) an aromatic heterocyclic amine group wherein the amino bond is attached directly to a carbon of an aromatic heterocyclic group as defined in (gg) for the carbon substituents;

(IV) an aryl group having 6 or 10 carbon atoms;

(V) an aryl group having 6 or 10 carbon atoms, suitably substituted by 1 to 3 members independently selected from fluoro, chloro, bromo, iodo, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , Alkoxycarbonyl having 2 to 6 carbon atoms, carboxy, alkylcarbonylamino having 1 to 6 alkyl carbon atoms, 5-tetrazolo, and acylsulfonamido having 1 to 15 carbon atoms (eg, 4 - [(4-chlorophenyl) sulfonylaminocarbonyl] phenyl or 4 - [(4 Bromophenyl) sulfonylaminocarbonyl] phenyl);

(VI) a cycloalkyl group having 3 to 15 carbon atoms (eg, cyclohexyl, adamantyl or norbornyl);

(VI) - (I) a cycloalkyl group having 3 to 15 carbon atoms (eg cyclohexyl, adamantyl or norbornyl) substituted by a member selected from carbon and alkoxycarbonyl, the alkoxy group being from 1 to 4 in the case of alkoxycarbonyl Contains carbon atoms;

(VII) an aliphatic heterocyclic group of at least 5 atoms having 1 to 5 carbon atoms and 1 to

4 heteroatoms, each of which is independently selected from nitrogen and oxygen (eg, morpholine, piperazine), and which may be substituted at any nitrogen atom by a member selected from methyl, an alkanoyl group having from 2 to 6 carbon atoms, an aryloxycarbonyl group. A group having 6 or 10 aryl carbon atoms, an aralkoxycarbonyl group having 7 aralkyl carbon atoms and an alkoxycarbonyl group having 2 to 3 carbon atoms, provided that A has to be bonded to a carbon of the aliphatic heterocyclic group, if A is OCO or NHCO;

(VIII) an aromatic heterocyclic group having (a) 1 to 15 carbon atoms and 1 to 4 heteroatoms, each independently selected from sulfur, nitrogen and oxygen, and having (b) 1 to 2 five- or six-membered rings, of which at least one being aromatic and optionally having up to 3 carbon atoms of the aromatic ring (s) on any carbon atom with one of fluorine, chlorine, bromine, iodine, trifluoromethyl, metfiyl, alkoxy of 1 to 2 carbon atoms, alkanoyl of 2 to 3 carbon atoms, and Further, provided that any nitrogen may be substituted by an alkyl group of 1 to 6 carbon atoms, as well as provided that A must be bonded to a carbon of the aromatic heterocyclic group, as far as it is A is OCO or NHCO;

(IX) an alkenyl group of 2 to 10 carbon atoms having at least one double bond;

(X) an alkenyl group of 2 to 10 carbon atoms having at least one double bond and substituted by a member which has been selected from

(a) aryl of 6 or 10 carbon atoms;

(b) aryl of 6 or 10 carbon atoms substituted by 1 to 3 members independently selected from chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, acylsulfonamido (1 to 15 carbon atoms) and 5-tetrazolo were selected; and

(c) ureidocarbonyl.

R ⁴ and R ⁶ are each hydrogen; η = 1, and

A is under

selected;

0 0 0 0

-S-j - »- ο-, -ö-c- uftd -§-

More specific values include:

R- ^{1 is} isopropyl;

R ² is selected under:

(I) an alkyl group having 2 to 3 carbon atoms;

(II) (q) ethyl substituted by aralkoxycarbonyi wherein the aralkoxy group contains 7 carbon atoms;

(w) butyl substituted by an arylsulfonamido wherein the aryl moiety has 6 carbon atoms;

(x) ethyl substituted by acylsulfonamido of 7 carbon atoms (e.g., B 2 (penylsulfonylaminocarbonyl) ethyl);

(z) butyl substituted by aralkyloxycarbonylamino wherein the aralkoxy moiety contains 7 carbon atoms (e.g.

Benzyloxycarbonylamino);

(cc) methyl substituted by an aryl of 6 carbon atoms; and

(III) Aryl of 6 carbon atoms.

R ³ , selected under '. , ,

(I) branched alkyl of 4 carbon atoms;

(II) an alkyl group having 5 carbon atoms and 2 oxygen atoms;

(III) (k). Ethyl substituted by arylcarbonylamino, wherein the aryl moiety contains 6 carbon atoms;

(I) ethyl substituted by an aralkylcarbonylamino wherein the aralkyl moiety contains 13 carbon atoms;

(n) ethyl substituted by aralkylaminocarbonyl wherein the alkyl contains 7 carbon atoms;

(o) an alkyl group containing 2 or 10 carbon atoms and substituted by carboxy;

(w) an alkyl group having 5 carbon atoms and substituted by arylsulfonamido, wherein the aryl moiety

Contains 6 carbon atoms;

(x) ethyl substituted by an acylsulfonamide which is 2- (methylsulfonylaminocarbonyl) ethyl,

2- (phenylsulfonylaminocarbonyl) ethyl, 2 - [(1-adamantyl) sulfonylaminocarbonyl] ethyl and 2 - [(1-naphthyl) sulfonylaminocarbonyl] ethyl;

(y) an alkyl group having 2 or 10 carbon atoms and substituted by methoxycarbonyl;

(z) an alkyl group having 2 to 5 carbon atoms and substituted by aralkoxycarbonyi, wherein the aralkoxy moiety

Contains 7 carbon atoms;

(aa) an alkyl having 5 carbon atoms and substituted by aryloxycarbonylamino, wherein the aryloxy moiety

Contains 6 carbon atoms; (bb) ethyl substituted by an alkoxycarbonylamino wherein the alkyl group contains 4 carbon atoms; as well as one

Alkyl of 5 carbon atoms and substituted by an alkyloxycarbonylamino wherein the alkoxy group contains 2 carbon atoms and on the terminal carbon via a direct connection to a carbon atom of an aromatic heterocyclic group having 5 carbon atoms and 1 nitrogen atom

is substituted; (bb) - (3) a propyl group substituted by an aryloxyalkylcarbonylamine, wherein the aryl group is 6 carbon atoms

contains and the alkyl group is methyl; (cc) methyl or butyl substituted by aryl of 6 carbon atoms; and a branched alkyl group with

5 carbon atoms and substituted by two aryl groups, each containing 6 carbon atoms;

(dd) a member selected from an alkyl of 1 or 2 carbon atoms and substituted with an aryl

6 carbon atoms, wherein the aryl is further substituted by Darboxy; Methyl substituted by an aryl of 6 carbon atoms, wherein the aryl is further substituted by methoxycarbonyl; Ethyl substituted by an aryl of 6 carbon atoms, wherein the aryl is further substituted by ethoxycarbonyl; and ethyl substituted by an aryl having 6 carbon atoms, said aryl further being substituted by an acylsulfonamide

Substituted 7 carbon atoms;

(ee) ethyl substituted with a cycloalkyl of 10 carbon atoms (e.g., 1-adamantylethyl);

(ff) ethyl substituted by an aliphatic heterocyclic compound having 4 carbon atoms, a

Nitrogen atom and an oxygen atom (e.g., 2- (4-morpholinyl) ethyl); (gg) an alkyl of 1 to 2 carbon atoms and substituted by an aromatic heterocyclic compound with

4 carbon atoms and one sulfur atom (e.g., (2-thiophenyl) methyl or 2- (3-thiophenyl) ethyl); and ethyl substituted by an aromatic heterocyclic compound having 5 carbon atoms and a nitrogen atom;

(jj) -H) an alkyl group having 5 carbon atoms and substituted by an arylureido, wherein the aryl moiety contains 6 carbon atoms and wherein the aryl moiety is further substituted by ethoxycarbonyl or carboxy;

(zz) propyl substituted by aryloxy wherein the aryl contains 6 carbon atoms; a branched alkyl group with

5 carbon atoms and substituted by 2 aryloxy groups, each containing 6 carbon atoms; (zzz) methyl or propyl substituted by a 6-carbon aryloxy group, the aryloxy group being further substituted by aminocarbonyl; and methyl substituted by aryloxy of 6 carbon atoms, wherein the aryloxy group is further substituted by ethoxycarbonyl;

(IV) an aryl group having 6 or 10 carbon atoms, e.g., phenyl or naphthyl;

(V) an aryl group having 6 carbon atoms substituted by a member selected from fluoro, hydroxy, carboxy, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, methylcarbonylamino, an acylsulfonamide having 2 carbon atoms (e.g., 4- (methylsulfonaminocarbonyl) phenyl), an acylsulfonamide having 7 carbon atoms (eg 4- (phenylsulfonylaminocarbonyl) phenyl, 4 - [(4-chlorophenyl) sulfonylaminocarbonyl] phenyl or [(4-bromophenyl) sulfonylaminocarbonyl] phenyl), an acylsulfonamide having 11 carbon atoms (e.g. (1-naphthylsulfonylaminocarbonylphenyl), an acylsulfonamide having 14 carbon atoms (e.g., 4- (4-bromophenylsulfonylamino (benzyl) carbonyl) phenyl), an aryl group having 6 carbon atoms and substituted by 2 chlorine atoms, and an aryl group having 6 Carbon atoms and substituted by a chlorine and an amino group;

(VI) a cycloalkyl of 10 carbon atoms (e.g., 1-adamantyl);

(VI) - (D is a cycloalkyl having 5 carbon atoms and substituted by carboxy or ethoxycarbonyl;

(X) an alkenyl group having 2 carbon atoms and substituted by a member selected from

Carboxy, carboxyphenyl (e.g., E-4-carboxymethyl), ethoxycarbonyl, ureidocarbonyl (e.g.

Z-ß-aminocarbonylamino-S-oxo-i-propenylKAcylsulfonamidoiz. B.

4 - [(4-chlorophenyl) sulfonylaminocarbonyl] phenyl) and 4-carbonoxyphenyl (e.g., E-2- (4-carboxyphenyl) ethenyl) R ⁴ is selected as hydrogen;

R ⁵ is selected under:

(I) n-butyl

(II) (q) aralkoxycarbonyl-substituted ethyl wherein the aralkoxy contains 7 carbon atoms; and

(II) (z) araikyloxycarbonylamino substituted butyl wherein the aralkyl group contains 7 carbon atoms;

A corresponds to the above definition; and

η = 1.

The following clauses apply to the compounds according to the invention:

(1) alkyls may be straight or branched chain;

(2) no carbon atom of an alkyl may be attached directly to two heteroatoms;

(3) no heteroatom may be bonded directly to a sulfur, nitrogen or oxygen; and

(4) Alkenyls of IX and X for R ³ must not be 1,1-disubstituted and one carbon of a double bond must not be directly bonded to an oxygen or nitrogen.

The salts of the compounds of formulas I a, I b and I c include pharmaceutically acceptable base or acid addition salts such as those associated with a mineral acid such as e.g. Hydrochloric acid or an organic acid such as citric, maleic, fumaric or acetic acid. Base addition salts include those made with alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates and bicarbonates, alkaline earth hydroxides, and organic amine salts. Such salts can be obtained by dissolving the peptide derivative in a mixture of water and a water-miscible organic solvent, adding an aqueous solution of the base, and recovering the salt from the aqueous solution.

The preferred compounds of the invention correspond to the S configuration (i.e., the configuration of the naturally occurring L-amino acids), with the chiral centers being indicated by * in the formulas Ma, Il bund lic below. The synthetic methods described below in Methods A and B provide a diastereomeric mixture as a result of the presence of both the R and S configuration products at the chiral center indicated by the SymbolA. The separation and synthesis methods described below in Methods C and D provide enantiomeric and diastereomerically substantially pure compounds. The preferred compounds are those of the S configuration at the center indicated by the symbol Δ.

R t

CO »HR. CH, .CO »OT ₃

2'n -

, 3 _ »3 -

R ¹

CO. IiH, CHi CO. ι

CO.IH.GH.CO.

It is obvious to the person skilled in the art that the activity of the individual isomers is not the same, which is why it is preferable to use the more active isomer. The present invention includes both the diastereomeric mixture and the active S and R isomers.

It will be appreciated by those skilled in the art that the trifluoromethyl ketones may exist as solvates - especially hydrates - represented by the formulas IIIa, IMb and IMc and encompassed by the present invention.

R t

CO. HH.CH.C (OH) ₂ .

R '

R CO.UH, CH.C (OH) ₂ .C3? ₃

2 * Π

CO .HH. CH. C (OH) ₂ . CT ₃

Preferably, the peptide derivatives of the invention are prepared from commercially available alpha-amino acids (ie, those in which the NH ₂ group is attached to the carbon atom closest to the -COOH group). Accordingly, the preferred R ² and R ^s substituents in the above formulas for tri- and tetrapeptide derivatives are those derived from one of the following amino acids: alanine, valine, norvaline, leucine, isoleucine, norleucine, phenylalanine , Tryptophan, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysone, threonine, serine, alpha-aminobutyric acid and phenylglycine.

Preferred groups of compounds include those used as the major title for the following embodiments 6,11,15 to 18, 20 to 28,51 to 56,58,59,62,63,65,68,71,72,74,75, 77 to 79, 82, 84 to 91, 93 to 111, 114, 115, 117, 119 and 121 to 126 are listed. Among them, those preferred for the embodiments 16, 24, 27, 52, 58, 71, 74, 79 to 79, 85, 89, 93 to 96, 98, 100, 104 to 107, 110, 114, 115, 119 and 123 to 125 are more preferable, and those for the embodiments 77,95,104,114 and 115 are the most preferred.

According to another aspect of the invention, pharmaceutical compositions are mediated from a pharmaceutically effective amount of at least one peptide derivative of formulas Ia, Ib or Ic and a pharmaceutically acceptable diluent or carrier.

The compounds of the formulas Ia, Ibc can be prepared as follows:

Method A

Stage 1 is the preparation of the amino alcohols V

R ¹ OH H ₂ H.CH.GH «CP ₃ , ν

3 2 1-

(conveniently isolated as the hydrochloride salt). The Hervy condensation (McBee, ET et al., J.Amer.Chem.Soc, 78: 4053 [1956]) of a suitable nitroalkane of the formula R ¹ CH ₂ NO ₂ (prepared by standard methods unless otherwise available) with trifluoroacetaldehyde-ethyl-hemiacetal of the formula [CF ₃ CH (OH) OCH ₂ CH ₃ ] gives a nitroalcohol of the formula VI:

\ R ¹ QH

O ₂ H. CH. CH. GP ₃ vi

which is obtained as a mixture of two racemic diastereomers ([2 (RS), 3 (RS)] and [2 (RS), 3 (SR)]). (See, for example, Example 1 b.) Reduction of the nitro group in Compound VI with an appropriate reducing agent gives Compound V as a mixture of two racemic diastereomers ([2 (RS), 3 [RS)] and [2 (RS), 3 (SR)]). (See, for example, Embodiment 1c.) This amine salt is used directly for further synthesis.

Stage 2 is the conversion of compound V to key intermediates of formulas IVa, IVb and IVc

R ¹ OH.

.! Co H, ch.oh.c: f,

3 z

IVa

ROH

CO. IH. CII. CH. Ci ¹ -

, 3 2 1

IVb

2'-

R ¹ OH QO. HH. CH. OH, C

  3 2 1

IVc

using the methods normally known to those skilled in the art, such as M. Bodanszky, Principles of Peptide Synthesis, Springer Verlag Berlin (1984) and The Peptides. Analysis, Synthesis and Biology (Ed. E. Gross, J. Meienhofer), Vol. 1-5, (Academic Press, New York) 1979-1983. The use of appropriately N-protected cyclic amino acids (such as CBZ-proline) followed by peptide coupling procedures, as well as appropriate amino deprotection, provides compounds of Formula IVa. Similar coupling with suitably N-protected dipeptide acids and tripeptide acids as well as deprotection yields compounds of formulas IVb and IVc, respectively. In addition, compounds of formula IVa can be converted to compounds of formula IVb or IVc using the same peptide methodology. The products obtained here, as described here, are mixtures ([2 (RS), 3 (RS)] and [2 (RS), 3 (RS)]), unless a separation is carried out.

Step 3 is the conversion of intermediate compounds of the formulas IVa, IVb and IVc into intermediate compounds VII a, VII b, VIIc:

R ³ -A

R ¹ OH

CO. IJH. OH, GE. GP,

3 2 1

I ³ - A -

R ¹ .OH

CO.NH.CH.CH.CF.

3 2 1

R ³ - A

R ¹ OH CO. M. CH. GH *

3 2 1

by their reaction with suitable reagents to form amides, ureas, urethanes and sulfonamides including acid chlorides, anhydrides, mixed anhydrides, isocyanates, carbonates such as 4-nitrophenyl carbonates (prepared as described in Kunz, H. et al., Angew Chem. Int Ed. (Eng), 22, 783-784 [1983]), chloroformates, sulfonyl chlorides, and sulfinyl chlorides, followed by oxidation by methods well known in the literature. The products obtained according to the description given here are mixtures ([2 (RS), 3 (SR)] and [2 (RS), 3 (RS)]), unless separation is carried out.

It will be understood by those skilled in the art that the order of the steps in steps 2 and 3 may be altered as appropriate to the considerations of coupling methods, racemization, deprotection methods, and the like. Thus, under appropriate conditions, intermediates of formula Vila can also be prepared directly from compounds of formula V; Intermediates of formula VIIb can also be prepared directly from compounds of V or IVa; and intermediate compounds of the formula VIIc can also be prepared directly from compounds of V, IVa or IVb

Stage 4 is the oxidation of intermediate compounds of formulas Vila, VIIb or VIIc to produce products Ia, Ib or

I c. Useful processes include the use of oxalyl chloride, DMSO and a tertiary amine (see Marx, M. et al., J. Org. Chem., 49, 788-793 (1984), with the best results being 10-20 equivalents Oxidizing agent), the use of acetic anhydride and DMSO, the use of chromium trioxide-pyridine complex in methylene chloride and the use of Dess-Martin Periodinan [1,1,1-triacetoxy-2,1-benzoxiodol-3 (3H) - on] (Dess, DB et al., J. Org. Chem., 48, 4155-56 [1983]). The preferred method is the use of Dess-Martin Periodinan. Unless they have been separated, the products 1a, 1b and ice obtained in this process will contain a mixture [3 (RS)] which will consist essentially of two diastereomers, provided that the centers corresponding to those in the formulas Ha, Hb or ,

II c correspond to *, are essentially enantiomerically pure.

-27- £ f * l OOO

Step 5 is the conversion of products of formulas I a, I b or I c to other products of formulas I a, I b or I c and involves saponification, coupling and deprotection reactions. The stereochemistry of the product mixture is the same as in step 4.

Method B is the preferred method over Method A.

Step 1 involves separating the mixture of the racemic diastereomers of Formula VI obtained as the product of Process A, Step 1, by fractional distillation and crystallization to obtain nitroalcohol VI as a substantially pure racemic diastereomer [2 (RS), 3 (SR)]. which is essentially free of the other racemic diastereomer [2 (RS), 3 (RS)]. Reduction of the nitro group by the preferred method of hydrogenation over a 10% palladium on carbon catalyst yields V as a racemic diastereomer [2 (RS), 3 (SR)], which is substantially free of the other racemic diastereomer is. (Those skilled in the art will appreciate that, on the other hand, the diastereomer [2 (RS), 3 (RS)] can also be used for the preparation of compounds of the invention).

Step 2 is the same as in Method A, but using the amine V prepared as described in Method B, Step 1. The products made by this method are essentially pure [2 (RS), 3 (SR)]. solvent mixtures.

Step 3 is the same as in Method A, but using the product prepared according to Method B, Step 2. The products obtained by this procedure are essentially pure [2 (RS), 3 (SR)] mixtures.

As in method A, the order of the steps in stage 2 and stage 3 can be changed under given circumstances.

Stage 4 corresponds to stage 4 of method A. The same product mixture is obtained as in method A, stage 4.

Level 5 corresponds to Level 5 of Procedure A.

Method C is a method for the direct synthesis of individual ("dissolved") isomers of formulas Ia, Ib and Ic, which are substantially free of the other diastereomers, for example for products corresponding to IIa, IIb and Ilc, in which the * and Δ corresponding centers all represent S.

Stage 1 involves the re-dissolution of the RazematsV prepared according to Method B, Step 1. After the V corresponding free base is released, the re-dissolution occurs by formation of diastereomeric salts with D-tartaric acid and the separation of those salts by fractional crystallization. The desired amine is then recovered by releasing the base on the separated salts to convert, for example, the 2 (R) 3 (S) corresponding free base to a compound of Formula V. The product thus obtained is essentially enantiomerically and diastereomerically pure.

Steps 2 and 3 correspond essentially to steps 2 and 3 in methods A and B, but they are limited to methods which prevent the racemization of centers corresponding to those centers represented by formulas IIa, Ilb and lic are marked by ». The products thus obtained are essentially enantiomeric and diastereomeric

Step 4 is limited to methods which will prevent racemization at the centers indicated by the formulas Il a, Il b and Il c by * and Δ. The preferred method is to use Dess-Martin Periodinan. The products 1a, 1b and 1c obtained in this way are essentially enantiomerically and diastereomerically pure.

Step 5 is limited to methods which will prevent racemization at the centers identified by the formulas Il a, Il b and lic by * and Δ.

Method D

Step 1 is a separation of compounds of the formulas I a, I b or Ic into their individual isomers which are substantially diastereomerically and enantiomerically pure, prepared by methods A or B and (thanks to the 3 (RS) center) diastereomeric mixtures , The preferred method for accomplishing this separation is the use of preparative chromatography, e.g. Medium pressure liquid chromatography and high pressure liquid chromatography.

Stage 2 is the same as Stage 5 in Procedure C.

inhibition measurements:

The ability of the compounds of the invention to act as elastase inhibitors was first determined by the ability of a compound of the invention to inhibit the action of human leukocyte elastase (HLE) on a low molecular weight peptide substrate. The potency of an inhibitor is assessed by obtaining a kinetic determination of the dissociation constant Kienes complex resulting from the interaction of the inhibitor with HLE. The substrate used was the anilide methoxysuccinyl-alanyl-alanyl-prolyl-valine-p-nitroanilide as described by K. Nakajima et al. in J. Biol. Chem., 254: 4027-4032 (1979) and by T. Teshima et al. in J. Biol. Chem., 257: No. 9, 5085-5091 (1982). The HLE enzyme used in these studies may be obtained from Elastin Products, St. Louis, Missouri, or it may be prepared according to B. R. Viscarelloetal. in Preparative Biochemistry, Vol. 13, pp. 57-67 (1983) in the following manner, all work being carried out in a cold room at 4 ° C.

Salt Extraction DNase Treatment: The starting material, 193g purulent sputum, was homogenized with 200 ml of cold distilled water and centrifuged at 30,000xg for 20 minutes at 4 ° C. The supernatant was discarded and the pellet was extracted with high-potency salt and purified according to the method of DYTwumasi et al. in J. Biol. Chem., 252: 1917-1926 (1977) treated with DNase. Chromatography on elastin-agarose: The precipitate of DNase digest was taken up in two 40 ml portions of 50 mM Tris, 1.0 M NaCl, pH 8; the suspension was centrifuged and the resulting supernatant was applied directly to a column of soluble elastin Sepharose 4B (2.5 x 20 cm). The column was washed with equilibration buffer (50 mM Tris, 50 mM NaCl, pH 8.0) until the optical density at 280 nm (OD ₂ %) of the eluate returned to the baseline. Additional contaminating protein was eluted with two column volumes of 50 mM acetate, 1.0 M NaCl, pH 5.0. Elastase and cathepsin G (HLC-G) were finally eluted with 50 mM acetate, 1.0 M NaCl, 20% DMSO, pH 5.0. The column was developed at 6 ml / min with the collection of 10 ml fractions. The active fractions were pooled, dialyzed against two 6 L envelopes of 50 mM acetate, 0.1 M NaCl, pH 5.5, and concentrated to 40 ml on an Amicon® ultrafiltration unit (YM-10 membrane). CM chromatography: The concentrated active fraction was applied to a column of CM-Sephadex® C-50 (2.2 x 10 cm), which had been previously equilibrated with 50 mM acetate, 0.1 M NaCl, pH 5.5, whereupon the Column was washed with this buffer to eliminate contaminating protein. Elution was continued with 50 mM acetate, 0.2 M NaCl, pH 5.5 and resulted in the displacement of an activity peak tested against Bz-Phe-Val-Arg-pNa. Next, HLE was eluted with the acetate buffer containing 0.45 M NaCl, while elution of HLC-G required the presence of 1.0 M NaCl in the buffer as described by R. Martodam et al. in Preparative Biochemistry, Vol. 9, pp. 15-31 (1979)

becomes. This column was developed at 30 ml / h with the collection of 5.5 ml fractions. From the thus purified HLE, a standard rate of production of p-nitroaniline was measured at 25 ^° C., which was spectrophotometrically in the visible spectrum at 410 nanometers with automatic data acquisition by a Varian Associates-supplied Cary 210 spectrophotometer. The reactions were induced by injection of 10 microliters of the HLE solution into a 3 ml cuvette containing 2.89 ml buffer (10 mM sodium phosphate, 50 mM NaCl, pH 7.6), 50 microliters of substrate solution in DMSO and 50 microliters of DMSO. Initially, dynamic equilibrium reaction rates of p-nitroaniline production were calculated by fitting the experimental data to a linear time dependence based on the linear least squares. This rate determined in the absence of inhibitor was used as standard in the calculation of inhibitor Kr values.

All of the peptide derivatives of the present invention invariably proved to be "slow-moving" HLE inhibitors and therefore required special analytical methods for accurately determining the Kj values for their inhibition of HLE (see Williams, JW and Morrison, JF, Meth. Enz. 63,437 [1979] for a) Description of these Methods.) In a typical experiment, 2.89 ml buffer (10 mM sodium phosphate, 500 ml sodium chloride, pH 7.6), 50 microliter inhibitor solution in DMSO, and 50 microliter substrate solution in DMSO were added to a 3 ml cuvette Plug closed, inverted several times to mix their contents and then held in the spectrophotometer at (25 ^° C.) After a period of five minutes to obtain a thermal equilibrium of the reaction solution, 10 microliters of the stock enzyme solution was added to the cuvette to initiate the reaction Double or triple repeats were performed at a zero inhibitor concentration ation. The calculation of the K _r values was carried out according to the illustrations of Williams and Morrison according to the above reference. The Kj values for selected compounds were below 10 ~ ⁷

animal models

Animal emphysema models involve the intratracheal (i.t.) administration of an elastolytic protease to produce a slowly progressing, destructive lesion of the lung. These lesions are usually scored a few weeks to a few months after the original insult. However, these proteases also induce a lesion that is detectable within the first few hours. The early lesion is initially hemorrhagic, progresses to an inflammatory lesion by the end of the first 24 hours, and resolves in the first week after the insult. To use this early lesion, the following model was used.

Hamsters are initially slightly anesthetized with Brevital. Then, phosphate buffered saline (PBS), pH 7.4, either alone or containing 400 micrograms of human leukocyte elastase (HLE), is administered directly into the trachea. Forty-four hours later, the animals are killed, whereupon the lungs are removed and carefully freed of foreign tissue. After determination of the wet lung mass, the lungs are washed out with PBS to determine the total amount of recovered washable red and white blood cells. The values for wet lung mass, total redisable red and total amount of washable white blood cells are determined in a dose-dependent manner after administration of HLE. Compounds that are effective elastase inhibitors can eliminate or reduce the severity of the enzyme-induced lesion, resulting in lower wet lung mass and reduced total cell washable levels - both red and white - relative to the sole administration of HLE results. Compounds may be evaluated by either co-administering with or at various times prior to administration of HLE to determine their utility in preventing HLE lesion. Compounds of the invention produced statistically-assured reductions in wet lung mass as well as the amount of total leachable cells relative to sole HLE administration. Compounds of the invention exhibited activity in at least one of the further described tests under inhibition measurement or animal model. It should be noted that there was not always a direct correlation between the compounds' activity measured as Kr values in the inhibition measurement assay and the reduced total cell wash and wet lung mass readings relative to the sole administration of HLE as obtained in the animal model assay were. It is believed that the animal model test is more meaningful in the efficacy of such compounds in the treatment of emphysema.

Pharmacokinetics: The test compound is injected intravenously into male Syrian hamsters (80 to 120g). Before injection, and at various intervals thereafter, they are lightly anaesthetized with ether, taking blood samples of about 0.2 ml each by means of cardiac puncture. The blood is expressed in 2 ml centrifuge tubes and allowed to clot for one hour. The sample is then centrifuged, after which the serum is withdrawn. Drug levels are first determined by inactivating endogenous elastase inhibitors by incubating 50 microliters of serum with an equal volume of 5mg / ml buffer containing bovine pancreatic trypsin, the incubation lasting 5 min. The trypsin-inactivated serum (10 microliters) is then added to a 0.52 ml cuvette containing buffer adjusted to 2OnM with respect to HLE. After an additional 30 minute incubation, the reaction is started by adding substrate (350 microliters) (MeOSuc-Ala-Ala-Pro-Val-pNA, 1.6 mm) and the reaction is monitored spectrophotometrically at a wavelength of 41OnM. The serum persistence of the test compounds is determined for comparison in the following manner: The percent inhibition of the serum samples was calculated as follows:

Vo-Vi

percent inhibition = χ 100

Vo

where Vo corresponds to the speed obtained in the presence of control serum, and Vi is the rate of the inhibited reaction. The data is expressed as a logarithmic percent inhibition as a function of time after inhibitor administration. From the resulting curve, an approximate serum half life (t V2) is calculated.

The compounds of the invention may be administered to a warm-blooded animal, especially a human, as needed for the treatment of pulmonary emphysema, atherosclerosis, rheumatoid arthritis and osteoarthritis, but especially emphysema. The mode of administration may be oral, parenteral - including subcutaneous deposition by means of an osmotic pump - or via a powdered or liquid aerosol. This may be a conventional formulation in an oral or parenteral dosage form by combining from about 10 to 250 mg per dosage unit with conventional carrier, excipient, excipient, preservative, stabilizer, flavoring or the like, as required by accepted pharmaceutical practice as described, for example, in U.S. Patent No. 3,753,540. For parenteral administration, a 1 to 10 ml complete intravenous, intramuscular or subcutaneous injection containing about 0.02 to 10 mg / kg body mass of a compound of the invention and administered 3 or 4 times daily is considered to be given. The injection could contain a compound of the invention in an aqueous isotonic sterile solution or suspension optionally with a preservative such as phenol or a solubilizing agent such as ethylenediaminetetraacetic acid (EDTA). In a powdered aerosol, the compounds of the invention can be prepared in the same way as cromolyn sodium by means of a Spinhaler® Turbo inhaler device from Fisons Corp. of Bedford, Massachusetts at a rate of about 0.1 to 50 mg per capsule, with a human receiving on average 1 to 8 capsules per day. Each capsule to be used in the Spinhaler® contains the required amount of a compound of the invention while the remainder of the 20 mg capsule consists of a pharmaceutically acceptable carrier such as lactose. In the case of a liquid aerosol, the compounds according to the invention are administered in a dosage of about 100 to 1000 micrograms per puff or per active substance-containing release of a standard propellant volume. The liquid aerosol is expected to be administered at a rate of 1 to 8 puffs per day, depending on the particular dose, the severity of the disease being treated, the mass of the patient, and the particle size distribution of the aerosol, particularly as the latter factor affects smaller particles into the lungs. Propellants, such as a fluorinated hydrocarbon or isobutane, liquid aerosol sols, containers, valves, and actuators have been described by L. Lachman et al. in The Theory and Practice of Industrial Pharmacy, Lea and Febiger, Philadelphia (1976).

In the following as well as throughout the specification, the following abbreviations and conventions are used: at (atmospheres); K (boiling point); ⁰ C (degrees Celsius), all temperatures being in ⁰ C, unless otherwise noted; g (grams); h (hours); mg (milligrams); min (minutes); ml (milliliters); I (liters); Moles (moles); mmol (millimoles); Sp (melting point); K (boiling point); N (normal); nm (nanometers); nM (nanomolar); ges. (saturated); aq. (aqueous); conc. (concentrated); χ (times); Room temperature (2O ... 23 ° C); DCC (IS-dicyclohexylcarbodiimide); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); Et ₂ O (diethyl ether); EtOAc (ethyl acetate); HOAc (acetic acid); HOBT (hydroxybenzotriazole); MeOH (methyl alcohol); EtOH (ethyl alcohol); Pd / C (palladium-on-charcoal catalyst); pNA (paranitroanilide); THF (tetrahydrofuran); CBZ (benzyloxycarbonyl); t-BOC (tertiary butyloxycarbonyl); DMF (dimethylformamide); TEA (triethylamine); DCC dS-dicyclohexylcarbodiimide); AcOH (acetic acid); AM (starting material); NMM (N-methylmorpholine); <(less or equal); TEA (triethylamine); TFA (trifluoroacetic acid); Ac ₂ O (acetic anhydride); CDI (carbonyldiimidazole); WSCDI (water-soluble carbodiimide-ethyl-3- (3-dimethylaminopropylcarbodiimide hydrochloride); DMAP (4-dimethylaminopyridine); Dess-Martin periodinane (1,1,1-triacetoxy-2,1-benzoxiodol-3- (3H) -one); HCI gas (gaseous hydrochloric acid) - otherwise HCl is an aqueous solution, Rh / C (rhodium-on-charcoal catalyst); 0 (phenyl group); TLC (thin layer chromatography on silica gel unless otherwise indicated); R _f ( relative mobility in TLC), MPLC (medium pressure liquid chromatography), HPLC (high pressure liquid chromatography), t _R (HPLC retention time in min), FR (HPLC flow rate in ml / min), CoI A (Zorbax® ODS analytical column, 4,6mm χ 25cm); CoI B (Phenomenex® Zorbax® C-8 analytical column, 4,6mm χ 35cm); CoI C (Altex Ultrasphere® / Octyl 10mm internal diameter χ 25cm 5 micron analytical and preparative column); Column chromatography on silica gel unless otherwise specified); In addition, C, H, N, etc. (the conventional element symbols) are used; 133.3 Pascal = 1 Torr as conversion factor at 760 Torr = 14.7 pounds per square inch (psi); ¹ H NMR (nuclear magnetic resonance) spectra were obtained using an 80 MHz or 250 MHz instrument and using tetramethylsilane (TMS) as the internal standard (the solvent for the specific example is noted in each embodiment); δ (ppm downfield from TMS); with s (singlet); d (doublet); dd (doublet doublet); m (multiple ").

Nomenclature: For the sake of uniformity and unambiguity, "amino acid sequence type" designations are used whenever possible. In addition, amines of the formula V and the N-substituents of C-terminal amides of the formulas I, II, III, IV and VII, which are formally derived from V, are numbered in the manner shown:

R ¹ OH (R ¹ OH ζ R ¹

CH.GH "* CT _{3 /} · S - ^^ SH.CH.CH.Ciy | ~ v ^ IH, CH., CO.C

3 2 1- 3 2 1- 3 2 1

Y IY, YII Ί,

II

(Portion) (portion)

If necessary or in the specified case, different embodiments were repeated if more material was needed.

ZIRSJ fSRJ ^-a-amino-^ -methyl-I.IJ trifluoro-a-pentanol hydrochloride salt

a. 2-methyl-i-nitropropane.

1-iodo-2-methyl propane (94,0g, 0.51 mol) was added dropwise in Et ₂ O (180 ml) was added a precooled (0 ⁰ C) suspension of AgNO ₂ (100.0 g, 0.65 mol). The reaction mixture was protected from light and stirred overnight, allowing to warm to room temperature. The reaction mixture was filtered through Celite®. The filtrate was concentrated under vacuum and the residue was distilled under vacuum (caution: potentially explosive) to give the product (37.7 g, 0.366 mol); K 61 ... 65 ° C at 6913.6 Pascal (52mm Hg).

b. 2 (RS), 3 (SR) -4-Methyl-3-nitro-1,1,1-trifluoro-2-pentanol.

1-Nitro-2-methylpropane (37.7 g, 0.366 mol) from Example 1 a.Trifluoroacetaldehyde-ethyl-hemiacetal (58.5 g, 0.366 mol, 90% purity) and K ₂ CO ₃ (3.4 g, 0.025 mol ) were mixed and stirred for 3 days at 6O ⁰ C for 3h and then at room temperature. Then brine (75 ml) and 1N aqueous HCl (50 ml) were added, after which the lower organic layer was separated. The aqueous layer was extracted with Et ₂ O (twice with 250 ml each time) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified by means of flash chromatography on silica gel with a gradient elution of CH ₂ Cl _2: hexane (50:50), CH ₂ Cl _2: hexane (75:25), CH ₂ CI ₂ (100%) and MeOH: CH ₂ Cl ₂ (5:95) to give the product (44.9g, TLC, Rf = 0.65, silica gel, EtOAc: CHCl ₃ (5:95).

c. 2 (RS), 3 (SR) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol hydrochloride salt.

A solution of one portion of the product of Example 1b (37.0 g, 0.184 mol) in Et ₂ O (200 mL) was added dropwise to a suspension of lithium aluminum hydride (22.0 g, 0.58 mol) in Et ₂ O ( 800ml) was added. The reaction mixture was stirred for 45 min and cautiously treated with a saturated aqueous solution of Na ₂ SO ₄ (110 ml). The resulting suspension was filtered; the filtrate was treated with ethereal HCl and concentrated under vacuum to give the product (37.6g), which was used without further purification. ¹ H NMR data (CD ₃ COCD ₃ ) (250 MHz): 1.28, m, 6H; 2.38, m, 1H; 3.58δ, m, 1H; 4,986, m, 2H; 7.78δ, m, (NH ₂ ).

Embodiment 2

2 (RS), 3 (SR) -N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide

a. 2 (RS), 3 (SR) -1 - [(phenylmethoxy) carbonyl] -N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide.

A solution of 1.01 g Isobutylchloroformiatd, 0.08 mol) in dry THF (30 ml) was added dropwise over 5min of time a pre-cooled solution (-15 ⁰ C) (CBZ-L-proline 19.21 g, 0.077 mol) and Add N-methylmorpholine (8.18 g, 0.081 mol) in THF (300 mL) under a nitrogen atmosphere. The reaction mixture was stirred at -15 C 15min ^0th The reaction temperature was then reduced to -40 ⁰ C and a solution of a subset of the product of Embodiment 1 c (16,00g, 0.077 mol) and N-methylmorpholine (8,18g, 0.081 mol) in THF (200ml) was added dropwise to the reaction mixture has been. The reaction mixture was stirred for one hour at C -4o ^0, then was allowed to gradually warm to room temperature and was stirred for an additional hour. The reaction mixture was filtered and concentrated under vacuum. The resulting syrup was dissolved in CHCl ₃ and washed with aqueous 20% citric acid (75 ml twice). The organic layer was concentrated under vacuum to give the crude product as a white cloudy syrup. The crude product was triturated with ether: hexane (1: 2) to give 3 yields of the product as a white powder (17.11 g); TLC, R _f = 0.47, silica gel, MeOH: CHCl ₃ (3:97); Sp 152 ... 154 ° C; HPLC, t _R = 14.06, 16.63, 18, 23, 19.00, Zorbax® ODS analytical column, H ₂ O: CH ₃ CN (70:30), flow rate = 3 ml / min.

b. 2 (RS), 3 (SR) -N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide.

The product of Embodiment 2a (2.00 g, 4.79 mmol) was dissolved in absolute ethanol (50 mL), then 10% Pd / C (0.5 g) was added, and the reaction was hydrogenolysed at room temperature for 3 h (310126.53 Pascals, 45psi hydrogen). The reaction mixture was filtered through Celite® and the solvent was removed in vacuo to give the product (1.36 g), which was used without further purification.

Embodiment 3

2 (RS), 3 (SR) -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide

a. N-KPhenylmethoxyJcarbonylj-L-valyl-L-proline.

1-Hydroxybenzotriazole (163.3g, 1.2 moles) was added to a pre-cooled (0 ° C) solution of N-benzyloxycarbonyl-L-valine (151.8g, 0.6 mol) in DMF (1.3 liters) and Stirred for 15min. Then, a suspension of L-proline methyl ester hydrochloride (100.0 g, 0.6 mol) and TEA (64.2 g, 0.63 mol) in DMF (0.7 liter) was added followed by DCC (137.1 g, 0 The reaction mixture was stirred for 3 hours at 0 ° C and then at room temperature for a further 3 days The reaction mixture was filtered and the filtrate was concentrated in vacuo The residue was mixed with EtOAc (0.75 liters) and filtered The filtrate was washed successively with 20% aqueous citric acid (0.75 liter), saturated aqueous NaHCO ₃ and brine The organic phase was dried over MgSO ₄ , filtered and concentrated under vacuum to give the crude product (271.3 g) The product was purified by flash chromatography on silica gel using gradient elution starting with CH ₂ Cl ₂ and ending with MeOHiCH ₂ Cl ₂ (4:96) to give the product (218.1 g); TLC, R, = 0.48, silica gel, MeOH: CHCl ₃ (5:95).

b. N - [(phenylmethoxy) carbonyl] -L-valyl-L-proline.

To a solution of a portion of the product of Example 3a (158.8 g, 0.438 mol) in MeOH (1.6 L) was added 1 N aqueous NaOH (500 mL) and the solution was stirred at room temperature for 17 h. Then, 1N aqueous NaOH (100 ml) was added and stirring was continued for an additional 5 hours. An additional 1N aqueous NaOH (50 ml) was then added and the reaction mixture was stirred overnight. The reaction was concentrated under vacuum to remove the MeOH. H ₂ O (1.0 liter) was added and the aqueous solution was extracted with Et ₂ O. The aqueous solution was acidified with 1N aqueous HCl (700 ml) and extracted with EtOAc. The EtOAc extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product (159.2 g); R f = 0.34, silica gel, MeOH: CHCl ₃ : AcOH (5: 94: 1).

c. 2 (RS), 3 (SR) - [(phenylmethoxy) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide.

Isobutylchloroformate (77,3g, 0.566 MoDwurdeeinervorgekühlten ((-15 ⁰ C) solution of N-methylmorpholine 59,25g, 0.566 mol) and the product of embodiment 3b (197.2 g, 0.566 mole) (in 2.5 liters THF getrockenem ) was added and the reaction mixture was stirred 10 minutes long. the temperature was reduced to -40 ⁰ C, followed by N-methylmorpholine (59,25g, 0.566 mol) and then dropwise a solution of the product of embodiment 1 c (117,5g, 0.566 The reaction mixture was allowed to warm to room temperature and stirred for three days The reaction mixture was filtered and the filtrate was concentrated in vacuo The residue was dissolved in EtOAc and washed successively with H 2 ₂ 0.1 N aqueous HCl and brine. the organic layer was dried over Na ₂ sO _4, filtered and concentrated to give the crude product (267.8 g). the product was by means of flash chromatography on Silica using a gradient elution of THF: toluene (5:95) to THF: toluene (25:75) to give the product (183.8 g); TLC, R _f = 0.4, silica gel, THF: toluene (20:80). d. 2 (RS), 3 (SR) -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide.

A mixture of one portion of the product of Example 3c (36.7g, 0.073 mole) and 10% Pd / C (10%, 50% water wet) in EtOH (0.6 liter) was loaded on a Parr shaker (303,924 Pascal, 3at H ₂ ) hydrogenated. After 1 h, the reaction vessel was evacuated and then repressurized with H ₂ . After another half hour, the reaction mixture was filtered through Celite® and concentrated under vacuum to give the product (26.0g); TLC, R _f = 0.16, silica gel, MeOH: CHCl ₃ (5:95).

Embodiment 4

2 (RS), 3 (SR) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol hydrochloride salt

a. 2-Methyl-1-nitropropane.

An alternative process for preparing the compound of Example 1 a is as follows. A 5-liter, 3-neck round bottom flask was equipped with a mechanical stirrer, thermometer, addition funnel, and N ₂ inlet. The flask was charged with AgNO ₂ (1006.8.6.54 mol) in Et ₂ O (2.5 L) and isobutyl iodide (927.2 g, 5.03 mol) was added to the addition funnel. Both the flask and the addition funnel were wrapped in aluminum foil to protect the reaction from light. After cooling the stirred suspension to about 5 ° C (ice bath), the dropwise addition started the iodide over a 2 hour period. Throughout the addition, the reaction temperature was maintained at or below 5 ° C. After completion of the addition, the reaction vessel was packed in ice and allowed to warm slowly to room temperature overnight. The NMR analysis of an aliquot removed from the reaction mixture after stirring for 48 hours showed that all of the isobutyl iodide had been consumed. The reaction mixture was filtered through Celite® to remove silver salts and the filter cake was washed with Et ₂ O (3 x 500 mL). The composite filtrates were dried MgSO ₄ filtered, and concentrated on a rotary evaporator (bath temperature = 35 ⁰ C) to about 600 ml. Fractional distillation (atmospheric pressure) (Caution: potentially explosive) gave the purified nitro compound (350.4g, 68% yield); K 135 ... 142 ° C.

b. 2 (RS), 3 (SR) -4-Methyl-3-nitro-1,1,1-trifluoro-2-pentanol.

A 3 liter 3-necked round bottom flask equipped with a mechanical stirrer and N ₂ inlet was charged with K ₂ CO ₃ (470.0g, 3.4 moles), the product of Working Example 4a (350.0g, 3.4 moles) and finally charged with trifluoroacetaldehyde-ethyl-hemiacetal (708.0g, 4.4 mol). The mixture was stirred vigorously at room temperature for 76 hours, whereupon ¹ H NMR revealed almost complete consumption of the nitroalkane. The reaction mixture was diluted with CH ₂ Cl ₂ and filtered. The filtrate was treated with aqueous HCl until pH = 3. The layers were separated and the aqueous layer was washed with CH ₂ Cl ₂ (500 ml). The combined CH ₂ Cl ₂ portions were washed with H ₂ O (1 liter) and brine (1 liter). Drying (MgSO ₄ ) and concentration afforded 854.6 g of crude product in the form of a yellow oil. The ¹ H NMR showed the two diastereomeric nitro alcohols (quantified by the integration of the alcohol protons in the ratio of about 3: 1) that pass through in acetoh-d ₆ , which is contaminated by solvents and small amounts of starting materials is, constantly in the range δ6,0 ... 6,5 emerge

 Distillation under reduced pressure gave the following fractions:

Boiling point (° C)

42 ... 50 ° C / at A.M. + solvent

35 ° C / 1 Torr ... 45 ° C / 0.5 Torr

45 ° C / 0.5 Torr ... 1.5 Torr

95 ° C / 1,5Torr ... 105 ° C / 2Torr

Volatile substances in the collecting vessel

To simplify the purifications in the following synthetic steps, it has been tried at this point to recover the diastereomeric main pair in a substantially pure state and to process only this material in sequence. The diastereomeric parent crystallizes from both the diastereomeric mixture and cold pentane to yield colorless needles. Thus, fraction C from the above distillation was allowed to crystallize overnight in a refrigerator. The product was collected, washed with cold pentane and dried for several hours in a vacuum oven (note, this material is volatile to some extent, so that considerable amounts may be lost upon extensive vacuum treatment) to give 52.0 g of substantially pure material. The fractions, which are known to contain (by NMR) significant amounts of the desired isomer, were repeatedly treated in this manner (and redistilled to provide new fractions of material further enriched with the desired diastereomer), eventually to a total of 197.7 g of essentially pure nitro-alcohol. This amount corresponds to the manner of the procedure, but does not reflect the upper limit of the yield.

c. 2 (RS), 3 (SR) -3-amino-4-methyl-1,1,1-trifluoro-2-pentanol hydrochloride salt.

Anhydrous ethyl alcohol (232 ml) was added to 10% Pd / C catalyst (2.30 g) under N ₂ *. The product of Example 4b (22.93 g, 0.144 mol) was then added and the resulting mixture was placed on a Parr hydrogenator (approximately 480,000 Pascal, 55 psi H ₂ ) overnight. The catalyst was removed by filtration through Celite®. The filter cake was then washed with EtOH. HCl gas was bubbled through the pooled filtrates to about 8g

Dimensions A 191,7g B 34.8 g C 213.6 g D 337.8 g e 114.0 g

(about 0.22 mol) were absorbed. The solution was concentrated on a rotary evaporator and the resulting residue was concentrated several times from Et ₂ O to give a white solid. The solid was washed with Et ₂ O and dried in a vacuum oven overnight to afford 20.79g (88%) of amine hydrochloride. With slow heating, the material softens at 90 ⁰ C and melts at 118 ... 120 ° C. If a sample is immersed in a bath preheated to 110 ° C, it melts immediately.

* Less active catalysts (eg 10% Pd / BaSO ₄ , wet 10% (Pd / C) or insufficient reaction times can lead to the production of one or more by-products.

Embodiment 5

2 {RS), 3 (SR) -L-Valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide

a. N - [(phenylmethoxy) carbonyl] -L-valyl-L-proline methyl ester.

A solution of CBZ-L-valine (100.0g, 0.40 mol) in DMF (1 liter, dried over sieves) was added to a 3 liter 3-neck round bottom flask equipped with mechanical stirrer, N ₂ inlet and thermometer. The reaction mixture was cooled to ⁰ ° C. and treated with HOBT hydrate (108.1 g, 0.80 mole). Stirring was then carried out for about 15 minutes before adding a DMF (500 ml) slurry of L-proline methyl ester hydrochloride (66.2g, 0.40 mole) and TEA (41.8g, 0.42 mole) in one portion has been. Additional DMF (500ml) was used to complete the transfer of the slurry. To the reaction mixture was added DCC (90.8 g, 0.44 mol) and washed down with DMF (100 mL). The reaction mixture was stirred at 0 ^° C. for 3 hours before allowing to warm to room temperature and stirring for three days. The reaction mixture was then filtered, and the filtrate was concentrated at reduced pressure. The filter cake was washed with EtOAc (3x1 liter) and the concentration of the resulting filtrate gave material which was combined with the residue from the DMF solution concentration. The combined product mixture (about 2.5 liters) was diluted with Et ₂ O (2 liters) and stored in the refrigerator overnight. The precipitate was removed by filtration. After washing the filtrate with 1N HCl (1 liter), further precipitate formed, which was also removed by filtration. The filtrate was then washed with 1N HCl (1 liter), H ₂ O (0.5 liter), saturated NaHCO ₃ (2 x 1 liter) and brine (0.5 liter). Drying with MgSO ₄ and concentration yielded 587.2 g of crude product. This material was subjected to flash chromatography on silica gel (3.5kg) with a gradient elution (CH ₂ Cl ₂ to 5% MeOH: CH ₂ Cl ₂ [5:95]). Mixed fractions were repeatedly chromatographed to remove impurities. The pooled fraction containing the desired product gave 500.7 g (87% material contaminated with a small amount of low Rf impurity; TLC, R _f = 0.37, silica gel, Et ₂ O: hexane (3: 1 R _f = 0.53, silica gel, MeOH: CHCl ₃ (5:95).

b. N - [(phenylmethoxy) carbonyl] -L-valyl-L-proline.

A methanolic (4 liter) solution of the product of Embodiment 5a (500.7 g, 1.38 mol) was added to a 12-liter, 3-neck round bottom flask equipped with a mechanical stirrer and an N ₂ inlet. To the stirred solution was added 1 N NaOH (1.4 L) which brought the pH to about 13. After stirring the reaction mixture for 3 hours, the pH dropped to 11. Additional 1N NaOH (0.1 liter) was used to bring the pH to 12, after which the reaction mixture was stirred at room temperature overnight. MeOH was removed from the reaction mixture by concentration on a rotary evaporator. In the course of the solvent removal, a total of 1 liter of H ₂ O was added to reduce the concentration of the base. The aqueous solution was washed with Et ₂ O before being acidified with 1N HCl (1.5 liters) to a pH of about 3.5. The layers were separated and the aqueous layer was extracted with EtOAc (3 χ 1 liter). The combined organic extracts were washed with brine (1 liter), dried (MgSO ₄ ) and concentrated to give 493.0 g (100%) of product as a white solid; TLC, R _f = 0.51, silica gel, MeOH: CHCl ₃ (5:95) with AcOH added.

c. 2 (RS), 3 (SR) - [(phenylmethoxy) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide. The product of Example 5b (105.3g, 0.302 mole) was dissolved under N ₂ in dry THF (1.5 liter) in a 3 liter 3-neck round bottom flask equipped with a mechanical stirrer, thermometer, N ₂ inlet and addition funnel , The solution was cooled to -35 ° C and treated with one equivalent (34 mL, 0.309 mol) of NMM. Across 20 min isobutylchloroformate (39 ml, 0.307 mol) was added dropwise while the temperature be "<-35 ⁰ C. After complete addition, the reaction mixture was stirred for 1 h at -35 ° C. Then a second equivalent of NMM (34 ml) was added. Next, the product of Example 4c (62.8 g, 0.302 mol) in THF (300 mL) was added at such a rate as to maintain the temperature <-35 ° C. After completion of the addition the temperature at -35 ⁰ S was kept C for one hour before the mixture was given the opportunity to heat up while stirring overnight at room temperature. The reaction mixture was filtered and the filter cake was washed with THF (1 liter). The pooled filtrates were concentrated to give 189 g of crude product. This material was flash chromatographed on silica gel (5000 mL) and eluted with THF: toluene (1: 9). After the product began to elute, the solvent polarity was changed in gradient fashion: THF: toluene (15:85); THF: toluene (20:80); and finally MeOH: THF: toluene (2.5: 30: 70) (the use of MeOH was minimized to prevent the elution of low Rf impurities). Concentration of the column fractions followed by drying under vacuum overnight yielded 12.0 g (8%) of slightly contaminated product and 131.6 g (87%) of substantially pure material. NOTE: Solutions of this material used to achieve complete dryness produced a foam which eventually solidified under prolonged vacuum treatment. Care should be taken that this operation was done in a sufficiently large flask to account for the expansion of the foam.) TLC, R _f = 0.25, silica gel, MeOH: CHCl ₃ (5:95); R _f = 0.37, silica gel, THF: toluene (20:80). If the material is slightly spotted, the two isomers are redissolved to give speckles at R _f = 0.37 and R _f = 0.46, silica gel, THF: toluene (20:80). (NOTE: Maintaining the internal temperature given for this procedure appears to be critical to recovery of a substantially pure product.)

VUn / -1_-Vaiyi-IH-1% J - \ * 1 ^ I1ICLI lyi-1,1,1-IIIIIUUIV Λ. iiy ^ i w ^ y ^ wm.7 i / j _ | ~. w .... * .....

The product of Example 5c (131.6g, 0.262 mol) was dissolved in EtOH (750 mL) and pooled under N ₂ with 10% Pd / C catalyst in a large Parr hydrogenation flask. The reaction mixture was shaken at 480000 Pascal, 55 psi H ₂ atmosphere on a Parr apparatus. The repressurization with H ₂ was continued until no further uptake was observed. Examination of the reaction by TLC showed complete consumption of starting material. The reaction mixture was filtered through Celite® and concentrated to a foam. This material was triturated with Et ₂ O, filtered and dried to give 81.4 g (84%) of a light gray solid; TLC, Rf = 0.41, silica gel, CHCl ₃ IMeOH (10 μl). *

Embodiment 6

3S (or R) -phenylmethoxycarbonyl-L-valyl-N- [3- (1,1,1-trifluoromethyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = OCH ₂ , R ⁴ = H, A = OCO, n = 1)

a. 2R _/ 3S-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol-D-tartaric acid salt.

Amine hydrochloride (20 g), prepared as in Example 4e, was dissolved in H ₂ O and neutralized with solid NaHCO ₃ . The aqueous solution was extracted several times with CH ₂ Cl ₂ . The pooled extracts were dried (Na ₂ SO ₄ ) and concentrated to give the amine-free base (14.04 g) as a white solid. This material was combined with D-tartaric acid (12.31g) in boiling EtOH (100ml) and the resulting cloudy solution was filtered hot through filter paper. The solution was first slowly cooled to room temperature overnight and then placed in the refrigerator for several hours. The precipitate was collected on a filter funnel, washed with cold EtOH, and dried overnight in a vacuum oven at 4O ⁰ C. A sample of the dried white solid (4,56g) melted at 127 ... 13O ⁰ C. Most of this material (4,05g) was dissolved in boiling EtOH (20 ml) and the solution was slowly cooled to room temperature. The settling white, gel-like solid was collected in a sintered glass funnel and washed with several portions of EtOH. The several hours drying in a vacuum oven at 4O ⁰ C gave a white solid, melting point 132 ... 134 ° C.

b. 2S, 3S - [(Phenylmethoxy) carbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃₎ CH _3, R ² = CH (CH ₃₎ CH _3, R ³ = 0CH _2, R ⁴ = H, A = OCO, n = 1).

Acid prepared according to Example 5b (1.00 g, 2.87 mmol) was dissolved under N ₂ in dry THF (16 mL) in a 50 mL three-neck round bottom flask equipped with a thermometer, N ₂ inlet, septum and magnetic stir bar was equipped. NMM (0,34ml, 3.09 mmol) was added, and the resulting mulled solution was cooled to an internal temperature of -35 ⁰ C. Then, isobutyl chloroformate (0.37 ml, 2.85 mmol) was added over 2 minutes, taking care that the internal temperature did not rise above -35 ° C. The reaction mixture was stirred for 1 h at -45.degree.-35.degree. The D-tartrate salt of embodiment 6a (0.92 g, 2.86 mmol) in a mixture of THF (5 mL) and DMSO (2 mL) was treated with NMM (0.68 mL) and the cloudy solution was added to the reaction mixture in a added at such a rate that the temperature was kept below -40 ⁰ C. The reaction mixture was for 1 hour at -45 ...- 15 ⁰ C is stirred before it was allowed to warm to room temperature overnight. The mixture was diluted with CHCl ₃ and then washed (H ₂ O, saturated aqueous NaHCO ₃ ), dried (Na ₂ SO 4) and concentrated to give the title product (1.15 g, 80%) as a white solid Spectrum of this material in DMSO-d ₆ showed a doublet at 36.43, which corresponds to the corresponding chemical shift of the alcohol proton in material with the designated relative configuration.

c. 3S (or R-phenylmethoxycarbonyl-L-valyl-N-tS-d.iJ-trifluoro- ^ methyl ^ -oxopentyDl-L-prolinamide (Formula Ib, R ¹ = CH (CH ₃₎ CH _3, R ² = CH ( CH ₃₎ CH _3, R ³ = 0CH _2, R ⁴ = H, A = OCO, η = 1). _v

A portion of the alcohol produced in Example 6b (0.25 g, 0.5 mmol) was dissolved in CH ₂ Cl ₂ and treated with Dess-Martin periodinane (0.42 g, 0.99 mmol) in a single portion. TFA (0.08 mL, 1.04 mmol) was added and the slightly cloudy mixture was stirred overnight. The reaction mixture formed a white suspension. By detection by TLC, essentially no starting material was present. Then, hydrous Na ₂ S ₂ O ₃ (0.78 g) and NaHCO ₃ (0.42 g) were added and stirred with the reaction mixture. In case of clarification of the organic layer from the white solid suspension, this was separated from the aqueous phase. The organic layer was washed (saturated aqueous NaHCO ₃ ), dried (Na ₂ SO ₄ ) and concentrated to give an oil. This material was redissolved and concentrated from Et ₂ O / hexane to give a white solid (0.21 g, 84% yield). Recrystallization from hot Et ₂ O / hexane afforded a substantially pure sample of the title compound in the form of a substantially pure isomer which on HPLC gave a single peak with a retention time consistent with that of an authentic sample of the title product after preparation as described in Example 117 identical; HPLC, t _R = 5.65, CoI A, H ₂ OiCH ₃ CH (55:45), FR = 2.0.

Embodiment 7

1- [2- (tricyclo [3.3.1.1 ^{3> 7} ] dec-1-yl) ethoxycarbonyl] - N - [3 (RS) -3- (4-methyl-1,1,1-trifluoro-2-oxopentyl )] - L-prolinamide

a. 4-Nitrophenyl 2- [tricyclo (3.3.1.1 ³ ' ⁷ ) dec-1-yl] -ethyl carbonate.

A solution of p-nitrophenyl chloroformate (1.17 g, 5.82 mmol) in Et ₂ O) (25 ml) at 0 ⁰ C was added (5 ml) is added pyridine, followed then added dropwise over 1 hour period 2- (1- Adamantyl) ethanol (1.00g, 5.54 mmol) in Et ₂ O (20 mL). The resulting mixture was stirred at room temperature for 12 h and partitioned between H ₂ O and Et ₂ O. The ethereal layer was washed with 5% aqueous HCl, pH 7.0 phosphate buffer, dried over MgSO ₄ , filtered, and the solvents were removed under vacuum. The crude product was purified by flash chromatography on silica gel eluting with EtOAc-hexane (5:95) to give the product (1.10 g) as a white powder; TLC, R _f = 0.29, silica gel, EtOAc: hexane (5:95).

b. 1- [2- (tricyclo [3.3.1.1 ^3J ] dec-1-yl) ethoxycarbonyl] -N- [2 (RS), 3 (SR) -3- (4-methyl-1,1,1-trifluoro- 2-hydroxypentyl)] - L-prolinamide.

A solution of the product of Example 7a (731.0 mg, 2.98 mmol), a product prepared by the procedure of Example 2b (500 mg, 1.8 oM mol) and K ₂ CO ₃ (2.57 g, 18.6 mmol). in DMF (50 ml) was stirred at room temperature for 18 h, filtered and freed from the solvent under vacuum. The residue was taken up in EtOAc, washed with three portions of 10% aqueous NaOH, dried over solid K ₂ CO ₃ : Na ₂ SO ₄ (10:90), filtered

MeOH: CHCl ₃ (1:99) was eluted. The resulting solid was washed with hexane to give the product (340 mg) as a white solid; HPLC, t _R = 5.86, 6.38, Zorbax® ODS analytical column, flow rate = 2 mL / min, CH ₃ CN: H ₂ O: TFA (70: 30: 0.1).

c. 1- [2- (Tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl) ethoxycarbonyl] -N-3 (RS) - [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl )] - L-prolinamide. A solution of oxalyl chloride (1.09 g, 8.6 μmol) in dry CH ₂ Cl ₂ (15 ml) cooled to -43 ° C was added dropwise over 15 min DMSOi 1.37 g, 17.3 mmol in dry CH ₂ Cl ₂ (10ml) added. The solution was stirred for 10 min and then the product of Example 7b (340 mg, 0.72 mmol) was added dropwise over 30 min. After further stirring the solution at -43 ° C for 1 h, TEA (4.80 mL, 34.5 mmol) was added slowly, whereupon the solution was allowed to warm to room temperature and was stirred for 2 h. The solution was diluted with CH ₂ Cl ₂ , washed with 10% aqueous HCl, then washed with 5% aqueous NaOCl, dried over solid K ₂ CO ₃ INa ₂ SO ₄ (10:90), filtered and evaporated from the solvent under vacuum freed. The crude product was purified by 2 consecutive flash chromotographies on silica gel eluting with MeOH: CHCl 3 (0.1: 99.9) or EtOAc: hexane (1: 5) to give the product (130 mg) as a white solid; TLC7R _f = 0.50, silica gel, MeOH: CHCl ₃ (5:95); HPLC, t _R = 5.31, Zorbax® ODS analytical column, flow rate = 2 mL / min, CH ₃ CN: H ₂ O: TFA (70: 30: 0.01).

Analysis calculated for:

C ₂₄ H ₃₅ N ₂ F ₃ O ₄ -0.25 H ₂ O: C, 60.43; H, 7.50; N, 5.87

Found: C, 60.50; H, 7:45; N, 5.74

Embodiment 8

3 (RS) -1- (4-Phenylbutylcarbonyl) -N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide

a. 2 (RS), 3 (SR) -1- (4-Phenylbutylcarbonyl) -N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide.

A solution of 5-phenylvaleric acid (0,330g, 1.86 mmol) and N-methylmorpholine (0.280 g, 2.79 mmol) in THF (100 ml) was cooled to -15 ⁰ C. Then, a solution of isobutyl chloroformate (0.280 g, 2.05 mmol) in THF (5 mL) was added dropwise and the mixture was stirred at -15 ° C for 10 minutes, after which the temperature was lowered to -40 ° C and a solution of a procedure of Example 2b (0.500 g, 1.86 mmol) in THF (25 mL) was added dropwise. The mixture was stirred for 1 h at ⁰ -4o C and overnight at room temperature. The mixture was filtered and the filtrate concentrated under vacuum. The crude product was purified by flash chromatography on silica gel using MeOH: CHCl ₃ (3:97) as eluent to give the product (0.60 g) as a white solid; TLC, R, = 0.40-0.51, silica gel, MeOH: CHCl ₃ (3:97).

b. 3 (RS) -1- (4-Phenylbutylcarbonyl) -N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide.

A solution of DMSO (4.22 g, 54 OmMoI) in dry CH ₂ Cl ₂ (80 mL) was added (under a nitrogen atmosphere was added dropwise over 10 minutes of time a pre-cooled (-6O ⁰ C) solution of oxalyl chloride mulled 3,43g, 27 , OmMoI) in CH ₂ Cl ₂ (10 ml). The temperature exceeded during desZusetzens not -55 ⁰ C. The mixture was stirred at -6O C ⁰ 15 minutes, and then also at -6O ⁰ C a solution of the product of Embodiment 8a (0,580g, 1.35 mmol) in CH ₂ CI ₂ (100ml) was added dropwise over 10min. The reaction mixture was stirred at -60 ° C. for ¹ h. Now (OmMoI 6,98g, 54) was added at -6O ⁰ C diisopropylethylamine was added dropwise over 10 min time. Upon subsequent warming to room temperature, the reaction mixture was stirred for one hour. The reaction mixture was washed successively with two portions of 1N aqueous HCl and brine, and concentrated under vacuum to give the crude product (0.85 g as an orange syrup.) The crude product was purified by three successive flash chromatographies on silica gel, each eluted with 1) MeOH: CHCl ₃ (3:97), 2) MeOH: CHCl ₃ (3:97) and 3) Et ₂ O: hexane (90:10) to give the product (319 mg) as a to give white foam; TLC, R f = 0.33-0.40, silica gel, Et ₂ O: hexane (90:10); HPLC, t _R = 17.93, 18.55, Zorbax® ODS analytical column, H ₂ O: CH ₃ CN (55:45), flow rate = 2 ml / min

 Analysis calculated for:

C ₂₂ H ₂₉ N ₂ O ₃ F ₃ -25 H ₂ O: C, 58.85; H, 7.07; N, 6,24

Found: C, 58.91; H, 6.83; N, 6,13

Embodiment 9

3 (RS) -1 - [(phenylmethoxy) carbonyl] -N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L -prolineamide A solution of dimethyl sulfoxide (0.890g, 11 , 4 mmol) and dry methylene chloride (5ml) was added dropwise under nitrogen to a mulled solution of oxalyl chloride (0.75 g, 5,9mMol) and dry methylene chloride (5ml) at ⁰ C -6O. The reaction mixture was given the opportunity to warm up to -25 ⁰ C, then a solution of a prepared according to procedure of embodiment 2a product (0,2000g, 0,497mMol) and dry methylene chloride (5 ml) was added. The resulting mixture was stirred at -25 ° C for 0.5h. Then, triethylamine (1.94 g, 19.2 mmol) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was filtered. The filtrate was evaporated. The residue was dissolved in chloroform. The chloroform solution was washed successively with 1 N aqueous HCl and brine, and dried over Na ₂ SO ₄ . The solution was filtered. The solvent was removed under vacuum to give the crude product (0.147 g). The crude product was purified by flash chromatography on silica gel with CHCl ₃ : MeOH (97: 3) as eluent to give the product (0.11 g); TLC, R _f = 0.25, CHCl ₃ : EtOAc (90:10)

 Analysis calculated for:

C ₁₉ H ₂₃ F ₃ N ₂ O ₄ -1.5 H ₂ O: C, 53.39; H, 6,13; N, 6.55

Found: C, 53.55; H, 5.78; N, 6.56

-35- Z47 683 Embodiment 10

2 (RS), 3 (SR) -L-ValyRM3- (4-methyl, 1,1-trifluoro-2-hydroxypentyl) L-prolinamide (formula)

a. N - [(phenylmethoxy) carbonylH - valyl-L-proline methyl ester

 The procedure of embodiment 3a was repeated.

b. N - [(phenylmethoxy) carbonyl] -L-valyl-L-proline.

Using the material of embodiment 10a, the procedure of embodiment 3b was repeated.

c. 2-methyl-i-nitropropane.

The procedure of Example 1 a was repeated. - "

d. 2 (RS), 3 (SR) -4-Methyl-3-nitro-1,1,1-trifluoro-2-pentanol.

The procedure of embodiment 1 b was repeated using the material of embodiment 10c.

e. 2 (RS), 3 (SR) -3-amino-4-methyl-1,1, i-trifluoro-2-pentanol hydrochloride salt.

The procedure of Example 1c was repeated using the material of Example 10d.

f. 2 (RS), 3 (SR) - [(phenylmethoxy) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide.

The process of Embodiment 3c was repeated using the compounds of Embodiments 10b and 10e.

G. 2 (RS), 3 (SR) -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyi)] - L-prolinamide.

The method of Embodiment 3d was repeated using the connection of Embodiment 10f.

Embodiment 11

3 (RS) - [(phenylmethoxy) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide a.-f. The steps af were repeated as explained in the embodiments 10a-f, g. SIRSJ-KPhenylmethoxyJcarbonyll-L-valyl-N-tS-t ^ methyl-Ijji-trifluoro ^ -oxopentyDl-L-prolinamide. A solution of DMSO (12,46g, 159,5OmMoI) in dry CH2Cl2 (12 ml) under a nitrogen atmosphere was added dropwise over 10 minutes of time a pre-cooled (-60 ⁰ C) mulled solution of oxalyl chloride (10,12g, 79.75 mmol ) in CH ₂ Cl ₂ (160 ml). During the addition, the temperature of the reaction mixture never exceeded -50 ° C. Then, C a solution of the alcohol of Embodiment 11 f (2.00 g, 3,99mMol) in CH ₂ CI ₂ (160 ml) dropwise over 10 min added at -6O away ^0th The reaction mixture was stirred at -60 ° C. for ¹ h. Now, C diisopropylethylamine (20,62g, 159,5OmMoI) was added dropwise over 10 minutes of time at -60 ^c. Upon allowing to warm to room temperature, the reaction mixture was stirred for 1 h. The reaction mixture was washed with 1N aqueous HCl followed by brine and then concentrated under vacuum to give the crude product as an orange syrup (2.76g). The crude product. was subjected to three consecutive flash chromatographies on silica gel eluting 1) with ether: hexane (80:20), 2) MeOHiCHCl ₃ (2.5: 97.5) and 3) MeOH: CHCl ₃ (2.5: 97.5 ) to give the product as a white foam (0.88 g); TLC, R _f = 0.45, silica gel, MeOH: CHCl ₃ (3:97); HPLC, t _R = 6.45, 11.10, Zorbax® ODS Analysis Column, H ₂ O = CH ₃ CN (55:45) with O, 1% trifluoroacetic acid, flow rate = 2 mL / min

 Analysis calculated for:

C ₂₄ H ₃₂ N ₃ O ₅ F ₃ -0.5 H ₂ O: C, 56.68; H, 6.54 N, 8.26

Found: C, 56.58; H, 6.52; N, 8,21

Embodiment 12

3 (RS) - [2- (2-Oxopyrrolidinyl) ethoxycarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxypentyl)] - L-prolinamide

a. 4-Nitrophenyl-2- (2-oxopyrrolidinyl) ethyl carbonate.

N- (2-Hydroxyethyl (pyrrolidone (3.00 g, 23.2 mmol) was dissolved in diethyl ether (20 mL) under a nitrogen atmosphere and stirred at room temperature.) To the mixture was added a solution of p-nitrophenyl chloroformate (4.68 g, 23.2 mmol in diethyl ether (25 ml) dropwise over 2 h, the mixture was stirred at room temperature for a further 2 h, and the mixture was concentrated in vacuo to give the crude product (7.90 g) The crude product was purified by silica gel chromatography MeOH: CHCl ₃ (5:95) to give the product as a white powder (4.62g); TLC, R _f = 0.51, silica gel, MeOH: CHCl ₃ (3:97).

b. 2 (RS), 3 (SR) - [2- (2-oxopyrrolidinyl) ethoxycarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L -prolinamid.

Potassium carbonate (2.820 g, 40.8 mmol) was added to a solution of ethyl 2-pyrrolidone p-nitrophenyl carbonate (1.20 g, 4.08 mmol) and a product prepared according to the procedure of Example 3d (1.50 g, 4.08 mmol) DMF (100 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc and the excess K ₂ CO ₃ was filtered off. The filtrate was concentrated under vacuum to give a residue, which was dissolved in EtOAc and washed successively with aqueous 10% NaHCO ₃ , water, aqueous 5% citric acid and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the crude alcohol. The alcohol was purified by flash chromatography on silica gel with MeOH: CHCl ₃ (5:95) to give the product (0.72 g); TLC, R _f = 0.46, silica gel, MeOH: CHCl ₃ 7:93).

c. 3 (RSM2- (2-oxopyrrolidinyl) ethoxycarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxypentyl)] - L-prolinamide.

A solution of DMSO (4,310g, 55,2OmMoI) in dry CH ₂ Cl ₂ (6 ml) was added dropwise over 10 minutes of time a pre-cooled (-60 ⁰ C) mulled solution of oxalyl chloride (3.500 g, 27,6OmMoI) in CH ₂ CI ₂ (80 ml) was added under a nitrogen atmosphere. During the addition the temperature of the reaction mixture never exceeded -50 ⁰ C. A solution of alcohol of Embodiment 12b (0,720g, 1.38 mmol) in CH ₂ CI ₂ (80 ml) was added dropwise over 10 min at -60 ⁰ C away , The Reaktionsgemiscfi was stirred two hours at -60 ⁰ C. 1 Then, a solution of diisopropylethylamine (7,13g, 55,2mMol) in CH ₂ Cl ₂ (50ml) was added dropwise over 10 minutes of time at -60 ⁰ C. Upon allowing to warm to room temperature, the reaction mixture was stirred for 1 h. The reaction mixture was washed with 1N aqueous HCl and brine and then concentrated under vacuum to give the crude product as an orange syrup. The crude product was purified by flash chromatography on silica gel with MeOH: CHCl ₃ (5:95) to give the product as a white foam (0.43 g); TLC, R _f = 0.33, silica gel, MeOH: CHCl ₃ (5:95); HPLC, t _R = 3.50, 4.63, Zorbax® ODS analytical column, H ₂ O: CH ₃ CN (55:45), flow rate = 1 ml / min

 Analysis calculated for:

C ₂₃ H ₃₅ N ₄ O ₆ F ₃ H ₂ O: C, 51.29; H, 6.92; N, 10.40

Found: C, 51.20; H, 6.86; N, 10.03

Embodiment 13

3 (RS) - [2-Methoxycarbonyl) ethylcarbonyl] -L-valyl-IM [3- (4-methyl-1,1,1-trifluoromethyl-2-oxopentyl)] - L-prolinamide

a. Benzyloxycarbonyl-L-valyl-L-proline t-butyl ester.

A solution of N-benzyloxycarbonyl-L-valine (56,25g, 0.244 mol) and HOBT (60,67g 0.45 mol) in DMF (565ml) was cooled to 5 ⁰ C. Next, DCC (50.89 g, 0.247 mol) was added in one portion. The mixture was stirred at 5 ° C for a further 15 min and then L-proline t-butyl ester (38.36 g, 0.224 mol) was added. The mixture was stirred at 5 ^° C. for a further 2 h and then at room temperature for 48 h. The mixture was filtered and concentrated under vacuum. The oily residue was dissolved in EtOAc (1 liter) and washed successively with 20% aqueous citric acid, saturated aqueous NaHCO ₃ and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to afford the product (92.0g) as a white foam; TLC, R _t = 0.9, silica gel, CHCl ₃ : EtOAc (85:15).

b. L-valyl-L-proline t-butyl ester.

A mixture of the product of Example 13a (92.0g, 0.227 mol) and 10% Pd / C (10g) in EtOH (1 liter) was hydrogenated on a Parr shaker for 6h at Pascal, 60 psi and room temperature. The mixture was filtered through Celite® and concentrated under vacuum to afford the product (62 g) as a viscous yellow oil; TLC, R _f = 0.3, silica gel, MeOH: CHCl ₃ (10:90).

c. N- [2- (Methoxycarbonyl) ethylcarbonyl] -L-valyl-L-proline 1,1-dimethylethyl ester.

1N Aqueous NaOH (8.0 mL) was added to a precooled (O ⁰ C) solution of the product of Example 13b (2.1 g, 7.8 mmol) in CH ₂ Cl ₂ (60 mL). The mixture was stirred and 3-carbomethoxypropionyl chloride (0.96 ml, 7.8 mmol) added. The reaction mixture was stirred vigorously at 0 ^° C. for 15 minutes. The solution was taken out of the ice bath, diluted with H ₂ O (30 ml) and acidified with 1 N aqueous HCl. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ . The organic layers were pooled, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The resulting residue was purified by flash chromatography on a silica gel column eluting with Et ₂ O and then EtOAc to give the product (2.68 g); TLC, R _f = 0.28, silica gel, Et ₂ O.

d. N- [2- (Methoxycarbonyl) ethylcarbonyl] -L-valyl-L-proline. ,

To a solution of the product of Example 13c (2.68 g, 6.98 mmol) in CH ₂ Cl ₂ (11 mL) was added trifluoroacetic acid (11.0 mL, 143 mmol). The mixture was stirred for 4 hours and concentrated under vacuum to give the product (2.13 g), which was used without further purification.

e. 2 (RS), 3 (SR) - [2- (Methoxycarbonyl) ethylcarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide ,

Isobutyl chloroformate (0.85ml, 6.5mmol) was added to a pre-cooled (-15 ° C) solution of N-methylmorpholine (0.71ml, 6.5mmol) and the product of Example 13d (2.13g, 6, 5 mmol) in THF (50 ml). The reaction mixture was stirred 10 minutes long, and the temperature was reduced to -50 ⁰ C. Then a suspension of N-methylmorpholine (0.71 ml, 6.5 mmol) and a product prepared according to the procedure of Example 1c (1.39 g, 6.5 mmol) in THF (50 ml) was added in one portion, after which Reaction mixture was stirred overnight while warming to room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken up in EtOAc and washed successively with 1 N aqueous HCl and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel eluting with MeOH: CHCl ₃ (5:95) to give the product (1.92 g); TLC, R _f = 0.24, silica gel, MeOH: CHCl ₃ (5:95). ,

f. 3 (RS) - [2-Methoxycarbonyl) ethylcarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide. A solution of DMSO (11.2 ml, 0,158MoI) in CH ₂ CI ₂ (12 ml) was slowly added a pre-cooled (-60 ⁰ C) solution of oxalyl chloride (6,9ml, 0.079 mol) in CH ₂ Cl ₂ (160ml ) was added. A solution of the product of Example 13e execution (1,90g, 3,95mMol) in CH ₂ CI ₂ (160 ml) was added to the reaction mixture, followed by stirred for 1 h at -60 ⁰ C. Diisopropylethylamine (28.0 mL, 0.158 mol) was added slowly, whereupon the reaction mixture was allowed to warm to ambient temperature. The solution was washed with 1 N aqueous HCl (2 × 80 ml) and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product (3.5 g). The product was purified by filtration through silica gel with EtOAc followed by flash chromatography on silica gel using MeOH: CHCl ₃ (5:95) to give the product (1.49 g); TLC, R _f = 0.31, silica gel, MeOH: CHCl ₃ (5:95); Diagnostic ¹ H NMR shifts (CD ₃ SOCD ₃ , 250MHz): 0.9, m, 12H; 3.54, s, 3H; 3.54 ... 3.68, m, 2H; 4.34, m, 1H; 4.40, m, 1H;

4,48, dd, 1 / 2H; 4.58, dd, 1 / 2H;, 8.1, d, 1H; 8.58, dd, 1H.

Embodiment 14

3 (RS) -1 (2-carboxyethyl) carbonyl] -L-valyl-N-13- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide 1 N aqueous NaOH (0 , 92 ml) was added to a solution of the product of Example 13f (0.20 g, 0.42 mmol) in MeOH (10 ml) and the reaction mixture was stirred overnight at ambient temperature. Next, 1N aqueous HCl (1 ml) was added and the reaction was concentrated under vacuum to remove MeOH. The remaining aqueous solution was extracted with EtOAc and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product (0.18g); TLC, R _f = 0.2, silica gel, MeOH: CHCl ₃ : TFA (5: 94: 1); HPLC, t _R = 2.9, 5.86, Applied Science Absorbosphere® C 8.4.6 mm x 10 cm, CH ₃ CN: H ₂ O: TFA (20: 80: 0.1), flow rate = 1.6 ml / minute

Embodiment 15

3 (RS) - [(4-ethoxycarbonyl) phenyl) aminocarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide

a. 2 (RS), 3 (SR) - [(4-ethoxycarbonylphenyl) aminocarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide

A solution of ethyl 4-isocyanatobenzoate (0.86 g, 4.5 mmol) in CHCl 3 (2 mL) was added dropwise to a solution of a product prepared according to the procedure of Example 3d (1.65 g, 4.5 mmol) in CHCl ₃ (20 mL ) was added and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under vacuum to give the crude product. The product was purified by flash chromatography on silica gel. Using MeOH: CHCl ₃ (2.5: 97.5) and MeOH: CHCl ₃ (5:95) as eluents to give the product (1.76 g); TLC, R, = 0.34, silica gel, MeOH: CHCl ₃ (5:95).

b. 3 (RS) - [(4-Ethoxycarbonylphenyl) aminocarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide. A solution of DMSO (4.5 mL, 63 mmol) in CH ₂ Cl ₂ (5ml) was added slowly a pre-cooled (-6O ⁰ C) solution of oxalyl chloride (2,75ml, 31.5 mmol) in CH ₂ CI ₂ (60 ml) was added. The reaction mixture was stirred at -60 ° C for 15 minutes. Then a solution of the product of Example 15a (1.76 g, 3.15 mmol) in CH ₂ Cl ₂ (60 mL) was added to the reaction mixture, followed by stirring at -60 ° C for 1 h. Then diisopropylethylamine (11 mL, 63 mmol) was added slowly, whereupon the reaction mixture was allowed to warm to ambient temperature. The solution was washed with 1N aqueous HCl (2 x 60 ml) and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the crude product (2.3 g). The product was purified by flash chromatography on silica gel using a step gradient of CHCl ₃ , MeOH: CHCl ₃ (2.5: 97.5) and MeOH: CHCl ₃ (5:95) to afford the product (0.91 g) yield; TLC, R _f = 0.42, silica gel, MeOH: CHCl ₃ (5:95); HPLC, t _R = 6.77, 11.27 Zorbax® ODS analytical column, CH ₃ CN: H ₂ O (45:55), flow rate = 2 ml / min.

Embodiment 16

3 (RS) - [(4-Carboxyphenyl) aminocarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide 1N aqueous NaOH (1 ml) was added to a solution of the product of Example 15b (0.48 g, 0.86 mmol) in MeOH: H ₂ O (8 mL: 7 mL). The reaction mixture was stirred for 3 hours, then additional 1N aqueous NaOH (1 mL) was added and the reaction mixture was stirred overnight at ambient temperature. Next, 1N aqueous HCl (2.5 ml) was added and the methanol was removed in vacuo. To the residue was added H ₂ O (10 ml) followed by extraction with EtOAc (2 × 50 ml). The pooled organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product (0.42 g); TLC, R f = 0.17, silica gel, MeOH: CHCl ₃ : AcOH (5: 94: 1); HPLC, t "= 2.38, 2.78, Zorbax® ODS analytical column, CH ₃ CN: H ₂ O (30:70), flow rate = 1 ml / min.

Embodiment 17

3 (RS) - [(4-phenylbutyl) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide

a. 2 (RS), 3 (SR) - [(4-phenylbutyl) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide ,

DCC (0.906 g, 4.4 mmol) was added to a solution of 5-phenylvaleric acid (0.728 g, 4.08 mmol), a product prepared according to the procedure of Example 3d (1.5 g, 4.08 mmol) and HOBT (1.19 g , 8.8 mmol) in THF (75 ml) at ⁰ ° C. The mixture was stirred and allowed to slowly warm to room temperature overnight. The mixture was concentrated in vacuo and the resulting residue was taken up in CHCl ₃ (60 ml) and washed successively with 20% citric acid (30 ml), H ₂ O (30 ml), 5% aqueous NaHCO ₃ (30 ml) and brine (30 ml). 30ml). The organic phase was collected, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the crude product (2.0 g). Purification by flash chromatography on silica gel eluting with MeOH: CHCl ₃ (5:95) afforded the product (1.0 g) as a white foam; TLC, R _f = (0.5-0.55), silica gel, MeOH: CHCl ₃ (5:95).

b. 3 (RS) - [(4-phenylbutyl) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl] -L-prolinamide.

A solution of DMSO (3,4ml, 48 mmol) in dry CH ₂ Cl ₂ (4ml) was added dropwise to a mulled solution of oxalyl chloride (2,10ml, 24 mmol) in dry CH ₂ Cl ₂ (50ml) at ⁰ C -6O cooled, added under an N ₂ atmosphere. The solution was stirred ⁰ C for 15 min at -6O. Then, ₂ (30 ml) was added slowly in dry CH ₂ CI, a solution of the product of Embodiment 17a (1.00 g, 1.89 mmol), the solution temperature was kept below -50 ⁰ C. The mixture was stirred at (-50 ⁰ C) for 1 hour. Then diisopropylethylamine (8.48 ml, 48 mmol) was added dropwise, whereupon the reaction mixture was allowed to warm slowly to room temperature. The reaction mixture was washed successively with 1 N aqueous HCl and brine. The organic phase was collected, dried with Na ₂ SO ₄ , filtered and concentrated under vacuum to give the crude ketone. The ketone was isolated by 3 consecutive flash chromatographies of silica gel and eluents of (MeOH: CHCl ₃ ) (5:95), CHCl ₃ (100%) - MeOH: CHCl ₃ (3:97), and Et ₂ O (100%). MeOH: Et ₂ O (10:90) to give the final product (0.2 g) as a white waxy solid; HPLC, t _R = 6.80, 8.90, Zorbax® ODS column; H ₂ O: CH ₃ CN: TFA (40: 60: 0.1), flow = 0.75 ml / min.

Analysis calculated for:

C ₂₇ N ₃ O ₄ F ₃ H ₃₈ 0.5 H ₂ O: C, 60.65; H, 7:35; N, 7,85

Found: C, 60.68; H, 7.30; N, 7,67

Example of Implementation 18 »

3 (RS) -2 [2- (tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl) ethoxycarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro- 2-oxopentyl)] - L-prolinamide

a. 4-Nitrophenyl 2- (tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl) ethyl carbonate.

A product was obtained using the procedure of Example 7 a.

b. 2 (RS), 3 (SR) - [2- (tricyclo [3.3.1.1 3 ^l7 ] dec-1-yl) ethoxycarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1- trifluoro-2-hydroxypentyl)] - L-prolinamide.

A solution of the product of Example 18a (0.758 g, 2.19 mmol), a product prepared according to the procedure of Example 3d (0.768 g, 2.09 mmol) and K ₂ CO ₃ (2.89 g, 20.9 mmol) in DMF ( 75ml) was stirred at room temperature for 18h and filtered, whereupon the solvents were removed under vacuum. The residue was diluted with ethyl acetate, washed with 3 portions of 10% aqueous NaOH and brine, dried over solid K ₂ CO ₃ : Na ₂ SO ₄ (10:90) and filtered, whereupon the solvents were removed under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with MeOH: CHCl ₃ (2:98) to give the product (0.965 g) as a white foam; TLC, R _f = 0.14 and 0.18, silica gel, MeOH: CHCl ₃ (2:98).

c. 3 (RS) - [2- (tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl) ethoxycarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2 -oxopentyl)] - L-prolinamide. One to -43 ⁰ C cooled solution of oxalyl chloride (2.14 g, 16,8mMol) in dry CH ₂ Cl ₂ (30ml) was added DMSO (2,66g, 33,6mMol) in CH ₂ CI ₂ (20 ml) dropwise over 1 The product of Example 18b (0.965 g, 1.68 mmol) was added in the same manner over 30 minutes. After further stirring the solution at -43 ° C for one hour, triethylamine (8.50g, 84, OmMoI) was added and the solution was allowed to warm slowly to room temperature. The solution was diluted with CH ₂ Cl _2, washed with 5% aqueous HCl and 5% aqueous NaOCl, dried over MgSO ₄ and filtered and the solvent was removed under vacuum. The crude product was purified by flash chromatography on silica gel eluting with CHCl ₃ after pretreating the silica gel with MeOH: CHCl ₃ (1:99) to give the product (410 mg) as a white foam; TLC, R _f = 0.39, silica gel, MeOH: CHCl ₃ (2:98); HPLC, t "= 8.12 and 10.75, Zorbax® ODS column, flow rate = 1.5 ml / min, CH ₃ CN = H ₂ O = TFA (^ OiSOiCI). Analysis calculated for: '

C ₂₉ H ₄₄ N ₃ F ₃ O ₅ -O ^ oH ₂ O: C, 59.52; H, 7.83; N, 7.18 Found: C, 59.48; H, 7.70; N, 7,17

Embodiment 19

3 (RS) - [(2-methoxyethoxy) ethoxycarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide

a. 2- (2-methoxyethoxy) ethyl 4-nitrophenyl carbonate.

To a solution of p-nitrophenyl chloroformate (2.00 g, 9.92 mmol) in Et ₂ O (50 mL) at ⁰ ° C was added dropwise over 1 h pyridine (8 mL) followed by 2- (2-methoxyethoxy) ethanol (1 , 14g, 9.45 mmol) in Et ₂ O (25 mL). The resulting mixture was stirred at room temperature for 12 h and partitioned between H ₂ O and Et ₂ O. The ethereal layer was washed with 5% aqueous HCl and phosphate buffer pH 7.0, dried over MgSO ₄ and filtered, whereupon the solvents were removed under vacuum. The crude product was purified by flash chromatography on silica gel eluting with EtOAc: hexane (30:70) to give the product (1.30 g) as a clear colorless oil; TLC, R _f = 0.11, silica gel, EtOAc: hexane (30:70).

b. 2 (RS), 3 (SR) - [(2-methoxyethoxyethoxy) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide , A solution of the product of Example 19a (1.11 g, 3.9 oM mol), a product prepared according to the procedure of Example 3d (1.37 g, 3.72 mmol) and K ₂ CO ₃ (5.14 g, 37.2 mmol) in DMF (100ml) was stirred at room temperature for 18h and filtered, whereupon the solvents were removed under vacuum. The residue was taken up in ethyl acetate, washed with 3 portions of 10% aqueous NaOH and brine, dried over solid K ₂ CO ₃ : Na ₂ SO ₄ (10:90) and filtered, whereupon the solvents were removed in vacuo. The crude product was purified by flash chromatography on silica gel eluting with EtOAc after pre-treating the silica gel with TEA: hexane (1: 9) to give the product (1.13g) as a clear colorless glass; TLC, R _f = 0.43 and 0.48, silica gel, MeOH: CHCl ₃ (1: 9).

Analysis calculated for:

C ₂₂ H ₃₈ N ₃ O ₇ F _3: C, 51.45; H, 7.45; N, 8.18

Found: C, 51.48; H, 7.35; N, 8.01

c. 3 (RS) - [(2-Methoxyethoxy) ethoxycarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide.

A solution of oxalyl chloride (3.26 g, 2.57 mmol) in dry CH ₂ Cl ₂ (70 mL) cooled to -43 ° C was added dropwise over 1 h DMSO (4.07 g, 51.4 mmol) in CH ₂ Cl ₂ (20 ml) was added and the product of Example 19b (1.10 g, 2.14 mmol) InCH ₂ Cl ₂ (25 ml) was added in the same manner over 30 minutes. After dem_Verrühren the solution at -43 ⁰ C for a further hour away TEA (10,80g, 107, OmMoI) was added, whereupon the solution was given the opportunity to slowly warm to room temperature. The solution was diluted with CH ₂ Cl _2, washed with 5% aqueous HCl and 5% aqueous NaOCl, dried over MgSO ₄ and then filtered, after which the solvents were removed under vacuum. The crude product was purified by flash chromatography on silica gel eluting with MeOH: CHCl ₃ (2:98) to give the product (420 mg) as a clear, pale yellow syrup; TLC, R _f = 0.32 and 0.37, silica gel, MeOH: CHCl ₃ (5:95); HPLC, t "= 7.38 and 9.55, Zorbax® ODS analytical column, flow = analysis calculated for:

C ₂₂ H ₃₆ N ₃ O ₇ F ₃ 0.75 H ₂ O: C, 50.33; H, 7.20; N, 8.00

Found: C, 50.34; H, 7,21; N, 7.58

-OS- £ 1f

Embodiment 20 SCRSI-K ^ Methoxyphenyllcarbonyll-L-valyl-N-O-l ^ methyl-i.i.i-trifluoro ^ -oxopentyOl-L-proiinamid

a. 2 (RS), 3 (SR) - [(4-Methoxyphenyl) carbonyl] -L-valyl-N- [3- (4-nnethyl-1,1,1-trifIuoro-2-hydroxypentyl)] - L-prolinannid ,

A cooled to ⁰ ° C. solution of a later procedure of Embodiment 3d product produced (1.50 g, 4,08mMol) and TEA (2.06 g, 20,4mMol) in CHCI ₃ (50 ml) was added dropwise over 1 hour period 4-methoxybenzoyl chloride (0.776g, 4.49 mmol) in CHCl ₃ (40 mL), and the solution was stirred at room temperature overnight. The solvents were removed in vacuo, the residue was taken up in EtOAc, washed with 5% aqueous HCl and 20% aqueous NaOH, dried over solid K ₂ CO ₃ INa ₂ SO ₄ (10:90) and then filtered, whereupon Solvent were removed under vacuum. The crude product was purified by flash chromatography on silica gel eluting with MeOH: CHCl ₃ (5:95) to give the product (1.84 g) as a white foam; TLC, R _f = 0.33, silica gel, MeOH: CHCl ₃ (5:95). Analysis calculated for:

C ₂₄ H ₃₄ O ₅ N ₃ F ₃ O ^ H ₂ O: C, 56.86; H, 6.88; N, 8.29

Found: C, 56.80; H, 6.88; N, 8.07

b. 3 (RS) - [(4-Methoxyphenyl) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide.

A solution of oxalyl chloride (3.79 g, 29.9 mmol) in dry CH ₂ Cl ₂ (50 ml) cooled to -43 ° C. was added dropwise over 40 minutes to DMSO (4.73 g, 59.8 mmol) in CH ₂ Cl ₂ ( 20ml) and the product of Example 20a (1.50 g, 2.99 mmol) in CH ₂ Cl ₂ (20 ml) was added in the same manner over 30 minutes. After stirring the solution at -43 ° C for an additional 1 h, TEA (15.1 g, 149.5 mmol) was added and the solution was allowed to warm slowly to room temperature. The solution was diluted with CH ₂ Cl _2, washed with 5% aqueous HCl and 5% aqueous NaOCl, dried over MgSO ₄ and then filtered, after which the solvents were removed under vacuum. The crude product was purified by flash chromatography on silica gel eluting with EtOAc: hexane (1: 1) after pretreating the silica gel with TEA: hexane (10:90) to give the product (489 mg) as a white foam; TLC, R _f = 0.15 and 0.19, silica gel, MeOH: CHCl ₃ (2:98); HPLC, t _R = 6.62 and 9.72, Zorbax® ODS column, flow rate = ImIZmIn ₁ CH ₃ CN = H ₂ OiTFA (SOiSOiCl)

 Analysis calculated for:

C ₂₄ H ₃₂ O ₅ N ₃ F _3: C, 57.71; H, 6:46; N, 8.41

Found: C, 57.39; H, 6.67; N, 8,18

Embodiment 21

3 (RS) -N ² , N ⁶ -dit (phenylmethoxy) carbonyl] -L-lysyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide

a. 2 (RS), 3 (SR) -N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide.

A product was obtained after applying the procedure of Example 2 b.

b. 2 (RS), 3 (SR) -N ² , N ⁶ -Di [(phenylmethoxy) carbonyl] -L-lysyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl) ] -L-prolinamide. DCC (0.84g, 4.09 mmol) was added at 0 ° C under nitrogen to a stirred solution of (N ² , N ⁶ -dibenzyloxycarbonyl) -L-lysine (1.54 g, 3.72 mmol), the product of Example 21 a (1.0g, 3.72mmol), 1-hydroxybenzotriazole (1.01g, 7.44mmol) and dry THF (70ml). The reaction mixture was stirred at 0 ^° C. for 1 h and left to warm slowly to room temperature overnight. The reaction mixture was filtered, the solvent was removed in vacuo, and the residue was dissolved in CHCl ₃ . The CHCl ₃ solution was washed with 20% aqueous citric acid and the organic layer was dried over Na ₂ SO ₄ and filtered. The solvent was removed under vacuum to give the crude product (3.14 g). The product was purified by flash chromatography on silica gel eluting with CHCl ₃ : MeOH (97: 3) to give 1.50 g of the final product; R _f = 0.33 ... 0.45, CHCl ₃ : MeOH (95: 5), silica gel.

c. 3 (RS) -N ² , N ^e -Di [(phenylmethoxy) carbonyl] -L-lysyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide ,

A solution of DMSO (3.59 g, 46 mmol) and dry CH ₂ Cl ₂ (30 mL) was added to a stirred solution of oxalyl chloride (3.04 g, 24 mmol) and dry CH ₂ Cl ₂ (50 mL) at -60 ° C added under nitrogen. The reaction mixture was stirred at -60 ⁰ C for 5 minutes, after which it was allowed to warm to -30 ° C. Then, a solution of the product of Example 21b (1.32 g, 2.0 mmol) and dry CH ₂ Cl ₂ (30 ml) was added dropwise. The resulting reaction mixture was stirred at -25 ° C for one hour. TEA (7.8 g, 77.4 mmol) was then added, whereupon the reaction mixture was allowed to warm slowly to room temperature. The reaction mixture was washed with 1 N aqueous HCl and brine.

The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was removed in vacuo to give the product (2.6 g). The product was purified by flash chromatography (silica gel, CHCl ₃ : MeOH, 97: 3) to give the product (0.99 g); TLC, R _t = 0.4 ... 0.52, CHCl ₃ : MeOH (95: 5), silica gel.

Embodiment 22

3 (RS) - [(phenylmethoxy) carbonyl] -L-phenylalanyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide

a. 2 (RS), 3 (SR) - [(phenylmethoxy) carbonyl] -L-phenylalanyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] - L-prolinamide. DCC (1.01 g, 4.92 mmol) was added to a stirred solution of one portion of the product of Example 21 a (1.41 g, 4.47 mmol), N- (benzyloxycarbonyl) -L-phenylalanine (1.20 g, 4 , 47 mmol), 1-hydroxybenzotriazole (1.21 g, 8.94 mmol) and dry THF (75 ml) were added at 0 ° C under nitrogen. The reaction mixture was stirred at ⁰ ° C. for ¹ h, allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered and the solvent was removed in vacuo to give the crude residue, which was dissolved in CHCl ₃ . The CHCl ₃ solution was washed with 20% aqueous citric acid and brine, and dried over Na ₂ SO ₄ . The CHCl ₃ solution was filtered and the solvent was removed under vacuum to give the crude product (3.57 g).

The product was purified by flash chromatography on silica gel eluting with CHCl ₃ : MeOH (97: 3) to give the product (1.45 g) as a white foam; TLC, R _f = 0.39-0.60, CHCl ₃ : MeOH (95: 5), silica gel, HPLC: Zorbax® ODS analysis column, CH ₃ CN: H ₂ O (50:50), flow rate 2.5 ml / min, t _R = 6.47 and 7.63.

b. SfRSJ-KPhenylmethoxylcarbonylJ-L-phenylalanyl-N-tS ^ i-methyl-U ^ ^ -trifluoro -oxopentylll-L-prolinamide.

A solution of DMSO (2,33g, 29,9mMol) and dry CH ₂ Cl ₂ (40ml) was added at -6O ⁰ C under nitrogen was added dropwise a mulled CI solution of oxalyl chloride (1.89 g, 14,9mMol) and dry CH _{2 2} (40ml) added. The reaction mixture was stirred at -60 ⁰ C for 0.5 h. At -50 ° C was then added a solution of the product of Example 22a (1.43 g, 2.49 mmol) and dry CH ₂ Cl ₂ (40 ml). The resulting mixture was stirred two hours at -60 ⁰ C. 1 Diisopropylethylamine (7.70 g, 59.7 mmol) was then added, whereupon the reaction mixture was allowed to warm to room temperature. The mixture was then washed twice with 1N aqueous HCl and then brine. The organic layer was dried over Na ₂ SO ₄ and filtered, whereupon the solvent was removed under vacuum to give the crude product (1.87 g). The product was purified by flash chromatography on silica gel, CHCl ₃ : MeOH (98: 2) to give the product (0.771 g) as a white foam; TLC, R _f = 0.62 ... 0.69, CHCl ₃ : MeOH (95: 5), silica gel; HPCL:

Zorbax® ODS analysis column, CH ₃ CN: H ₂ O (50:50), flow rate = 2.5 ml / min, t _R = 6.11 and 6.21.

Analysis calculated for:

C ₂₈ H ₃₂ F ₃ N ₃ O _5: C, 61.41; H, 5.84; N, 7,67

Found: C, 61.53; H, 5.82; N, 7,67

Embodiment 23

3 (RS) - [2- (Methoxycarbonyl) ethylcarbonyl] -L-norleucyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide

a. N- [2- (Methoxycarbonyl) ethylcarbonyl] -L-norleucine.

A solution of 1 N sodium hydroxide (100 ml, 100 mmol) was added dropwise to a vigorously mulled mixture of L-norleucine (6,55g, 5OmMoI) and methylene chloride (250ml) was added at 0 ⁰ C under nitrogen. Then, 3-carbomethoxypropionyl chloride (7.52 g of 5OmMoI) was added dropwise. The resulting reaction mixture was stirred at ⁰ C for 15 min. The cooling bath was removed whereupon water (100 ml) was added. The pH was adjusted to 1 with 3 N aqueous HCl. Now, ethyl acetate (200 ml) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, washed with brine and dried over Na ₂ SO ₄ . The solution was filtered. The solvent was removed in vacuo to give the crude product (10.73 g). A portion of the crude product (6.47 g, 26.4 mmol) was purified by flash chromatography on silica gel, CHCl ₃ : MeOH, (97: 3) to give the product (5.31 g; TLC, R _f = 0); 45, silica gel, CHCl ₃ : MeOH: AcOH (95: 4.75: 0.25).

b. 2 (RS), 3 (SR) - [2- (Methoxycarbonyl) ethylcarbonyl] -L-norleucyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] -L-prolinamide.

Dicyclohexylcarbodiimide (3.46g, 16.8mmol) was added to a precooled solution of a product prepared according to the procedure of Example 3d (5.60g, 15.3 mmol), the product of Example 23a (3.75 g, 15.3 mmol), and 1 -Hydroxybenzotriazole (4.13g, 30.6 mmol) in THF (70 ml). The resulting solution was allowed to warm to room temperature, moreover, it was stirred overnight. The reaction mixture was filtered and concentrated under vacuum. The residue was diluted with EtOAc and the resulting solution was washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ and filtered and concentrated under vacuum to give the high product. The product was purified by flash chromatography on a silica gel column eluting with a gradient of Et ₂ O (100%), Et ₂ O = EtOAc (90:10), Et ₂ O = EtOAc (75:25), Et ₂ O: EtOAc ( 50:50) to give the product (5.6 g); TLC, R _f = 0.45, silica gel, MeOH: CHCl ₃ (1: 9).

c. 3 (RS) - [2- (Methoxycarbonyl) ethylcarbonyl] -L-norleucyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide. A solution of DMSO (27.0 mL, 0.378 mol) in CH ₂ Cl ₂ 27 mL) was added slowly to a precooled (-65 ° C) solution of oxalyl chloride (16.5 mL, 0.189 mol) in CH ₂ Cl ₂ (350 mL) , The resulting solution was stirred for 15 min, whereupon a solution of the product of Example 23b (5.60 g, 0.00943 mol) in CH ₂ Cl ₂ (250 mL) was added. The reaction mixture was stirred for 1 h at -65 ° C, dropwise adding diisopropylethylamine (67.0 mL, 0.378 mol). The reaction mixture was allowed to warm to room temperature whereupon it was washed with 1N aqueous HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the crude product. The crude product was purified by flash chromatography on a silica gel eluting with a stepwise gradient of Et ₂ O (100%), Et ₂ O: EtOAc (50:50, EtOAc (100%) to give a partially purified product which was still purified by flash chromatography on silica gel eluting with a stepwise gradient of CHCl ₃ (100%), MeOHiCHCl ₃ (2.5: 97.5) and MeOH: CHCl ₃ (5:95) to give the final product (3.24g). HPLC, t _R = 6.80 and 12.98, Zorbax * ODS analysis column, H ₂ O: CH ₃ CN (65:35), flow = 2 mL / min.

Embodiment 24

3 (RS) - [(2-carboxyethyl) carbonyl] -L-norleucyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide 1N Aqueous NaOH (9.5 ml) was added to a solution of the product of Example 23c (2.60 g, 4.39 mmol) in MeOH (95 ml). The reaction mixture was stirred overnight at room temperature and treated with 1 N aqueous HCl (10.5 ml). The reaction mixture was concentrated under vacuum and treated with H ₂ O (35 ml). The suspension was extracted with EtOAc and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product (2.1 g). HPLC, t _R = 12.63 and 19.05, Zorbax® ODS analysis column, H ₂ O: CH ₃ (65:35), flow = 0.5 mL / min.

Embodiment 25

SIRSl-llPhenylmethoxyJcarbonyll-L-alpha-glutamyl-L-valyl-N-IS-t ^ methyl-i.i.i-trifluoro ^ -oxopentyDl-L-prolinamide phenylmethyl ester

a. 2 (RS), 3 (SR) - [(phenylmethoxy) carbonyl] -L-aipha-glutamyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-hydroxypentyl)] -L-prolinamide phenylmethyl ester. _t

Isobutylchloroforminate (0.53 mL, 4.1 mmol) was added to a precooled (-15 ° C) solution of N-benzyloxycarbonyl-L-glutamic acid-alpha-benzyl ester (1.52 g, 4.1 mmol) and N-methylmorpholine (0 , 45ml, 4.1mmol) in THF (30ml). The reaction mixture was stirred for 10 minutes and then cooled to -40 ⁰ C. Next, a solution of the product of Example 3d (1.5 g, 4.1 mmol) in THF (30 mL) was added dropwise, and the reaction mixture was stirred overnight and allowed to warm slowly to room temperature. The reaction mixture was filtered and concentrated under vacuum. The residue was taken up in EtOAc, washed with 1N aqueous HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The product was purified by flash chromatography on a silica gel column eluted with a gradient of CHCl ₃ (100%), MeOH: CHCl ₃ (2.5: 97.5) and MeOH: CHCl ₃ (5:95) to afford the product ( 2,13g); TLC, R _f = 0.43, silica gel, MeOH = CHCl ₃ (5:95).

b. 3 (RS) - [(phenylmethoxy) carbonyl] -L-alpha-glutamyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamidphenylmethylester.

A solution of DMSO (8.40 ml, 0.118 mol) in CH ₂ Cl ₂ (SMI) was carefully a pre-cooled (-65 ⁰ C) solution of oxalyl chloride (5.2 mL, 0.059 mol) in CH ₂ CI ₂ (100 ml ) was added. The solution was stirred for 15 minutes and treated dropwise with a solution of the product of Example 25a (2.13 g, 2.96 mmol) in CH ₂ Cl ₂ (100 mmol). The reaction mixture was stirred for 1 h at -60 ° C and then treated dropwise with N, N-diisopropylethylamine (20.9ml, 0.118 mol). The reaction mixture was allowed to warm to room temperature, then it was washed with 1N aqueous HCl and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The product was partially purified by flash chromatography on a silica gel column eluted with a stepwise gradient of Et ₂ O (100%), Et ₂ O: EtOAc (50:50) and EtOAc (100%). The product was finally purified by flash chromatography on a silica gel column eluting with a stepwise gradient of CHCl ₃ (100%), MeOH: CHCl ₃ (1:99), MeOH: CHCl ₃ (2:98), MeOH: CHCl ₃ (3: 1). 97) and MeOH: CHCl ₃ (5:95) to give the product (1.35 g); HPLC, t _R = 7.2 and 11.5, Zorbax®ODS analysis column, H ₂ OiCH ₃ CN (50:50), flow rate = 2 mL / min.

Embodiment 26

(3 (RS) -N ² - [(2-methoxycarbonyl) ethylcarbonyl] -N ⁶ - [(phenylmethoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1,1, 1-trifluoro-2-oxopentyl] -L-prolinamide

a. N ² - [(2-methoxycarbonyl) ethylcarbonyl] -N ⁶ -phenylmethoxycarbonyl-lysine.

1N aqueous NaOH (43 ml) was added ₂ (160 ml) was added a precooled (0 ⁰ C) solution of N-benzyloxycarbonyl-L-lysine (6.06 g, 0.0216 mol) in CH ₂ CI. The reaction mixture was stirred vigorously and 3-carbomethoxypropionyl chloride (2.66 ml, 0.0216 mol) added. The reaction mixture was stirred vigorously at 0 ^° C. for 15 min. Water (100 ml), 1 N aqueous HCl (25 ml) and EtOAc (500 ml) were added successively, followed by separation of the layers. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the product (6.78 g). The product was used without further purification.

b. 2 (RS), 3 (SR-N ² - [2- (methoxycarbonyl) ethylcarbonyl] -N ⁶ -phenylmethoxycarbonyl-L-lysyl-L-valyl-N- [3- (4-methyl-1,1,1- trifluoro-2-hydroxypentyl)] - L-prolinamide.

DCC (2.85g, 13.9mmol) was added to a mixture consisting of a product prepared according to the procedure of Example 3d (4.63 g, 12.6 mmol), the product of Example 26a (5.00 g, 12.6 mmol). and HOBT (3.76g, 27.8 mmol) in THF (65 ml) and which was pre-cooled to ± 0 ° C. The mixture was stirred at 0 ° C for 1 h, warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was diluted with EtOAc and washed successively with saturated NaHCO ₃ and brine. The organic phase was dried over solid K ₂ CO ₃ : Na ₂ SO ₄ (10:90) and filtered, and the solvent was removed in vacuo to give the crude product. Purification by flash chromatography on silica gel with eluent consisting of MeOH: CHCl ₃ (1:99) afforded the product (6.22g) as a white foam; TLC, R _f = 0.40, silica gel, MeOH: CHCl ₃ (5:95).

c. 3 (RS) -N ² - [2- (methoxycarbonyl) ethylcarbonyl] -N ⁶ - [(phenylmethoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1,1 , 1-trifluoro-2-oxopentyl] -L-prolinamide.

A solution of DMSO (15.9 g, 10OmMoI) in dry CH ₂ CI ₂ (50 ml) was added dropwise to a mulled solution of oxalyl chloride (8,8ml, 20OmMoI) in dry CH ₂ Cl ₂ (150ml) at -43 ⁰ C. cooled, added under nitrogen. In the same manner, a solution of the product of Example 26b (6.22 g, 8.37 mmol) in CH ₂ Cl ₂ (60 mL) was added. The reaction mixture was stirred for 1 h at -20 ° C, followed by the dropwise addition of TEA (70 mL, 400 mmol). To the mixture was time allowed to warm slowly to room temperature, it was for one more hour stirred, and then diluted with CH ₂ Cl _2, washed with 5% aqueous NaOCl, (over solid K ₂ CO ₃ = Na ₂ SO ₄ 10 : 90) and filtered, whereupon the solvent was removed under vacuum to give the crude product. Purification by flash chromatography on silica gel with eluent consisting of MeOH: CHCl ₃ (1:99) gave the product (4.5 g) as a pale yellow foam; TLC, R _f = 0.51, silica gel, MeOH: CHCl ₃ (1: 9); HPLC, t _R = 6.99 and 12.01, flow rate = 1 ml / min, Zorbax®ODS analysis column, H ₂ O: CH ₃ CN: TFA (50: 50: 0.1).

Embodiment 27

3 (RS) -N ^z - [(2-carboxyethyl) carbonyl] -N ⁶ - [(phenylmethoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1,1,1 -trifluoro-2-oxopentyl)] - L-prolinamide

A solution of the product of Example 26c (2.0 g, 2.7 mmol) in MeOH (60 mL) and 1 N NaOH (5.4 mL, 6.5 mmol) was stirred at room temperature for 121 minutes and then quenched with 1 N aqueous HCl (6 , 0ml, 6, OmMoI) to pH 7. The MeOH was removed under vacuum; the resulting residue was dissolved in EtOAc, washed with brine, over MgSO ₄

dried and filtered, whereupon the solvent was removed under vacuum to give the crude product. Purification by flash chromatography on silica gel (pH 5.5 Baker®) with chloroform afforded the product (1.7 g) as a white foam; HPLC, t _R = 4.06 and 5.56, flow rate = 1 ml / min, Zorbax®ODS analysis column, H ₂ OiCH ₃ CNiTFA (SO 4 SO ₄ ).

Analysis calculated for:

C ₃₄ H ₄₈ N ₅ O ₉ F ₃ -UBH ₂ O: C, 53.78; H, 6.83; N, 9.22

Found! C, 53.46; H, 6:39; N, 9.03

Embodiment 28

3S (or R) -N ² , N ⁶ -Di [(phenylmethoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] -L-prolinamide

a. 2 (RS), 3 (SR) -N ² , N ⁶ -di [(phenylmethoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro- 2-hydroxypentyl)] - L-prolinamide.

DCC (0.93 g, 4.49 mmol) was added to a stirred solution of N ² ', N ⁶ -benzyloxycarbonyl-L-lysine (1.69 g, 4.08 mmol), a product prepared according to the procedure of Example 3d (1.50 g , 4.08 mmol), 1-hydroxybenzotriazole (1.10 g, 8.16 mmol) and dry THF (75 ml) at ⁰ ° C. under nitrogen. The reaction mixture was stirred two hours at 0 ⁰ C1, then allowed to warm to room temperature and was stirred overnight. The reaction mixture was filtered. The filtrate was evaporated under vacuum. The residue was dissolved in CHCl ₃ and the solution was washed with 1N aqueous HCl and brine and dried over Na ₂ SO _4. The Na ₂ SO ₄ was filtered off and the filtrate was concentrated in vacuo to give the crude product (3 , 94 g), which was purified by flash chromatography on silica gel, CHCl ₃ : MeOH (95: 5), to give 2.48 g of product: TLC, R _f = 0.36 to 0.56, CHCl ₃ : MeOH (95: 5), silica gel; HPLC, Zorbax® ODS analytical column, flow rate = 1.5 ml / min, CH ₃ CN: H ₂ O (50:50); t _R = 18.33, 14.99. Analysis calculated for:

C ₃₃ H ₄ IF ₃ N ₄ O ₇ : C, 59.01; H, 6.24; N, 8.45 ^ - "'

Found: C, 58.89; H, 6,33; N, 7,89

b. 3S (or R) -N ² , N ⁶ -Di [(phenylmethoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] -L-prolinamide. A solution of DMSO (2.8 g, 36,13mMol) and dry CH ₂ Cl ₂ (40ml) was mulled a solution of oxalyl chloride and dry CH ₂ CI ₂ (40 ml) examples 60 ⁰ C under nitrogen. Then, to the reaction mixture at -50 ⁰ C was added a solution of the product of Embodiment 28a, (2.30 g, 3.01 mmol) and dry CH ₂ CI ₂ (40 ml). The resulting reaction mixture was stirred at -60 ° C. for ¹ h. Triethylamine (7.290g, 72.26 mmol) was then added, whereupon the reaction mixture was allowed to warm to room temperature. The mixture was washed twice with 1 N aqueous HCl and then brine, and dried over Na ₂ SO ₄ . The Na ₂ SO ₄ was filtered off and the filtrate was concentrated under vacuum to give the crude product (2.67 g). The product was purified by flash chromatography on silica gel with an eluent of CHCl ₃ : MeOH (97: 3) to afford 64 mg of product; TLC ₁ Rf = 0.6, CHCl ₃ : MeOH (95: 5); HPLC, Zorbax® ODS analysis column, CH ₃ CN: H ₂ O (60:40), flow = 1.5 mL / min, t _R = 5.29.

Analysis calculated for:

C ₃₈ H ₅₀ F ₃ N ₅ O ₈ H ₂ O: C, 58.53; H, 6.72; N, 8.98

Found: C, 58.95; H, 6.59; N, 8.74

Exemplary embodiment 29

3 (RS) -1- (12-Methoxy-12-oxododecyloxy) carbonyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] -L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = CH ₃ OCO (CHz) ₁₁ , A = OCO, η = 1)

a. Methyl 12-hydroxydodecanoate.

A mixture of 1-hydroxydodecanoic acid (4.0 g, 18.5 mmol), MeOH (450 mL), concentrated H ₂ SO ₄ (2.5 mL) and 3A molecular sieves (3 mL) was stirred at reflux for 16 h. The mixture was neutralized with concentrated aqueous NaHCO ₃ , concentrated under vacuum and partitioned between Et ₂ O and water.

The ethereal solution was washed (water, saturated aqueous NaHCO ₃ , brine), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum to give the product (3.94g) as a white dye: NMR (DMSO); d ₆ ) δ 83.65 (3H, s); 1.7 ... 1.0 (22H, m).

b. 11-methoxycarbonylundecyl 4-nitrophenyl carbonate.

Following the procedure of Example 7a, the product of Example 29a was converted to the title compound and purified by flash chromatography (EtOAc: Hexane [1: 9]) to afford the title compound in 59% yield; TLC, R _f = 0.20, ETOAc: hexane (1: 9).

c. 2 (RS), 3 (SR) -1- (12-methoxy-12-oxododecyloxy) carbonyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (formula VIIa, R ¹ = CH (CH ₃₎ CH _3, R ³ = CH ₃ OCO (CH ₂₎ n, A = OCO, η =. 1

Following the procedure of Example 7b, the product of Example 29b was given the opportunity to react with material previously prepared according to the procedure of Example 2b to give, after purification by flash chromatography (acetone: hexane [3: 7]), the title product (45 %) to get; HPLC, t _R = 4.43, column A, CH ₃ CN: H ₂ O (35:65), flow = 2.0 ml / min.

d. 3 (RS) -1- (12-methoxy-12-oxododecyloxy) carbonyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] -L-prolinamide (Formula I a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = CH ₃ OCO (CH ₂ ) H, A = OCO, η = 1).

To the product of Example 29c (1.1 mmol) was added DMSO (5 mL) and Ac ₂ O (5OmMoI). The resulting solution was stirred at room temperature for 18h and diluted with Et ₂ O. The organic solution was washed (saturated aqueous NaHCO ₃ [3x], water and brine), dried (Na ₂ SO ₄ ), filtered, concentrated under vacuum and purified by flash chromatography (Et ₂ O: hexane) [1: 1]), to yield the title product (100%): HPLC, t _R = 12.73, column A, CH ₃ CN: H ₂ O (60:40), flow = 2.0 mL / min

 Analysis calculated for:

C ₂₂ H ₂₈ F ₃ N ₃ O ₆ -0.4 H ₂ O: C, 55.91; H, 8.00; N, 5.21

Found: C, 56.05; H, 8.00; N, 5:19

Embodiment 30

StRSl-il ^ -hydroxy - ^ - oxododecyloxylcarbonyl-N-tS-li.ii-trifluoro- ^ methyl ^ -oxopentyDl-L-prolinamide (Formula Ia, R ¹ = CH (CH ₃₎ CH _3, R ³ = HOCO (CHz) ₁₁ , A = OCO, η = 1)

Following the procedure of Example 14, the product of Example 29d became the title compound

converted, purified by flash chromatography (EtOAc / hexane [1: 1]) and recovered in 10% yield; HPLC, t _R = 4.55, column A, CH ₃ CN: H ₂ O (60:40), flow = 2.0 ml / min.

Analysis calculated for:

C ₂₄ H ₃₉ F ₃ N ₂ O ₆ -O ^ H ₂ O: C, 56.48; H, 7.74; N, 5.49

Found C, 56.48; H, 7.96; N, 5,23

Embodiment 31

StRSI-i-EI-oxo-S-phenyl-methoxycarbonyl-aminolpentyl-NO-li.U-trifluoro-methyl-Z-oxopentyl-L-proline amide (Formula I a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCH ₂ OCONH (CHz) ₄ , A = CO, η = 1)

a. 5- (phenylmethoxycarbonylamino) valeric acid.

To a stirred, cooled (O ⁰ C) solution of 5-aminovaleric acid (5.00 g, 42.68 mmol) and 2N NaOH (32.0 mL, 32, OmMoI) was added simultaneously benzyl chloroformate (7.65 g, 6.40 mL, 44.81 mmol ) and 2N NaOH (32.0ml, 32, OmMoI). After half an hour of stirring at ⁰ ° C, the solution was washed with Et ₂ O. The Et ₂ O layer was acidified to pH 2.0 with 6N HCl, resulting in the precipitation of the product from the solution. The title compound was filtered, washed (H ₂ O) and dried (vacuum oven) to give the pure product as a white solid (8.55 g, 80.0%). Melting point 104 ... 105 ⁰ C; TLC, Rf = 0.48, MeOH: CHCl ₃ : AcOH (3: 97: 0.1). <

b. 2 (RS), 3 (SR) -1- [1-Oxo-5- (phenylmethoxycarbonylamino) pentyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L -prolinamide (formula Vila, R ¹ = CH (CH ₃ ) CH ₃₁ R ³ = OCH ₂ OCONH (CH) ₂ ) ₄ , A = CO, η = 1).

To a stirred, cooled (O ⁰ C) solution of the product of Example 31 a (0.47 g, 1.86 mmol), HOBT (0.50 g, 3.72 mmol) and DCC (0.40 g, 1.95 mmol ) in CHCl ₃ (50 ml) was added according to the procedure of Example 2 b product (0.50 g, 1.86 mmol). After the reaction mixture was stirred overnight at room temperature, it was filtered and concentrated to yield a syrup, which was partially dissolved in EtOAc. The insoluble material was filtered from the EtOAc solution before being washed (saturated aqueous NaHCO ₃ , 5% aqueous citric acid and brine), dried (Na ₂ SO ₄ ) and concentrated to a mixture which was purified by flash chromatography (MeOH: CHCl 2 ₃ [4:96]) to give the title product as a white foam (0.78 g, 84%); TLC, R _f = 0.4, MeOH: CHCl ₃ (4:94).

c. 3 (RS) -1- [1-Oxo-5- (phenylmethoxycarbonylamino) -pentyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula la, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCH ₂ OCONH (CH ₂ ) ₄ , A = Co, η = 1).

To the product of Example 31b (1 mmol) was added DMSO (85 mmol) and Ac ₂ O (64 mmol). The resulting solution was stirred for 18 hours at room temperature, poured into ice-water (50 ml) and stirred for an additional 1 to 4 hours. The crude product was extracted into EtOAc and the EtOAc solution was washed (saturated aqueous NaHCO ₃ , brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo before the product was purified by flash chromatography (CHCl ₃ : MeOH). 3]) to afford the product (58%); HPLC, t _R = 6.56 and 7.79, column A, H ₂ O: CH ₃ CN (60:40), flow = 2.0 mL / min

 Analysis calculated for:

C ₂₄ H ₃₂ F ₃ N ₃ O ₅ -1,5H ₂ O: C, 54.74; H, 6.69; N, 7,98

Found: C, 54.87; H, 6.20; N, 8.02

Embodiment 32

3 (RS) -1- (1-Oxo-4-phenoxybutyl) -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ia, R ¹ = CH (CH ₃₎ CH _3, R ³ = 00 (CHz) _3, A = CO, n = 1).

a. 2 (RS), 3 (SR) -1- (1-oxo-4-phenoxybutyl) -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide ( Formula VII a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = 00 (CH ₂ ) C ₃ , A = CO, n = 1).

To a 0.25 M solution of 4-phenoxybutanoic acid in THF was added one molar equivalent amount of CDI in one portion. After stirring the reaction mixture for one hour at room temperature, a molar equivalent amount of product prepared according to Example 2b was added in one position. After stirring the reaction overnight, excess saturated aqueous NaHCO _{3 was} added and the mixture was extracted with EtOAc. The EtOAc extracts were washed (in HCl, brine), dried (MgSO ₄ ), filtered and concentrated under vacuum to afford the title product (88%); TLC, R _f = 0.53 and 0.61, MeOH: CH ₂ Cl ₂ (1: 9).

b. 3 (RS) -1- (1-Oxo-4-phenoxybutyl) - N - [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl] -L-prolinamide (Formula Ia ₁ R ¹ = CH (CH ₃₎ CH _3, R ³ = 00 (CH ₂ J _3, A = CO, N = 1).

Following the procedure of Example 31c, the product of Example 32a was converted to the title compound after crystallization from water in 39% yield; TLC; Rf = 0.68 and 0.64, CH ₂ Cl _2: MeOH (9: 1).

Analysis calculated for:

C ₂₁ H ₂₇ F ₃ N ₂ O ₄ -1,25H ₂ O: C, 55.93; H, 6.59; N, 6.21

Found: C, 55.88; H, 6.67; N, 6.15

Embodiment 33

3 (RS) -1- [2- (4-Morpholinyl) ethoxycarbonyl] -N- [3-1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = 4-morpholinyl- (CH ₂ ) ₂ , A = OCO, η = 1)

a. 2- (4-morpholinyl) ethyl-4-nitrophenylcarbonathydrochlorid.

Using the procedure of Example 7a, but omitting the pyridine (and the acid wash), 2- (4-morpholinyl) ethanol was treated with 4-nitrophenyl chloroformate. The crude product was filtered, washed with Et ₂ O and dried under vacuum. The recovered product (91%) was used without further labeling for the following reaction.

b. 2 (RS), 3 (SR) -1- [2- (4-morpholinyl) ethoxycarbonvl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula Vila, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = 4-morpholinyi (CH ₂ ) ₂ , A = OCO, N = 1).

Following the procedure of Example 7b, the product of Example 33a was given the opportunity to react with the product prepared according to the procedure of Example 2b to give, after purification by flash chromatography (MeOH = CHCl ₃ [1:99]), the title product (68 %) to get; TLC, R _f = 0.34, MeOH: CHCl ₃ (5:95), flow = 2.0 ml / min.

c. 3 (RS) -1- [2- (4-Morpholinyl) ethoxycarbonyl] - N - [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ia), R ¹ = CH (CH ₃ ) CH ₃ , R ³ = 4-morpholinyl (CH ₂ ) ₂ , A = OCO, n = 1).

To the product (1, ImMoI) of Example 33b was added DMSO (65 mmol) and Ac ₂ O (50 mmol). The resulting solution was stirred for 18 hours at room temperature and diluted with CH ₂ Cl ₂ . The organic solution was washed (saturated aqueous NaHCO ₃ (3x), water and brine), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo by flash chromatography (MeOH: CHCl ₃ [2:98]) before purification to give to provide the title product (37%) _e ; HPLC, t _R = 8.44 and 9.88, column A, CH ₃ CN: H ₂ O (60:40), flow = 2.0 mL / min

 Analysis calculated for:

C ₁₈ H ₂₈ F ₃ N ₃ O ₅ -1.0 H ₂ O: C, 48.97; H, 6.85; N, 9.51

Found: C, 48.97; H, 6.61; N, 9,73

Embodiment 34 '

3 (RS) -1- [1-oxo-6- [2- (2-pyridyl) ethoxy] carbonylaminohexyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] -L-prolinamide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = te-pyridylMCHzfeOCONH-tCHzJs, A = CO, η = 1)

a. 4-Nitrophenyl 2- (2-pyridyl) ethyl carbonate.

A solution of 2-pyridineethanol (1.38 g, 11 mmol) in Et ₂ O (20 mol) was added over one hour at ⁰ ° C. under nitrogen to a stirred solution of p-nitrophenyl chloroformate (2.26 g, 11 mmol). The resulting mixture was stirred 1 h at 0 ⁰ C before the resulting precipitate was collected under a blanket of nitrogen and recrystallized from absolute EtOH to give 1.53 g (58%) of the title compound in the form of off-white crystals, melting point 125 ... 127 ^C C to surrender.

b. 2 (RS), 3 (SR) -1- [1-oxo-6- [2- (2-pyridyl) ethoxy] carbonylaminohexyl] -N- [3- (1,1,1-trifluoro-2-hydroxy- 4-methylpentyi)] - L-prolinamide (Formula VII a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = (2-pyridyl) - (CH ₂ ) ₂ OCONH (CH ₂ ) ₅ , A = CO, η = 1).

A solution of the amine product of embodiment 50 b (0.75 g, 1.8 mmol), the product of embodiment 34a (0,675g, 1.8 mmol), TEA (0,52ml, 3,6mMol, CH ₃ CN (25ml) and water (25ml) was stirred at room temperature for 2 days before removing the solvent under vacuum to afford the crude product which was purified by flash chromatography (CH ₃ OH: CHCl ₃ [2.5: 97.5]). to afford the product (1.13 mmol, 60%) as a pale yellow solid; TLC; R _f = 0.5, CH ₃ OH: CHCl ₃ (5:95).

c. 3 (RS) -1- [1-oxo-6- [2- (2-pyridyl) ethoxy] carbonylaminohexyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] -L-prolinamide (Formula I a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = (2-pyridyl) - (CH ₂ ) ₂ OCONH (CH ₂ ) ₅ , A = CO, η = 1).

Following the procedure of Example 31c, the product of Example 34c was converted to the title compound to afford the title product in 10% yield after purification by flash chromatography (MeOHiCH ₂ Cl ₂ [3:97]); HPLC, t _R = 1.84, column A, H ₂ O: CH ₃ CN (60:40), flow rate = 2.0 ml / min.

Analysis calculated for:

C ₂₅ H ₃₅ F ₃ N ₄ O ₅ -O ^ H ₂ O: C, 55.85; H, 6.75; N, 10.40

Found: C, 56.08; H, 6.82; N, 10,43

Embodiment 35 StRSM-K-phenylmethoxy-i-CphenylmethoxymethyDethoxycarbonyU-N - ^ - ^ -methyl ^ fi.U-trifluoro-L- -oxopentyDl

prolinamide

(Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = (OCH ₂ OCH ₂ ) ₂ CH, A = OCO, η = 1)

a. 4-Nitrophenyl 2-phenylmethoxy-1- (phenylmethoxymethyl) ethyl carbonate.

TEA (0.74 g, 7.34 mmol) was added dropwise to a solution of p-nitrophenyl chloroformate mulled (1.48 g, 7.34 mmol) and Et ₂ O (30 ml) between ⁰ ° C and 5 ⁰ C. To the above reaction mixture was added between O ⁰ C and 5 ° C a solution of 1,3-dibenzylglycerol (2.0 g, 7.34 mmol) and Et ₂ O (20 mL), whereupon the resulting mixture was between 0 ° C for 2 h and 5 ⁰ C was stirred before it was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered and concentrated under vacuum to leave 3.6 g of yellow oil, which was purified by flash chromatography (hexane: Et ₂ O [8: 2]) to give 2.19 g (68%) of the title compound as a clear oil yield; TLC, R _f = 0.33, hexane: ether (7: 3).

b. 2 (RS), 3 (SR) -1- [2-phenylmethoxy-1- (phenylmethoxymethyl) -ethoxycarbonyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyDR-prolinamide ( Formula VII a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = (O, CH ₂ OCH ₂ ) CH, A = OCO, η = 1).

Following the procedure of Example 7b, the product of Embodiment 35a was given the opportunity to react with the product prepared according to the procedure of Example 2b to give, after purification by flash chromatography (CHCl ₃ : ETOAc [95: 5]), the title product (62 %); HPLC, t _R = 5.81 and 6.29, column A, H ₂ O: CH ₃ CN (40:60), flow rate 2.0 ml / min.

c. 3 (RS) -1- [2-Phenylmethoxy-1- (phenylmethoxymethyl) ethoxycarbonyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = (OCH ₂ OCH ₂ J ₂ CH, A = OCO, η = 1).

The product of Example 35b was oxidized following the procedure of Example 31c to afford the title product (13%) after purification by flash chromatography (CHCl ₃ : EtOAc [98: 2]); HPLC, t _R = 5.62, column A, H ₂ O: CH ₃ CN (40:60), flow rate = 2.0 ml / min

 Analysis calculated for:>

C ₂₉ H ₃₅ F ₃ N ₂ O ₆ -0.25 H ₂ O: C, 61.20; H, 6.28; N, 4.92 Found: C, 61.28; H, 6.34; N, 5.15

Embodiment 36

3 (RS) -1 - [1-oxo-4- (1-oxo-2-phenoxyethylamino) butyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] -L-prolinamide (formula I a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OOCH ₂ CONH (CH ₂ I ₃ , A = CO, η = 1)

a. Ethyl 4- (1-oxo-2-phenoxyethylamino) butanoate.

To a stirred mixture of ethyl 4-aminobutanoate hydrochloride (3.4g) and phenoxyacetyl chloride (2.76ml) in 50ml Et ₂ O and 50ml water was added a portion of NaHCO ₃ (4.2g). After 2 h the layers were separated and the organic phase was washed (1N HCl, brine), dried (IvIgSO ₄ ) and filtered. Evaporation of the solvent under vacuum gave 3.1 g (53%) of the title compound as an oil.

b. 4- (1-oxo-2-phenoxyethylamino) butanoic acid.

A mixture of the product of Example 36a (3.1 g) in 1N NaOH (15 ml) was stirred for 6 hours at room temperature. The resulting solution was acidified with 2N HCl. The precipitated solid was collected, washed with water and dried under high vacuum. There were 2.5 g (95%) of the title compound obtained in the form of a white solid, melting point 91 .. .94 ⁰ C.

c. 2 (RS), 3 (SR) -1- [1-oxo-4- (1-oxo-2-phenoxyethylamino) butyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4 -methylpentyl)] - L-prolineamide (formula Vila, R ¹ = CH (CH ₃ ) CH ₃ , R ^3. = OOCH ₂ CONH (CH ₂ ) ₃ , A = CO, η = 1.

In accordance with the procedure of Example 32a, the product of Example 36b was given the opportunity to react with the product prepared according to the procedure of Example 2b to provide the title product (92%) after purification by an acid as well as by work-up wash with a base ; TLC, R, = 0.43 and 0.48, MeOH = CH ₂ Cl ₂ (1: 9).

d. 3 (RS) -1- [1-oxo-4- (1-oxo-2-phenoxyethylamino) butyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OOCH ₂ CONH (CH ₂ ) ₃ , A = CO, η = 1).

Following the method of Example 61c, the product of Embodiment 36d was oxidized to afford the title product (75%) after purification by flash chromatography (MeOHiCH ₂ Cl ₂ [3:97]); HPLC, t _R = 4.62 and 6.02, column A, CH ₃ CN: H ₂ O (65:35), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₃ H ₃₀ F ₃ N ₃ O _5: C, 56.26; H, 6.28; N, 8.56

Found: C, 56.28; H, 6.40; N, 8.30

Embodiment 37

3 (RS) -1- (4-methoxy-1,4-dioxobutyl) -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = CH ₃ OCO (CH ₂ J ₂ , A = CO, η = 1)

a. 2 (RS), 3 (SR) -1- (4-methoxy-1,4-dioxobutyl) -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L- prolinamide (formula VII a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = CH ₃ OCO (CH ₂ ) ₂ , A = CO, η = 1).

A mulled mixture by following the procedure of Example 2 b prepared product (1.34 g) in CH ₂ CI ₂ (50 ml) and 1 N NaOH (6ml), cooled in an ice water bath, was added dropwise 3-carbomethoxypropionyl chloride (0.75 g) added. After 1 hour, the layers were separated and the organic phase was dried (Na ₂ SO ₄ , *), filtered and evaporated to afford 1.1 g (58%) of the title compound as a white powder; TLC, R _f = 0.57, MeOH: CH ₂ Cl ₂ (1: 9).

b. 3 (RS) -1- (4-methoxy-1,4-dioxobutyl) -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = CH ₃ OCO (CH ₂ J ₂ , A = CO, η = 1).

The product of Example 37a was oxidized following the procedure of Example 61c to afford the title product (71%) after purification by flash chromatography (MeOH: CH ₂ Cl ₂ [2:98]); TLC, R _f = 0.58, MeOH = CH ₂ Cl ₂ (1: 9).

Analysis calculated for:

C ₁₆ H ₂₃ F ₃ N ₂ O ₅ -0.75 H ₂ O: C, 48.79; H, 6.27; N, 7.11

Found: C, 49.04; H, 6.12; N, 6,83

Embodiment 38

StRSl-i-lS-dJ-dimethylethoxycarbonyl-diamino-i-oxo-propyl-N-is-di-trifluoro-methyl-oxo-octoyl-L-proline amide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = ( CH ₃ ) ₃ COCONH (CH ₂ ) ₂ , A = CO, η = 1)

a. 2 (RS), 3 (SR) -1- [3- (1,1-dimethylethoxycarbonyl) amino-1-oxo-propyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4 -methylpentyl)] - L-prolineamide (Formula VII a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = (CH ₃ ) ₃ COCONH (CH ₂ ) ₂ , A = CO, η = 1).

In accordance with the procedure of Example 32a, 3- (BOC-amino) propanoic acid was allowed to react with a product prepared according to the procedure of Example 2b to provide the title product (80%); TLC, R _f = 0.35, MeOH: CH ₂ Cl ₂ (1: 9).

b. SfRSI-i-IS-dJ-dimethylethoxycarbonyl-diamino-i-oxo-propyl-N-1SdJl-trifluoro-methyl-oxo-pentyl-L-proline amide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ₃ = (CH ₃ ) ₃ COCONH (CH ₂ ) ₂ , A = CO, η = 1).

Following the method of Example 61c, the product of Embodiment 38a was oxidized to provide said product (61%) after purification by flash chromatography (MeOH: CH ₂ Cl ₂ [2:98]); TLC, R _f = 0.46, MeOH: CH ₂ Cl ₂

Analysis calculated for:

C ₁₉ H ₃₀ F ₃ N ₃ O ₆ 0.75 H ₂ O: C, 50.83; H, 6.62; N, 9,39

Found: C, 51.18; H, 7.00; N, 9.28

Exemplary embodiment 39

3 (RS) -1- (3-Benzoylamino-1-oxopropyl) - N - [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCONH (CH ₂ J ₂ , A = CO, η = 1

a. 2 (RS), 3 (SR) -1- (3-benzoylamino-1-oxopropyl) -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide ( formula VIIa, R ¹ = CH (CH ₃₎ CH _3, R ³ = 0CONH (CH _{2) 2,} A = CO, η = 1).

By the method of Example 32a, 3- (benzoylamino) propanoic acid was allowed to react with a product prepared by the procedure of Example 2b to afford the title product (83%); TLC, R f = 0.39 and 0.42, MeOH: CH ₂ Cl ₂ (1: 9).

b. 3 (RS) -1- (3-Benzoylamino-1-oxopropyl) - N - [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCONH (CH ₂ J ₂ , A = CO, η = 1).

Following the method of Example 61c, the product of Example 39a was oxidized to afford the title product (48%) after purification by flash chromatography [MeOH: CH ₂ Cl ₂ (2: 9)]; TLC, R _f = 0.54, MeOH: CH ₂ Cl ₂ (1: 9).

Analysis calculated for:

C ₂₁ H ₂₆ F ₃ N ₃ O _4: C, 57.14; H, 5.94; N, 9.52

Found: C, 57.12 H, 6.59; N, 9.45

Embodiment 40

3 (RS) -1- [3- (1-oxo-2,2-diphenylethyl) amino] -1-oxobutyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl) ] -L-prolinamide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = O ₂ CHCOIMH (CH _Z ) ₃ , A = CO, η = 1)

a. Ethyl 3- (1-oxo-2,2-diphenylethyl) aminobutanoate.

Mulled a solution of ethyl 4-aminobutyrate hydrochloride (2.51 g) and diphenylacetyl chloride (3,46g) in 50ml CH ₂ CI ₂ were 50 ml of water and then added in one portion NaHCO ₃ (3.4 g) was added. After two hours, the layers were separated and the organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated. There were obtained 3.5 g (72%) of the title compound as a white solid; TLC, R _f = 0.71, MeOH: CH ₂ Cl ₂ (5:95).

b. 3- (1-oxo-2,2-diphenylethyl) aminobutanoic acid.

A mixture of the product of Example 40a (3.5 g) in 1N NaOH (30 ml) and EtOH (10 ml) was stirred for 10 h. The solution was then extracted with Et ₂ O. The aqueous phase was acidified with 2N HCl and the precipitated solid collected, washed with water and dried under high vacuum. There were recovered 2.9 g (93%) of the title compound as a white powder.

c. 2 (RS), 3 (SR) -1- [3- (1-oxo-2,2-diphenylethyl) amino] -1-oxobutyl-N- [3- (1,1,1-trifluoro-2-hydroxy 4-methylpentyl)] - L-prolinamide (Formula Vila, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = O ₂ CHCONH (CH ₂ ) ₃ , A = CO, η = 1).

By the method of Embodiment 32a, the product of Embodiment 40b was given an opportunity to react with a product prepared by the procedure of Embodiment 2b to provide the title product (81%); TLC, R, = 0.13, MeOH: CH ₂ Cl ₂ (5:95).

d. 3 (RS) -1- [3- (1-oxo-2,2-diphenylethyl) amino-1-oxobutyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl] - L-prolinamide (formula Ia, R ¹ = CH (CH ₃ CH ₃ , R ³ = O ₂ CHCONH (CH ₂ ) ₃ , A = CO, η = 1).

Following the method of Example 61c, the product of Example 40c was oxidized to give, after purification by flash chromatography [MeOH: CH ₂ Cl ₂ (2:98)], the title product (27%); TLC, R _f = 0.24, MeOH: CH ₂ Cl ₂ (5:95).

Analysis calculated for:

C ₂₉ H ₃₄ F ₃ N ₃ O ₄ - ^ OH ₂ O: C, 61.31; H, 6:48; N, 7,39

Found: C, 61.58; H, 6.77; N, 7,43

Embodiment 41

3 (RS) -1- [2- (2-Methoxyethoxy) ethoxycarbonyl] - N - [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = CH ₃ O (CH ₂ ) ₂ O (CH ₂ J ₂ , A = OCO, η = 1)

a. 2 (RS), 3 (SR) -1- [2- (2-methoxyethoxy) ethoxycarbonyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylphenyl)] - L-prolinamide (Formula VII a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = CH ₃ O (CH ₂ ) ₂ O (CH ₂ ) ₂ , A = OCO, η = 1).

Following the method of Example 7b, the product of Embodiment 19a was given the opportunity to react with a product prepared according to the procedure of Example 2 b, after purification by flash column flash chromatography on silica gel with gradient elution with acetone: hexane (10:90 ) to (50:50) give the title product (75%); TCL, R _f = 0.30 and 0.35, acetone: hexane (40:60).

b. 3 (RS) -1- [2- (2-methoxyethoxy) ethoxycarbonyl] - N - [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formal Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = CH ₃ O (CH ₂ I ₂ O (CH ₂ J ₂ , A = OCO, η = 1).

Following the method of Example 61c, the product of Example 41 a was oxidized to afford the title compound (42%) after purification by flash chromatography [acetone: CHCl ₃ (1: 3J]; HPLC, t _R = 5.69, column A. , H ₂ O: CH ₃ CN (75:75), flow rate = 2.0 ml / min.

Analysis calculated for:

C ₁₇ H ₂₇ F ₃ N ₂ O ₆ : C, 49.39; H, 6.83; N, 6.78

Found: C, 49.27; H, 6.80; N, 6,48

Embodiment 42

3 (RS) -1- [1,4-dioxo-4- (phenylmethylamino) butyl] -N-t3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I a, R ¹ = CH (CH ₃ ) CH ₃ , R ^{3 =} ^ ₂ NHCO (CH ₂ J ₂ , A = CO, η = 1

a. 4-Oxo-4- (phenylmethylamino) butansäu're.

A mixture of benzylamine (10.7 g) and succinic anhydride (10 g) was stirred in THF (1 liter) for 2 days. The solid was filtered and dissolved in 1 N NaOH (110 mL). The aqueous phase was washed with Et ₂ O and then acidified with concentrated HCl during cooling in an ice-water bath. The solid was collected, washed with water and dried under high vacuum. There were obtained 10.9 g (53%) of the title compound as a white powder, m.p. 137.4 ... 138 ° C.

b. 2 (RS), 3 (SR) -1- [1,4-Dioxo-4- (phenylmethylamino) butyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] -L-prolinamide (formula VII a, R ¹ = CH (CH ₃ , R ³ = eCH ₂ NHCO (CH ₂ ) j, A = CO, η = 1)

By the method of Embodiment 32a, the product of Embodiment 42a was given an opportunity to react with a product prepared by the procedure of Embodiment 2b to afford the title compound (74%); TLC, R _f = 0.48, MeOHiCH ₂ Cl ₂ (1: 9).

c. 3 (RS) -1- [1,4-dioxo-4- (phenylmethylamino] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolineamide (Formula la , R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCH ₂ NHCO (CH ₂ ) ₂ , A = CO, η = 1).

Following the method of Example 61c, the product of Example 42b was oxidized to afford, after purification by flash chromatography [MeOH: CH ₂ Cl ₂ (2:98)], the title product (40%); TLC, R _f = 0.56, MeOH = CH ₂ Cl ₂ (1: 9).

Analysis calculated for:

C ₂₂ H ₂₈ F ₃ N ₃ O _4: C, 58.10; H, 6.20; N, 9,23

Found: C, 57.90; H, 6.36; N, 9.27

Embodiment 43

3 (RS) -1- [1-Oxo-3- (phenylmethoxycarbonylamino] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolineamide (Formula I a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCH ₂ OCONH (CH ₂ ) ₂ , A = CO, η = 1)

a. 2 (RS), 3 (SR) -1- [1-Oxo-3- (phenylmethoxycarbonylamino)) propyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl] -L -prolinamid

(Formula VII a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OOCONH (CH ₂ J ₂ , A = CO, η = 1).

By the method of Example 32a, CBZ- / 3-alanine was given the opportunity to react with product prepared according to the procedure of Example 2b to provide the title product (82%); TLC, R _f = 0.59, MeOH: CH ₂ Cl ₂ (1: 9).

b. StRSI-i-II-oxo-S-iphenylmetoxycarbonylaminol-propyl-N, N-di-trifluoro-methyl-oxo-pent-D-L-L-proline amide (Formula I a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCH ₂ OCONH (CH ₂ I ₂ , A = CO, η = 1).

The product of Example 43a was oxidized following the procedure of Example 61c to afford, after purification by flash chromatography [MeOHiCH ₂ Cl ₂ (2:98)], the title product (35%); TLC, R _f = 0.23, MeOH: CH ₂ Cl ₂ (5:95).

Analysis calculates fort "

C ₂₂ H ₂₈ F ₃ N ₃ O ₅ -O ^ H ₂ O: C, 55.20; H, 6.06; N, 8,77

Found: C, 55.28; H, 6.25; N, 8.55

Exemplary embodiment 44

SIRSJ-i-ti-oxo ^ -phenylmethoxycarbonylaminolbutyl-N-IS-fi.ii-trifluoro-methyl-a-oxopentyl-L-proline amide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCH ₂ OCONH (CH ₂ ) ₃ , A = CO, η = 1)

a. 2 (RS), 2 (SR) -1- [1-Oxo-4- (phenylmethoxycarbonylamino) butyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L -prolinamide (Formula Vila, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCH ₂ OCONH (CH ₂ ) ₃ , A = CO, η = 1).

By the method of Embodiment 32a, CBZ-4-aminobutyric acid was given an opportunity to react with a product prepared according to Example 2b to afford the title product (72%); TCL, Rf = 0.47, Et ₂ O: EtOAc (1: 1).

b. 3 (RS) -1- [1-Oxo-4- (phenylmethoxycarbonylamino) butyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl] -L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ ), R ³ = OCH ₂ OCONH (CH ₂ ) ₃ , A = CO, η = 1).

The product of Example 44a was oxidized by the method of Example 61c to afford the title product after purification by preparative TLC [MeOH: CHCl ₃ (2.5: 97.5)] (32%); TLC, R _f = 0.65 and 0.68, MeOH: CHCl ₃ (1: 9).

Embodiment 45

3R (or S) -1- [1-oxo-4-phenoxy-2- (2-phenoxyethyl) butyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxophenyl)] - L-prolinamide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = [eO (CH ₂ ) ₂ ] ₂ CH, A = CO, η = 1)

a. Diethyl 2,2-di (2-phenoxyethyl) malonate.

To a stirred solution of sodium (2.3 g) in absolute EtOH (50 ml) was added diethyl malonate (15.2 ml) followed by 2-phenoxyethyl chloride (15.7 g). The reaction mixture was then heated at reflux for 12 hours. The EtOH was evaporated in vacuo and the mixture was diluted with water (40 ml). The aqueous phase was extracted with Et ₂ O. The pooled Et ₂ O extracts were washed (brine), dried (MgSO ₄ ), filtered and evaporated. Piston-to-bulb distillation afforded 12.2 g (27%) of the tietlene diester in a clear liquid, b.p. 155 ... 175 ° C (106 Pascal, 0.8 Torr); TLC, R _f = 0.34, CH ₂ Cl ₂ .

b. 4-phenoxy-2- (2-phenoxyethyl) butanoic acid.

A mixture of the product of Example 45a (10.0 g) and potassium hydroxide (17.7 g) in water (22 ml) was heated under reflux for 4 hours. The reaction mixture was cooled and acidified with concentrated HCl. The precipitated solid was collected, washed with water and air dried. The solid (8,44g) obtained was heated for 2 hours at 170 ⁰ C and then cooled. Recrystallization of the solid from cyclohexane gave 4.1 g (93%) of the title compound as fine white needles; Melting point 85 ... 86 ° C

 Analysis calculated for:

C ₈ H ₂₀ O _4: C, 71.98; H, 6,71

Found: C, 71.92; H, 6,71

c. 4-phenoxy-2- (2-phenoxyethyl) butanoyl chloride.

A mixture of the product of Example 45 b (1.5 g) and thionyl chloride (0.73 ml) was heated on a steam bath for 1 h. The reaction mixture was then stripped off. The acid chloride title product was recovered as a clear oil in quantitative yield and used directly.

d. 2 (RS), 3 (SR) -1- [1-oxo-4-phenoxy-2- (2-phenoxyethyl) butyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4 -methylpentyl)] - L-prolinamide (formula Vila, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = [OO (CH ₂ ) ₂ ] ₂ CH, A = CO, η = 1).

In the method of Example 37a, the product of Embodiment 45c was given the opportunity to react with a product made according to the procedure of Example 2b to yield the title product (95%); TLC, R _f = 0.47 and 0.54, Et ₂ O.

e. 3R (or S) - [1-oxo-4-phenoxy-2- (2-phenoxyethyl) butyl] -N- [3- (T, 1,1-trifluoro-4-methyl-2-oxopentyl)] - L- prolinamide (formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = [OO (CH ₂ ) ₂ ] ₂ CH, A = CO, η = 1).

The product of Example 45d was oxidized by the method of Example 61c to give the crude product as a diastereomeric mixture which was separated by flash chromatography (Et ₂ O: hexane (gradient elution, 60:40 to 75:25) faster eluting diastereomer was the title compound, recovered in 27.7% yield; HPLC, t _R = 6.94, column A, CH ₃ CN: H ₂ O (65:35), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₉ H ₃₅ F ₃ N ₂ O _5: C, 63.49; H, 6:43; N, 5,11

Found: C, 63.39; H, 6:47; N, 5.07

Embodiment 46

3S (or R) - [1-Oxo-4-phenoxy-2- (2-phenoxyethyl) butyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamide {formula I a, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = [00 (CH ₂ J ₂ CH, A = CO, n = 1)

The slower eluting diastereomer from the diastereomer trenpation of the crude product of Example 45, obtained in a yield of 28.3%, was the title compound in this case; HPCL, t R = 5.04, column A, CH ₃ CH: H ₂ O (65:35), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₉ H ₃₅ F ₃ N ₂ O _5: C, 63.49; H, 6.43; N, 5,11

Found: C, 63.50; H, 6.45; N, 5,26

Embodiment 47

3 (RS) -1- [6 - [(4-Ethoxycarbonylphenyl) aminocarbonylaminol · 1-oxo] hexyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamid

(Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = 4- (CH ₃ CH ₂ OCO) C NCONH (CH ₂ ) ₅ , A = CO, η = 1)

a. 2 (RS), 3 (SR) -1- [b - [(4-ethoxycarbonylphenyl) aminocarbonylamino] -1-oxo] hexyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4- methylpentyUK-prolinamide (Formula Vila, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = 4- (CH ₃ CH ₂ OCO) -O-NHCONH (CH ₂ ) ₅ , A = CO, η = 1).

Ethyl p-isocyanatobenzoate (0.288 g, 1.5 mmol) was added to a stirred solution of the product of Example 50 b (0.6 g, 1.5 mmol), TEA (0.15 g, 1.5 mmol) and DMF (20 mL) Nitrogen added at room temperature. The resulting mixture was stirred at room temperature overnight before being concentrated under vacuum to give an amber residue, which was dissolved in EtOAc. The EtOAc solution was washed (1N HCl), dried (MgSO ₄ ), filtered and found under vacuum to give 1.15 g of an oily residue. This residue was purified by flash chromatography (CHCl ₃ : CH ₃ OH [97: 3]) to give 0.62 g (70%) of the title compound as a white solid; TLC, R _f = 0.28 and 0.35, CHCl ₃ = CH ₃ OH (95: 5).

b. 3 (RS) -1- [6 - [(4-Ethoxycarbonylphenyl) aminocarbonylamino] -1-oxo] hexyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-Prolineamide (Formula I a, R ¹ = CH (CH ₃ (CH ₃ , R ³ = 4- (CH ₃ CH ₂ OCO) -O-NHCONH (CH ₂ ) ₅ , A = CO, η = 1).

The product of Example 47a was oxidized by the method of Example 61c to give, after purification by flash chromatography (CHCl ₃ : MeOH [97.3]), the title compound (43%); HPLC, t _R = 12.39 and 15.79, column A, H ₂ O: CH ₃ CN (65:35), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₇ H ₃₇ F ₃ N ₄ O ₆ -I ₁ OH ₂ : C, 55.09; H, 6.68; N, 9.51

Found: C, 54.75; H, 6.63; N, 9,29

Exemplary embodiment 48

3 (RS) -1 - [6- (phenylmethoxycarbonylamino) -1-oxohexyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide Formula la, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCH ₂ OCOIMH (CHz) ₅ , A = CO, η = 1)

The product of embodiment 50a was oxidized by the method of embodiment 31c to give, after purification by flash chromatography (CHCl ₃ : MeOH [97: 3]), the title product (31%); HPLC, t _R = 4.06, column A ₁ CH ₃ CN: H ₂ O (1: 1), flow rate = 2.0 ml / min.

-49- Z47 ÖÖ3

Analysis calculated for: C, 57, 46; H, 6.75; N, 8.04 C ₂₅ H ₃₄ F ₃ N ₃ O ₅ -O ^ H ₂ O: C, 57.87; H, 6.24; N, 7.86 Found:

Embodiment 49 '

3 (RS) -1- [6 - [(4-hydroxycarbonylphenyl) aminocarbonylamino] -1-oxohexyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide

(Formula Ia, R ¹ = CH (CH ₃₎ CH _3, R ³ = 4- (HOCO) 0NHCONH (CH _{2) 5,} A = CO, η = 1) Following the method of embodiment 14, the product of embodiment 47 was b converted into the title product in 38% yield; HPCL, t _R = 6.24 and 8.0, column A, H ₂ O = CH ₃ CN (72:25), flow = 2.0 ml / min.

Analysis calculated for:

C ₂₅ H ₃₃ F ₃ N ₄ O ₆ -2.5 H ₂ O: C, 51.1; H, 6.50; N, 9.50

Found: C, 51.34; H, 5.93; N, 8.95

Embodiment 50

3 (RS) -1- (6-phenylsulfonylamino-1-oxohexyl) -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = O (O ₂ ) NH (CH ₂ J ₅ , A = CO, η = 1)

a. 2 (RS), 3 (SR) -1- [6- (phenylmethoxycarbonylamino) -1-oxohexyl] -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L- prolinamide

Formula Vila, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = OCH ₂ O CONH (CH ₂ ) ₅ , A = CO, η = 1).

DCC (6.35 g, 30.8 mmol) was added to a stirred solution of N-CBZ-aminocaproic acid (6.84 g, 25.7 mmol), according to the procedure of Example 2 b, prepared material (6.89 g, 25.7 mmol), HOBT (6.94g, 51.4 mmol) and dry THF (250 mL) at ⁰ ° C under nitrogen. The resulting reaction mixture was stirred at ⁰ ° C. for 1 h, then allowed to warm to room temperature, and was then stirred overnight before being filtered. The filtrate was concentrated under vacuum to a brown residue, which was dissolved in CHCl ₃ , after which the CHCl ₃ solution was washed (20% citric acid solution), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The residue was purified by flash chromatography (CHCl ₃ : MeOH [97.3]) to give 8.0 g (61%) of the title compound as a waxy solid; TLC, R _f = 0.35, CHCl ₃ : MeOH (95: 5).

b. 2 (RS), 3 (SR) -1- (6-amino-1-oxohexyl) -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide ( Formula VIIa, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = H ₂ N (CH ₂ J ₅ , A = CO, η = 1).

A mixture of the product of Example 50a (2.06 g, 3.99 mmol), EtOH (100 mL) and 10% Pd / C (0.3 g)

put on a Parr® shaker under Pascal (45psi) H ₂ for 3 hours. The mixture was filtered through Celite®, and the

Celite® cake was washed with EtOH. The EtOH washes and the above filtrate were pooled and concentrated under vacuum to afford 1.36 g (86%) of the title compound in the form of a pale green waxy oil; TLC, R, = 0.2, CHCl ₃ = MeOH (85:15).

c. 2 (RS), 3 (SR) -1- (6-phenylsulfonylamino-1-oxohexyl) -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide ( formula VIIa, R ¹ = CH (CH ₃₎ CH _3, R ³ = 0S _(O2) NH (CH _{2) 5,} A = CO, η = 1).

Benzene sulfonyl chloride (0.6 g, 1.5 mmol) was stirred under nitrogen at room temperature into a stirred solution of the product of Example 50 b (0.26 g, 1.5 mmol), TEA (0.3 g, 3, OmMoI) and dry DMF ( 20 ml) was added and the resulting mixture was stirred overnight at room temperature. The DMF was removed under vacuum to leave a brownish residue, which was dissolved in EtOAc. The EtOAc solution was washed (1N HCl), dried (MgSO ₄ ) and filtered. The filtrate was concentrated under vacuum to a residue which was purified by flash chromatography (CHCl ₃ : MeOH [97: 3]) to give 0.48 g (60%) of the title compound as a white powder; TLC, R _f = 0.30 and 0.40, CHCl ₃ : MeOH (95: 5).

d. 3 (RS) -1- (6-phenylsulfonylamino-1-oxohexyl) -N- [3- (1,1,1-trifluoro-4-rt * ethyl-2-oxopentyl)] - L-prolinamide (Formula Ia, R ¹ = CH (CH ₃ ) CH ₃ , R ³ = O (O ₂ ) NH (CH ₂ ) ₅ , A = CO, η = 1).

Following the method of Example 8b, the product of Example 50c was oxidized to give the title product after purification by flash chromatography (Et ₂ O: hexane [3: 1] followed by the second column using CHCl ₃ : MeOH [97: 3]) (36%); HPLC, t _R =, 48 and 10, 33, CH ₃ CN: H ₂ O (35:65), flow = 2.0 ml / min.

Embodiment 51

SfRSI-d-naphthylcarbonyD-L-valyl-N-tS-dJJ-trifluoro-methyl-oxopenty-Dl-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 1-naphthyl, R ⁴ = H, A = CO, η = 1)

a. 2 (RS), SfSRl-d-naphthylcarbonyD-L-valyl-N-IS-dJJ-trifluoro-hydroxy-methylpentyDl-L-proline amide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 1-naphthyl, R ⁴ = H, A = CO, n = 1).

The procedure of Example 20a was used to react with I-naphthalene carbonyl chloride to afford the title compound, which was prepared in 38% yield after purification by preparative thin-layer chromatography (hexane: Et ₂ O [4: 6] TCL, R _f = 0.46 and 0.41, MeOH: CHCl ₃ (5:95).

Analysis calculated for:

C ₂₇ H ₃₂ F ₃ N ₃ O _4: C, 60.32; H, 6:37; N, 7,82

Found: C, 60.89; H, 6.21; N, 7,68

b. 3 (RS) - (I-NaphthylcarbonyD-L-valyl-N-IS-d) J-trifluoro-methyl-oxopenty-Dl-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 1-naphthyl, R ⁴ = H, A = CO, η = 1).

A solution of DMSO (29,7g, 38OmMoI) in CH ₂ CI ₂ (81 ml) was slowly added a pre-cooled (-43 ⁰ C) solution of oxalyl chloride (24.0 g, 19OmMoI) in CH ₂ CI ₂ (350 ml) was added and the resulting solution was stirred for 15 minutes before adding a solution of the product of Example 51b (9.4 mmol) in CH ₂ Cl ₂ (83 ml). After a one-hour stirring the reaction mixture at -30 ⁰ C was added dropwise diisopropylethylamine (48,9g, 38OmMoI) was added, whereupon the reaction mixture was given the opportunity to warm to room temperature before it was washed (1 Nl, 5% aqueous NaOCl, brine ), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (hexane: Et ₂ O [40:60] to afford the title product (38%), HPLC, t _R = 5.21 and 7.31, column A, CH ₃ CN: H ₂ O: TFA (50: 50: 0.1), flow rate = 1.5 ml / min. Analysis calculated for:

C ₂₇ H ₃₂ F ₃ N ₃ O ₄ -0,75H ₂ O: C, 60.32; H, 6.37; N, 7.82 Found: C, 60.69; H, 6.21; N, 7,68

Embodiment 52 SCRSl - ^ - dVfethylsulfonylaminocarbonyllphenylaminocarbonyll-L-valyl-N-IS li.i.i-trifluoro methyl ^ ^ -oxopentyDI-L-

prolinamide

(Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 4-CH ₃ S (O ₂ ) NHCO O, R ⁴ = H, A = NHCO, π = 1) Following the procedure of Embodiment 89, material prepared according to the method of Embodiment 16 was allowed to react with methanesulfonamide to be purified by flash chromatography on Baker pH 5.0 silica gel (gradient, CHCl ₃ : MeOH [97: 3]). HPLC, t _R = 2.60 and 3.33, column C, H ₂ O = CH ₃ CN (60:40), flow = 6.0 mL / min.

Analysis calculated for: «

C ₂₅ H ₃₄ F ₃ N ₅ O ₇ SO ₄ H ₂ O: C, 48.85; H, 5.74; N, 11.39

Found: C, 49.03; H, 5.74; N, 10,86

Embodiment 53

3 (RS) - [2- (4-Morpholinyl) ethoxycarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib , R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 4-morpholinyl-CH ₂ CH _{2 /} R ⁴ = H, A = OCO, η = 1J

a. 2 (RS), Sorj - ^^ - MorpholinyDethoxycarbonyll-L-valyl-N-IS-d ^ J-trifluoro ^ -hydroxy ^ -methylpentyll-L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃₎ CH ₃ , R ² = CH (CH ₃ ) ₂ , R ³ = 4-morpholinyl-CH ₂ CH ₂ , R ⁴ = H, A = OCO, η = 1).

By the method of Example 7b, material prepared according to the procedure of Embodiment 3d was given the opportunity to react with material prepared according to the procedure of Example 33a to afford said compound which, after purification by flash chromatography (MeOH: CHCl ₃ [2.5 : 97.5]) was isolated in 55% yield; HPLC, t _R = 4.62 and 5.85, column A, CH ₃ CN: H ₂ O (1: 1), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₃ H ₃₉ F ₃ N ₄ O ₆ H ₂ O: C, 50.91; H, 7.61; N, 10.32

Found: C, 50.95; H, 7,20; N, 10.02

b. 3 (RS) - [2- (4-Morpholinyl) ethoxycarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib , R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 4-morpholinyl-CH ₂ CH ₂ , R ⁴ = H, A = OCO, η = 1).

A solution of DMSO (29,7g, 380 mmol) in CH ₂ CI ₂ (135ml) was dissolved in CH ₂ CI ₂ (350 ml) was added a pre-cooled (-43 ⁰ C) solution of oxalyl chloride (24.0 g, 19OmMoI) and the resulting solution was stirred for 15 minutes before a solution of the product of Example 53 a (9.4 mmol) in CH ₂ Cl ₂ (125 ml) was added. During a one-hour Verrührens was added to the reaction mixture opportunity of itself - 43 ° C to - warm to 20 ⁰ C; Diisopropylethylamine (48.9g, 38OmMoI) was added dropwise and the reaction was allowed to warm to room temperature before being further diluted with CH ₂ Cl ₂ , washed (aqueous NaOH pH = 10), dried (K ₂ CO ₃ / Na ₂ SO ₄ ) and concentrated under vacuum. The residue was purified by flash chromatography (MeOH: CHCl ₃ [2:98]) to afford the title product (18%); HPCL, t _R = 2.00 and 2.60, column A, H ₂ O: CH ₃ CN (1: 1), flow rate = 2.0 ml / min. Analysis calculated for:

C ₂₃ H ₃₇ F ₃ N ₄ O ₆ - 1.5H ₂ O: C, 50.26; H, 7.34; N, 10.19 Found: C, 50.49; H, 6.96; N, 9,96

Embodiment 54

3 (RS) - [(2,4-dichlorophenyl) carbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide Formula I b , R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 2,4-dichloro0, R ⁴ = H, A = CO, η = 1J

a. 2 (RS), 3 (SR) - [(2,4-dichlorophenyl) carbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L -prolinamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ I ₂ , R ³ = 2,4-dichloro0, R ⁴ = H, A = CO, η = 1).

By the method of Embodiment 20a, material prepared according to the procedure of Embodiment 3d was given the opportunity to react with 2,4-dichlorobenzoyl chloride to provide the title compound isolated in 98% yield; TLC, R _f = 0.54, MeOH: CHCl ₃ (5:95).

b. 3 (RS) - [(2,4-dichlorophenyl) carbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib ), R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ I ₂ , R ³ = 2,4-dichloroO, R ⁴ = H, A = CO, η = 1).

A solution of DMSO (29,7g), 38OmMoI) in CH ₂ CI ₂ (27 ml) was slowly added a pre-cooled (-65 ⁰ C) solution of oxalyl chloride (24.0 g, 19OmMoI) in CH ₂ CI ₂ (350ml) and the resulting solution was stirred for 15 minutes before adding a solution of the product prepared by the procedure of Example 54a (9.4 mmol) in CH ₂ Cl ₂ (250 ml). After the reaction mixture had been stirred for 1 h at -65 ⁰ C, diisopropylethylamine (48,9g, 38OmMoI) was added dropwise; then the reaction mixture was allowed to warm to room temperature before being washed (1N HCl, brine), dried

), filtered and concentrated under vacuum. The residue was purified by flash chromatography (MeOH: CHCl 3 [3:97]) to afford the title product (15%); HPLC, t _R = 17.93 and 18.55, column A, H ₂ OiCH ₃ CN (55:45), flow rate = 2.0 ml / min

 Analysis calculated for:

C ₂₃ H ₂₈ Cl ₂ F ₃ N ₃ O ₄ -H ₂ O: C, 49.65; H, 5:43; N, 7.55

Found: C, 49.95; H, 5.31; N, 7,35

Embodiment 55

SfRSi-phenoxycarbonyl-L-valyl-N-tS-d.iJ-trifluoro ^ -methyl-a-oxopentyDl-L-prolinamide (Formula Ib, R ¹ = CH (CH ₃₎ CH _3, R ² = CH (CH ₃ J ₂ , R ³ = O, R ⁴ = H. A = OCO, η = 1)

a. 2 (RS), 3 (RS) -phenoxycarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃₎ CH _3, R ² = CH (CHg) _2, R ³ = 0, R ⁴ = H, A = OCO, η = 1).

By the method of Embodiment 20a, material prepared according to the procedure of Example 3d was given the opportunity to react with phenylchloroformate to give the title compound, which after purification by flash chromatography (MeOH: CHCl ₃ [5:95]) in 61% yield was isolated; TLC, R _f = 0.31 and 0.36, MeOH: CHCl ₃ (3:97).

b. SlRSJ-phenoxycarbonyl-L-valyl-N-IS-di-trifluoro-methyl-oxopentyl-II-L-proline amide (formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ I ₂ , R ³ = 0, R ⁴ = H, A = OCO, η = 1).

The product of Example 55a was oxidized following the procedure of Example 54b to afford the title product (37%) after purification by flash chromatography (hexane: Et ₂ O [15:85]); HPLC, t _R = 2.72 and 3.55, column A, H ₂ O: CH ₃ CN (1: 1), flow rate = 2.0 ml / min.

Analysis calculated for:

C ₂₃ H ₃₀ F ₃ N ₃ O ₅ -O ₁ OH ₂ O: C, 55.86; H, 6:32; N, 8,50

Found: C, 56.07; H, 6.30; N, 8.48

Embodiment 56

3 (RS) - [2- (2-Pyridyl) ethoxycarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 2-pyrryl-CH ₂ CH ₂ , R ⁴ = H, A = OCO, η = 1)

a. 2 (RS), 3 (SR) - [2- (2-Pyridyl) ethoxycarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L -prolinamid (formula VIIb, R ¹ = CH (CH ₃₎ CH _3, R ² = CH (CH ₃ J _2, R ³ = 2-pyridyl-CH ₂ CH _2, R ⁴ = H, A = 0, η = 1).

By the method of Example 34b, material prepared according to the procedure of Example 3d was given the opportunity to react with material according to the method of Preparation of Example 34a to yield the indicated compound, which after purification was purified by flash chromatography (MeOH: CHCl ₃ [4:96]) was isolated in 50% yield; TLC, R _f = 0.30 and 0.34, CHCl ₃ : MeOH (95: 5).

b. SfRSl - ^^ - PyridyDethoxycarbonyn-L-valyl-N-tS-d ^ .i-trifluoro ^ -methyl ^ -oxopentyDl-L-prolinamide (Formula Ib, R ¹ = CH (CH ₃₎ CH _3, R ₂ = CH (CH ₃ ) ₂ , R ³ = 2-pyridyl-CH ₂ CH ₂ , R ⁴ = H, A = OCO, η = 1).

Following the procedure of Example 54b, but omitting the acid wash, the product of Embodiment 56a was oxidized to obtain after twice purification by flash chromatography (hexane: Et ₂ O [1: 1], then MeOH: CHCl ₃ [5:95]) Title product (19%); HPLC, t _R = 9.52 and 14.58, column A, H ₂ O: CH ₃ CN (60:40), flow = 1.0 mL / min.

Analysis calculated for:

C ₂₄ H ₃₃ F ₃ N ₄ O ₅ -0.75 H ₂ O: C, 54.59; H, 6.58; N, 10.61

Found: C, 54.63; H, 6:47; N, 10.55

Embodiment 57

3 (RS) - [4-fluorophenyl) aminocarbonyl)] - L -valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxo-penty)] - L-prolinamide (Formula Ib, R.B. ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 4-FO, R ⁴ = H, A = NHCO, η = 1)

a. 2 (RS), 3 (SR) - [(4-Fluorophenyl) aminocarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VII b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) ₂ , R ³ = 4-FO, R ⁴ = H, A = NHCO, η = 1).

The procedure of Example 15a was used to react with 4-fluorophenyl isocyanate to give the title compound which, after purification, was purified by flash chromatography (gradient, MeOH: CHCl ₃ (2.5: 97; 5) to [5:95]) in 84% yield; TLC, R, = 0.37, MeOH: CHCl ₃ (5:95).

b. 3 (RS) - [(4-Fluorophenyl) aminocarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R.B. ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 4-FO, R ⁴ = H, A = NHCO, η = 1).

The product of Example 57a was oxidized by the method of Example 54b to afford the title product (42%) after purification by flash chromatography (MeOH: CHCl ₃ [3:97]); HPLC, t _R = 8.87 and 12.10, column A, H ₂ O: CH ₃ CN (60:40), flow = 1.0 mL / min.

Analysis calculated for:

C ₂₃ H ₃₀ F ₄ N ₄ O _4: C, 54.97; H, 6.02; N, 11.15

Found: C, 55.18; H, 6.15; N, 11.08

Embodiment 58

prolinamide (formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ₂ = CH (CH ₃ ) ₂ , R ³ = 4- [O (O ₂ ) NHCO] O, R ⁴ = H, A = NHCO, η = 1) By the method of Example 89, material prepared according to the procedure of Embodiment 16 was given an opportunity to react with benzenesulfonamide to obtain after purification by flash chromatography on Baker pH 5.0 silica gel (CHCl ₃ : MeOH [97: 3]) To provide title product (42%); HPLC, T _R = 4.05 and 5.93, column C, H ₂ O: CH ₃ CN (60:40), flow rate = 6.0 ml / min.

Analysis calculated for:

C ₃₀ H ₃₆ F ₃ N ₅ O ₇ -0.5 H ₂ O: C, 53.25; H, 5.51; N, 10.34

Found: C, 53.38; H, 5.61; N, 10.02

Embodiment 59

SfRSJ - ^ - iS-thiophenyllethoxycarbonyl-L-valyl-N-tS-ti ^^ - trifluoro ^ -methyl ^ -oxopentyDl-L-prolineamide (formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 3-thiophenyl-CH ₂ CH ₂ , R ⁴ = H, A = OCO, η = 1)

a. 4-Nitrophenyl 2- (3-thiophenyl) ethyl carbonate.

Following the method of Example 7a, 3-thiophenethanol was treated with 4-nitrophenyl chloroformate to afford the title product (56%) after purification by flash chromatography (EtOAc: hexane [1: 9]); TLC, R _f = 0.25, EtOAc: hexane (1: 9).

b. 2 (RS), 3 (SR) - [2- (3-thiophenyl) ethoxycarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L -prolinamide (formula VII b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 3-thiophenyl-CH ₂ CH ₂ , R ⁴ = H, A = 0, η = 1).

By this method of Example 7b, material prepared according to the procedure of Embodiment 3d was given the opportunity to react with the product of Example 59a to afford the title compound which, after purification by flash chromatography (acetone: hexane [3: 7]) in Figure 58 % yield was isolated; TLC, Rf = 0.23 and 0.27, MeOH: CHCl ₃ (5:95).

Analysis calculated for:

C ₂₄ H ₃₄ F ₃ N ₃ O ₅ S: C, 52.96; H, 6.57; N, 8.06

Found: C, 53.28; H, 6:46; N, 7,77

c. SfRSl - ^ - O-ThiophenyDethoxycarbonyU-L-valyl-NO-ii ^ J-trifluoro ^ -methyl ^ -oxopentyDl-L-prolinamide (Formula Ib, R ¹ = CH (CH ₃₎ CH _3, R ² = CH (CH ₃ ) ₂ , R ³ = S-thiophenyl-CHzCH; R ⁴ = H, A = OCO, η = 1).

A solution of DMSO (29.7g, 38OmMoI) in CH ₂ Cl ₂ (135 mL) was added slowly to a precooled (-43 "C) solution of oxalyl chloride (24.0 g, 19OmMoI) in CH ₂ Cl ₂ (350 mL) The resulting solution was stirred for 15 minutes before adding a solution of material prepared according to Example 59b (9.4 mmol) in CH ₂ Cl ₂ (125 mL) and stirring the reaction mixture for an additional hour at -43 ° C. Diisopropylethylamine (48 , 9 g, 38 μmol) was added dropwise, whereupon the reaction mixture was allowed to warm to room temperature before it was washed (1 N, aqueous HCl, 5% aqueous NaOCl, brine), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum Purification of the residue by flash chromatography (acetone: hexane [1: 4]) gave the title product (23%), HPLC, t _R = 5.09 and 7.61, column A, H ₂ O: CH ₃ CN (1: 1 ), Flow rate = 2.0ml / min

 Analysis calculated for:

C ₂₄ H ₃₂ F ₃ N ₃ O ₅ S: C, 53.17; H, 6.21; N, 8.09

Found: C, 52.92; H, 6.26; N, 8.09

Embodiment 60

3 (RS) - (1,1,1-Dimethylethoxycarbonyl) -la: -aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-rolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = CH ₃ C (CH ₃ ) ₂ , R ⁴ = H, A = OCO, η = 1)

a. 2 (RS), 3 (SR) - (1,1-dimethylethoxycarbonyl) -la-aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide ( Formula VII b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = CH ₃ C (CH ₃ J ₂ , R ⁴ = H, A = OCO, η = 1).

DCC (5,90g, 28,7mMol) at 0 ⁰ C under nitrogen to a solution of HOBT mulled (7,76g, 57,4mMol), B0C-a-aminobutyric acid (5,60g, 27,4mMol) and following the procedure Example 2 b (7.00 g, 26.1 mmol) in dry THF (130 mL) was added. After stirring the resulting reaction mixture at ⁰ ° C. for one hour, it was allowed to warm to room temperature and was stirred overnight. The reaction mixture was filtered and the filtrate concentrated under vacuum to a residue which was redissolved in ETOAc. The resulting solution was washed (saturated NaHCO ₃ , brine), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum to a residue which was purified by flash chromatography (EtOAc: CH ₂ Cl ₂ [1: 3]) to give the To give title compound (95%); TLC, R, = 0.29, ETOAc: CH ₂ Cl ₂ (3: 7).

b. 3 (RS) - (I, i-Dimethylethoxycarbony O -la-aminobutyryl-N-IS-d, 1-J-trifluoro-methyl-oxo-P-C-D-D-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = CH ₃ C (CH ₃ J ₂ , R ⁴ = H, A = OCO, η = 1).

The product of Example 60a was oxidized by the method of Example 61c to give, after purification by flash chromatography (MeOH: CHCl ₃ [1.5: 98.5]), the title product (47%), HPLC, t _R = 10 , 21 and 14, 54, column A, H ₂ O: CH ₃ CN (65:35), flow = 2.0 ml / min.

Analysis calculated for:

C ₂₀ H ₃₂ F ₃ N ₃ O _5: C, 53.21; H, 7:14; N, 9,31

Found: C, 53.65; H, 7,21; N, 9.51

Embodiment 61

3 (RS) - [1-oxo-2- (2-thiophenyl) ethyl] -La-aminobutvrYl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L- prolinamide (formula Ib, R ¹ = CHCCH) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = (2-thiophenyl) CH ₂ , R ⁴ = H, A = CO, η = 1)

a. 2 (RS), 3 (SR) -La-aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide trifluoroacetic acid salt (Formula IVb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ⁴ = H, η = 1).

A solution of material prepared according to the procedure of Example 60a (4.0 g, 8.84 mmol) and TFA (32 mL, 415 (T) MoI) in CH ₂ Cl ₂ (32 mL) was stirred at room temperature for 22 h before the solvents are removed under reduced pressure to afford the crude product (5g> 100%) in the form of a colorless glass, which was used without further purification or characterization.

b. 2 (RS), 3 (SR) -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = (2-thiophenyl) CH ₂ , R ⁴ = H, A = CO, η = 1).

DCC (0.315 g, 1.53 mmol) was added to a stirred solution of HOBT (0.413 g, 3.06 mmol), 2-thiopheneacetic acid (0.222 g, 1.53 mmol), NMM (0.154 g, 1.53 mmol), and according to Working Example 61 a prepared material (0.650 g, 1.39 mmol) in dry THF (20 mL) at 0 ° C under nitrogen. After one hour of stirring the resulting reaction mixture at 0 ⁰ C, this was allowed to warm to room temperature and was stirred overnight. The reaction mixture was filtered; and the filtrate was concentrated under vacuum to a residue which was dissolved in EtOAc. The resulting solution was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum to a residue which was purified by flash chromatography (acetone: hexane [1: 1]) to afford the title compound (33%) TLC, R _f = 0.40 and 0.44, MeOH = CHCl ₃ (1: 9)

 Analysis calculated for:

C ₂₁ H ₃₀ F ₃ O ₄ S: C, 52.82; H, 6,33; N, 8,80

Found: C, 52.43; H, 6.53; N, 8.08

c. 3 (RS) -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = (2-thiophenyl) -CH ₂ , R ⁴ = H, A = CO, η = 1).

To a suspension of CrO ₃ (0.84 g, 8.4 mmol) in dry CH ₂ Cl ₂ (50 ml) was added dry pyridine (1.36 ml, 17 mmol) and the mixture was stirred at room temperature for 30 minutes. To the resulting burgundy suspension was added 1 g of Celite® followed by the product of Example 61b (0.20 g, 0.42 mmol) in CH ₂ Cl ₂ (5 mL).

The mixture was stirred until, by thin layer chromatography, all the alcohol was consumed. The mixture was filtered through a pad of silica gel with methanol / chloroform (1: 9) and the solvents were removed from the filtrate under vacuum. The crude product was purified by preparative TLC (MeOH: CHCl ₃ [5:95]) to afford the product (150 mg) as a white solid; HPLC, t _R = 4.18 and 5.65, column A, H ₂ O: CH ₃ CN (60:40), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₁ H ₂₈ F ₃ N ₃ O ₄ S -0.5 H ₂ O: C, 52.06; H, 6.03; N, 8.67

Found: C, 52.03; H, 6,19; N, 8,38

Embodiment 62

SIRSl-lPhenylmethoxycarbonyD-La-aminobutyryl-IM-tS-djj-trifluoro ^ -methyl ^ -oxopentyDl-L-prolinamide (Formula Ib, R ¹ = CH (CH ₃₎ CH _3, R ² = CH ₂ CH _3, R ³ = OCH ₂ , R ⁴ = H, A = OCO, η = 1)

a. 2 (RS), 3 (SR) - (phenylmethoxycarbonyl) -la -aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = OCH ₂ , R ⁴ = H, A = OCO, η = 1).

The procedure of Example 20a was used to produce the title compound using 1.5 equivalents of benzyl chloroformate in one-quarter of the amount of CHCl ₃ used in the process of Example 20a, following purification by flash chromatography. Acetone: hexane [1: 4]) in 51% yield; TLC, R _f = 0.38 and 0.43, acetone: hexane (40:60).

b. 3 (RS) - (Phenyimethoxycarbonyl) -la-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = OCH ₂ , R ⁴ = H, A = OCO, η = 1).

The product of Example 62a was oxidized by the method of Example 61c to afford the title product (64%) after purification by flash chromatography (acetone: hexane [30:70]); HPLC, t _R = 5.69 and 7.75, column A, H ₂ O: CH ₃ CN (55:45), flow = 2.0 ml / min.

Analysis calculated for:

C ₂₃ H ₃₀ F ₃ N ₃ O ₆ -0.80 H ₂ O: C, 55.26; H, 6:37; N, 8,40

Found: C, 55.10; H, 6.19; N, 8.77

Embodiment 63

SIRSl-iPhenoxycarbonyD-La-aminobutyryl-N-tS-IUJ-trifluoro-methyl-Z-oxopentyDl-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = 0, R ⁴ = H, A = OCO, η = 1)

a. 2 (RS), 3 (SR) - (phenoxycarbonyl) -la -aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = O, R ⁴ = H, A = OCO, η = 1).

In accordance with the method of Example 20a, but using NMM instead of TEA, the procedure of Example 61a prepared material afforded the opportunity to react with 1.5 equivalents of phenylchloroformate to produce the title compound, which after purification via preparative TLC (acetone: hexane [3: 7]) was isolated in 18% yield; TLC, R _f = 0.32 and 0.37, acetone: hexane (3: 7).

b. SiRSH-phenoxycarbonyD-La-aminobutyryl-N-tS-li.ii-trifluoro-methyl-oxopentyDJ-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = 0, R ⁴ = H, A = OCO, η = 1).

The product of Example 63a was oxidized by the method of Example 61c to afford the title product [60%] after purification by flash chromatography (EtOAc: Hexane [1: 9]; HPLC, t _R = 4.57 and 6.51 , Column A, H ₂ OiCH ₃ CN [55:45])

 Analysis calculated for:

C ₂₂ H ₂₈ F ₃ N ₃ O _5: C, 56.04; H, 5.98; N, 8.90

Found: C, 56.04; H, 6.18; N, 8,85

Embodiment 64

3 (RS) - [4- (1-Oxoethylamino) phenylsulfonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib , R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 4- (CH ₃ CONH) O, R ⁴ = H, A = S (O ₂ ), η = 1)

a. 2 (RS), 3 (SR) - [4- (1-oxoethylamino) phenylsulfonyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L -prolinamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 4- (CH ₃ CONH) O, R ⁴ = H, A = S (O ₂ ), η = 1).

A stirred solution of material prepared according to Example 3d (1.00 g, 2.72 mmol) and NMM (0.28 g, 0.30 mL, 2.8 mmol) in CH ₂ Cl ₂ (50 mL) under N _{2 gave} 4-acetamidobenzenesulfonyl chloride (0, 64g, 2.72 mmol). After stirring the reaction mixture overnight at room temperature, the solution was washed (5% aqueous citric acid, brine), dried (Na ₂ SO ₄ ), filtered and concentrated to leave an orange syrup, which was purified by flash chromatography over silica gel (350g) ( MeOH: CHCl ₃ [7:93]) to give the title product (810mg, 52.60%); TLC, R _f = 0.34 and 0.45, MeOH: CHCl ₃ (7:93).

b. 3 (RS) - [4- (1-Oxoethylamino) phenylsulfonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib , R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 4- (CH ₃ CONH) O, R ⁴ = H, A = S (O ₂ ), η = 1).

Following the method of Example 31c, the product of Embodiment 64a was oxidized to afford the title product (84%) after purification by flash chromatography (MeOH: CHCl ₃ [5:95]); HPLC, t _R = 3.22 and 4.58, column A, CH ₃ CN: H ₂ O (40:60), flow rate = 2.0 ml / min.

Analysis calculated for:

C ₂₄ H ₃₃ F ₃ N ₄ O ₆ SH ₂ O C, 49.65; H, 6.08; N, 9,65

Found: C, 49.73; H, 5.86; N, 9.53

Embodiment 65

3 (RS) -N ^z - (1,1-dimethylethoxycarbonyl) -N ⁶ -phenylmethoxycarbonyl-L-lysyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L prolineamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = OCH ₂ OCOI \ IH (CH ₂ ) ₄ , R ³ = (CH ₃ J ₃ C, R ⁴ = H, A = OCO, η = 1)

a. 2 (RS), 3 (SR) -N ² - (1,1-dimethylethoxycarbonyl) -N ⁶ -phenylmethoxycarbonyl-L-lysyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4- methylpentyOR-prolinamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = OCH ₂ OCONH (CH ₂ J ₄ , R ³ = (CH ₃ J ₃ C, R ⁴ = H, A = OCO, η = 1).

By the method of Example 84b, N ² -BOC-N ⁶ -CBZ-L-lysine was given the opportunity to react with material prepared according to the procedure of Example 2 b, after purification by flash chromatography (gradient elution, MeOH: CHCl ₃ [2, 5: 97.5] to [5:95]) to give the title product (73%); TLC, R, = 0.57, MeOH = ChTCI ₃ (5:95).

b. 3 (RS) -N ² - (1,1-dimethylethoxycarbonyl) -N ⁶ -phenylmethoxycarbonyl-L-lysyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamide (formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = OCH ₂ OCONH (CH ₂ ) ₄ , R ³ = (CH ₃ J ₃ C, R ⁴ = H, A = OCO, η = 1Y.

The product of Example 65a was oxidized by the method of Example 31c to give, after purification by flash chromatography (gradient elution, MeOH: CHCl ₃ [2.5: 97.5] to [5:95]), the title product (65%) thereunder; HPLC, t _R = 4.15 and 5.14, column A, H ₂ O: CH ₃ CN (45:55), flow = 2.0 ml / min.

Analysis calculated for:

C ₃₀ H ₄₃ F ₃ N ₄ O ₇ -O ^ H ₂ O: C, 56.51; H, 6.95; N, 8.79

Found: C, 56.45; H, 6.58; N, 8> 42

Embodiment 66

3 (RS) - [(2-Amino-5-chlorophenyl) carbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide ( Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 2-NH ₂ -5-CI-O, R ⁴ = H, A = CO, η = 1 )

a. 2 (RS), 3 (SR) - [(2-amino-5-chlorophenyl) carbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] -L-prolinamide (Formula VII b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ I ₂ , R ³ = 2-NH ₂ -5-CI-O, R ⁴ = H, A = CO, η = 1).

A solution of material prepared according to Example 3d (1 g, 2.7 mmol) in CH ₂ Cl ₂ (50 ml) was treated at room temperature with 5-chloroisotonic anhydride (0.54 g, 2.7 mmol) and the mixture was allowed to overnight before being washed (5% aqueous NaHCO ₃ , brine), dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by flash chromatography (MeOH: CHCl ₃ [3:97]) to give the title product (1, 4g, 78%) as a white foam; TLC, R _f = 0.30 and 0.25, MeOH: CHCl ₃ (5:95).

b. 3 (RS) - [(2-Amino-5-chlorophenyl) carbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide ( Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ J ₂ , R ³ = 2-NH ₂ -5-CI-O, R ⁴ = H, A = CO, η = 1 ).

The product of Example 66a was oxidized by the method of Example 31c to give, after purification by flash chromatography (MeOH: CHCl ₃ [3:97]), the title product (76%); HPLC, t _R = 3.41 and 4.62, column A, H ₂ O: CH ₃ CN (50:50), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₃ H ₃₀₃ N ₄ O ₄ -H ₂ O: C, 51.45; H, 6.01; N, 10,43

Found: C, 51.65; H, 5.74; N, 9.68

Embodiment 67

3 (RS) - (4-methoxyphenylcarbonyl) -la-aminobutyl-N- [3- (1 _/ 1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₂ CH ₃ , R ³ = 4- (CH ₃ O) -O, R ⁴ = H, A = CO, η = 1)

a. 2 (RS), 3 (SR) - (4-Methoxyphenylcarbonyi) -la-aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VII b , R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ , R ³ = 4- (CH ₃ O) -O, R ⁴ = H, A = CO, η = 1).

The procedure of Example 20a was used to react with 4-methoxybenzoyl chloride to afford the title compound, which was purified by flash chromatography (EtOAc: hexane [60:40]) in 34% according to the procedure of Example 61a. iger yield was isolated; TLC, R _f = 0.71 and 0.73, MeOH: CHCl ₃ (1: 9).

Analysis calculated for:

C ₂₃ H ₃₂ F ₃ N ₃ O ₅ -O ₁ SH ₂ O: C, 56.04; H, 6.67; N, 8,52

Found: C, 56.06; H, 6.60; N, 8.14

b. 3 (RS) - (4-methoxyphenylcarbonyl) -La-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ , R ³ = 4- (CH ₃ O) -O, R ⁴ = H, A = CO, η = 1).

The product of Example 67 a was oxidized by the method of Example 61c except that the alcohol was dissolved in five times the amount of solvent to give, after purification by preparative TLC (MeOH: CHCl ₃ [1: 9]), the title product (40%). ) to give; HPLC, t _R = 8.89 and 11.75, column A, H ₂ O: CH ₃ CN (70:30), flow rate = 2.0 ml /

Analysis calculated for:

C ₂₃ H ₃₀₃ N ₃ O ₅ -H ₂ O: C, 54.86; H, 6.41; N, 8.35

Found: C, 54.89; H, 6:38; N / 7.48

Embodiment 68

3 (RS) - [2- (tricyclo [3.3.1.1 ^{3 7} ] dec-1-yl) ethoxycarbonyl-L-α-aminobutyryl-IM- [3- (1,1,1-trifluoro-4-methyl) 2-oxopentyl) IL-prolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = (1-adamantyl) -CH ₂ CH ₂ , R ⁴ = H , A = OCO, η = 1)

a. 2 (RS), 3 (SR) - [2- (Tricyclo [3.3.1.1 ³ ' ⁷ ] -dec-1-yl) ethoxycarbonyl] -Lo: -aminobutyryl-N- [3- (1,1,1- trifluoro-2-hydroxy-4-methylpentyDR-prolinamide (formula VIIb, R ¹ = CH (CH ₃₎ CH _3, R ² = CH ₃ CH _2, R ³ = (1-adamantyl) -CH ₂ CH _2, R ⁴ = H, A = OCO, n = 1).

By the method of Embodiment 34b, according to the procedure of Embodiment 61a, a prepared material was allowed to react with material prepared according to the procedure of Embodiment 7a to afford the title compound which after purification was purified by flash chromatography (EtOAc: hexane [20:80], then [50:50]) was isolated in 42% yield; TLC, R _f = 0.33 and 0.44, MeOH: CHCl ₃ (5:95).

b. 3 (RS) - [2- (Tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl) ethoxycarbonyl] -la: -aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl 2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ , R ³ = (1-adamantyl) -CH ₂ CH ₂ , R ⁴ = H, A = OCO, η = 1).

The product of Example 68a was oxidized by the method of Example 61c to afford the title product (66%) after purification by flash chromatography (Et ₂ O: hexane [50:50], then [90:10]); HPLC, t _R = 4.64 and 5.63, column A, H ₂ O: CH ₃ CN (25:75), flow = 2.0 mL / min

 Analysis calculated for: V

C ₂₈ H ₄₂ F ₃ N ₃ O ₅ -OJoH ₂ O: C, 60.01; H, 7.60 Found: C, 59.76; H, 7,65

Embodiment 69

3 (RS) -N ² - (1,1-dimethylethoxycarbonyl) -N ⁶ -phenylsulfonyl-L-lysyl-N [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L- prolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = OS (O ₂ ) NH (CH ₂ J ₄ , R ³ = (CH ₃ J ₃ C, R ⁴ = H, A = OCO , η = 1)

a. 2 (RS), 3 (SR) -N ² - (1,1-dimethylethoxycarbonyl) -L-lysyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L -prolinamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = H ₂ N (CH ₂ J ₄ , R ³ = (CH ₃ J ₃ C, R ⁴ = H, A = OCO, η = 1).

To a solution of material prepared according to Example 65a (3.0 g, 4.8 mmol) in absolute EtOH (60 ml) was added 10% Pd on carbon (0.6 g). The resulting suspension was kept overnight under a H ₂ atmosphere

(Pascal) stirred. Then additional 10% Pd on carbon was added (0.3g) and stirring was over

continued for several hours. The reaction mixture was filtered through Celite® and concentrated under vacuum to give the product (2.48 g), which was processed directly.

b. 2 (RS), 3 (SR) -N ² - (1,1-dimethylethoxycarbonyl) -N ⁶ -phenylsulfonyl-L-lysyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4- methylpentyl)] - L-prolinamide (formula VIIb, R ¹ = CH (CH ₃₎ CH _3, R ² = 0S _(O2) NH (CH _{2) 4,} R ³ = (CH _{3) 3,} C, R ⁴ = H, A = OCO, η = 1J.

Following the method of Example 72b, but using NMM instead of TEA, the product of Example 69a was treated with benzenesulfonyl chloride to produce the title product, which was purified by flash chromatography (CHCl ₃ : MeOH [95: 5]) in 69%. iger yield was isolated; TLC, R _f = 0.29, MeOH: CHCl ₃ (95: 5).

c. StRSI-N, dJ-dimethylethoxycarbonyD-N-phenylsulfonyl-L-lysyl-N-tS-di-trifluoro-methyl-oxo-p-en-D-J-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = 0S (O ₂ ) NH (CH ₂ J ₄ , R ³ = (CH ₃ J ₃ C, R ⁴ = H, A = OCO, η = 1J.

The product of Example 69b was oxidized by the method of Example 31c to give, after purification by flash chromatography (gradient elution, MeOH: CHCl ₃ [0: 100] to [2.5: 97.5]), the title product (57%) thereunder; HPLC, t "= 7.48 and 9.11, column A, CH ₃ CN: H ₂ O (1: 1), flow = 1.0 ml / min.

Analysis calculated for:

C ₂₈ Hi ₆ F ₃ N ₄ O ₇ SH ₂ O: C, 51.52; H, 6.64; N, 8.58

Found: C, 51.47; H, 6.46; N, 7.80

Embodiment 70

SfRSI-f ^ EthoxycarbonylphenyDaminocarbonyl-L-aaminobutanoyl-N-tS-d.iri-trifluoro ^ -methyl-Z-oxopentyDl-L-prolinamide (Formula Ib, R ¹ = CH (CH ₃₎ CH _3, R ² = CH ₃ CH ₂ , R ³ = 4- [CH ₃ CH ₂ OC (O)] O, R ⁴ = H, A = NHCO, nn = 1)

a. 2 (RS), 3 (SR) - (4-ethoxycarbonylphenyl) amino-cienyl-la-aminobutyroyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VII b, R ¹ CH (CH ₃ ) CH ₃ , R ² CH ₃ CH ₂ , R ³ = 4- [CH ₃ CH ₂ OC (O)] O, R ⁴ = H, A = NHCO, η = 1) ,

By the method of Embodiment 15a, an opportunity of reacting with ethyl 4-iso-cyanatobenzoate according to the procedure of Example 61a to afford the title compound isolated in 46% yield was obtained; TLC, R _f = 0.53, MeOHrCHCl ₃ (5:95).

b. 3 (RS) - (4-ethoxycarbonylphenyl) aminocarbonyl-La-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ , R ³ = 4- [CH ₃ CH ₂ OC (O)] O, R ⁴ = H, A = NHCO, η = 1.

The product of Example 70a was oxidized following the procedure of Example 61c to afford the title product (68%) after purification by flash chromatography (CHCl ₃ : MeOH [97: 3]); HPLC, t _R = 6.35 and 8.70, column A, H ₂ O: CH ₃ CN (60:40), flow rate = 2.0 ml / min.

Analysis calculated for:

C ₂₅ H ₃₃ F ₃ N ₄ O ₆ -O ₁ OH ₂ O: C, 54.44; H, 6.21; N, 10.15

Found: C, 54.76; H, 6.13; N, 10.27

Embodiment 71

3 (RS) - (4-hydroxycarbonylphenyl) aminocarbonyl-La-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ , R ³ = 4 [HOC (O)] O, R ⁴ = H, A = NHCO, η = 1) By the method of Embodiment 14, according to Material converted from Example 70b into the title product and isolated by flash chromatography on Baker pH 5.0 silica gel (CHCl ₃ : MeOH [97: 3]) in 61% yield; HPLC, t _R = 3.68 and 4.69, column A, H ₂ O: CH ₃ CN (3: 1), flow = 2.0 ml / min.

Analysis calculated for:

C ₂₃ H ₂₉ F ₃ N ₄ O ₆ H ₂ O: C, 51.88; H, 5.86; N, 10.52

Found: C, 51.98; H, 5.69; N, 10.19

Embodiment 72

3 (RS) -N- ⁶ -phenylmethoxycarbonyl-N ² -phenylsulfonyl-L-lysyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ J ₄ NHCOOCH ₂ O, R ³ = O, R ⁴ = H, A = S (O ₂ ), η = 1)

a. 2 (RS), 3 (SR) -N ⁶ -phenylmethoxycarbonyl-L-lysyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide trifluoroacetic acid salt (Formula IVb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = OCH ₂ OCONH (CH ₂ J ₄ -, R ⁴ = H, η = 1).

To a solution of product (2.75g, 4.4m mol) in CH ₂ Cl ₂ (7ml) prepared according to procedure of embodiment 65a was added TFA (10.4g, 90mMoI) and the solution was stirred at room temperature for 1h. Then, toluene OmI) was added and the reaction mixture was concentrated under vacuum to afford the title product (3.4 g), which was used without further purification.

b. 2 (RS), 3 (SR) -N ⁶ -phenylmethoxycarbonyl-N ² -phenylsulfonyl-L-lysyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L- prolinamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ J ₄ NHC (O) OCH ₂ O, R ³ = O, R ⁴ = H, A = S (O ₂ ), η = 1).

To a solution of the product of Example 72a (0.83 g, 1.3 mmol) in CH ₂ Cl ₂ (6.5 ml) was added TEA (0.39 g, 3.9 mmol) and benzenesulfonyl chloride (0.25 g, 1.4 mmol), whereupon the reaction mixture was stirred overnight at room temperature. After concentrating the reaction mixture under vacuum, the residue was dissolved in EtOAc. The EtOAc solution was filtered and concentrated under vacuum to give a residue, which was purified by flash chromatography (gradient elution, MeOH: CHCl ₃ [2.5: 97.5] to [5:95]) to give the title product (m.p. 81%): TLC, Rf = 0.52, MeOH = CHCl ₃ (5:95).

c. SfRSI-N, phenylmethoxycarbonyl-N, phenylsulfonyl-L-lysyl-N-IS-d, J-trifluoro-methyl-oxo-p-D-D-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ ) ₄ NHC (O), R ³ = O, R ⁴ = H, A = S (O ₂ ), η = 1).

The product of Example 72b was oxidized by the method of Example 31c to give, after purification by flash chromatography (gradient elution, CHCl ₃ to CHCl ₃ : MeOH [97.5: 2.5]), the title product (63%); HPLC, t _R = 5.0 and 6.3, column A, CH ₃ CN: H ₂ O (3: 2), flow = 1.0 mL / min.

Analysis calculated for:

C ₃ IH ₃₉ F ₃ N ₄ O ₇ SH ₂ O: C, 54.22; H, 6.02; N, 8.16

Found: C, 54.17; H, 5.80; N, 7.86

Embodiment 73

3 (RS) - [2- (2-Methoxyethoxy) ethoxycarbonyl] -la -aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = CH ₃ O (CH ₂ ) ₂ O (CH ₂ ) ₂ , R ⁴ = H. A = OCO, η = 1)

a. 2 (RS), 3 (SR) - [2- (2-methoxyethoxy) ethoxycarbonyl] -La-aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L -

prolinamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = CH ₃ O (CH ₂ ) ₂ O (CH ₂ ) _{2 /} R ⁴ = H, A = OCO, η = 1). By the method of Embodiment 34b, according to the procedure of Embodiment 61a, a prepared material was allowed to react with material prepared according to the procedure of Example 19a to afford the title compound which after purification was purified by flash chromatography (gradient, acetone: hexane [1: 9 ] to [7: 3]) in 75% yield; TLC, Rf = 0.30 and 0.35, acetone: hexane (40:60). Analysis calculated for:

C ₁₇ H ₂₉ F ₃ N ₂ O ₆ -0.5 H ₂ O: C, 48.22; H, 7:14; N, 6.61

Found: C, 48.13; H, 6.90; N, 6.07

b. 3 (RS) -t 2 - (2-methoxyethoxy) ethoxycarbonyl] -la -aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ , R ³ = CH ₃ O (CH ₂ ) ₂ O (CH ₂ ) 2, R ⁴ = H, A = OCO, η = 1) ,

The product of Example 73a was oxidized by the method of Example 61c to give, after purification by flash chromatography (gradient elution, EtOAc: hexane [1: 1] to EtOAc to acetone: EtOAc [1: 9]), the title product (40%) thereunder; HPLC, t _R = 5.70 and 8.95, column A, H ₂ O: CH ₃ CN (75:25), flow = 2.0 mL / min. Analysis calculated for:

C ₂ IH ₃₄ F ₃ N ₃ O _7: C, 48.77; H, 7 \ 14; N, 6.61

Found: C, 48.13; H, 6.90; N, 6.09

Embodiment 74

3 (RS) - [Z- (4-aminocarbonylamino-1,4-dioxo-2-butenyl)] - L -valyl-N- [3- (1,1,1-trifluoro-4-methyl-2- oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = ZH _Z NC (O) NHC (O) CH = CH- , R ⁴ = H, A = CO, η = 1).

a. 2 (RS), 3 (SR) - [Z- (4-aminocarbonylamino-1,4-dioxo-2-butenyl)] - L-valyl-N- [3- (1,1,1-trifluoro-2- hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = ZH ₂ NC (O) NHC (O) CH = CH-, R ⁴ = H, A = CO, η = 1).

The procedure of Example 21b was used to react with Z-4-aminocarbonylamino-4-oxo-2-butenoic acid according to the procedure of Example 3d to afford the title compound, which after purification by flash chromatography (MeOH: CHCl ₃ [5:95]) was isolated in 26% yield; TLC, R _f = 0.17 and 0.25, MeOH: CHCl ₃ (5:95).

b. 3 (RS) - [Z- (4-aminocarbonylamino-1,4-dioxo-2-butenyl)] - L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl )] - L-prolinamide (formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = ZH ₂ NC (O) NHC (O) -CH = CH- , R ⁴ = H, A = CO, η = 1).

The product of Example 74a was oxidized by the method of Example 31c to give, after purification by flash chromatography (MeOH: CHCl ₃ [4:96]), the title product (29%); HPLC, t _R = 1.78 and 2.45, column A, H ₂ O: CH ₃ CN (65:35), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₁ H ₃₀ F ₃ N ₅ O ₆ - 1.5 H ₂ O: C, 47.37; H, 6.25; N, 13:15

Found: C, 47.29; H, 5:77; N, 13.02

Embodiment 75

SiRSl-phenylaminocarbonyl-L-valyl-N-fS-fU.I-trifluoro-methyl-oxo-pentyl-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CHa) ₂ CH -, R ³ = 0, R ⁴ = H, A = NHCO, η = 1)

a. 2 (RS), 3 (SR) -phenylaminocarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = O, R ⁴ = H, A = NHCO, η = 1).

The procedure of Example 15a was used to react with phenyl isocyanate to afford the title compound which, after purification by flash chromatography (MeOH: CHCl ₃ [2:98]), isolated in 62% yield according to the procedure of Example 3d has been; TLC, R _f = 0.24 and 0.32, MeOH: CHCl ₃ (2:98).

b. SiRSl-phenylaminocarbonyl-L-valyl-N-IS-d ^ J-trifluoro-methyl-oxopenty-Dl-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ ) ₂ CH -, R ³ = 0, R ⁴ = H, A = NHCO, η = 1).

The product of Example 75a was oxidized by the method of Example 31c to afford the title product (75%) after purification by flash chromatography (MeOH: CHCl ₃ [2:98]); HPLC, t _R = 5.70 and 8.77, column A, H ₂ O: CH ₃ CN (60:40), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₃ H ₃₁ F ₃ N ₄ O ₄ -0.75 H ₂ O: C, 55.47; H, 6.58; N, 11.25

Found: C, 55.46; H, 6.50; N, 10.72

Embodiment 76

3 (RS) - (4-ethoxycarbonylphenyl) aminocarbonyl-L-phenylalanyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = BCH ₂ -, R ³ = 4-CH ₃ CH ₂ OC (O) O, R ⁴ = H, A = NHCO, η = 1)

a. 2 (RS), 3 (SR) -1-phenylmethoxycarbonyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula Vila, R ¹ = CH ( CH ₃ ) CH ₃ , R ³ = OCH ₂ -, A = OCO, n = 1).

By the method of Embodiment 2a, a material prepared according to the procedure of Embodiment 4 was given an opportunity to react with CBZ-L-proline to give the title compound (100%); TLC, Rf = 0.37 and 0.45, MeOH = CH ₂ Cl ₂ (5:95).

b. 2 (RS), 3 (SR) -N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula IVa, R ¹ = CH (CH ₃₎ CH ₃ , η = 1).

The product of embodiment 76a was converted to the title product (100%) by the method of example 2b; TLC, R, = 73 and 0.81, MeOH: CH ₂ Cl ₂ , saturated with NH ₄ OH (15:85).

c. 2 (RS), 3 (SR) -phenylmethoxycarbonyl-L-phenylalanyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃₁ CH ₃ , R ² = CH ₂ O, R ³ = X) CH ₂ -, R ⁴ = H, A = OCO, η = 1).

A stirred solution of CBZ-L-phenylalanine (2.29g, 10, OmMoI) was prepared by DCC (2.27g, 11, OmMoI) HOBT (2.70g, 17.6 mmol) and material prepared according to Example 76b (2.68g , 10, OmMoI) in dry THF (45 ml) and cooled to -17 ° C, whereupon the mixture was allowed to stand at room temperature overnight, filtered and concentrated to remove the THF before being taken up in Et ₂ O and EtOAc. The resulting solution was washed (saturated NaHCO ₃ (2x), 1N HCl, brine), dried (MgSO ₄ ), filtered, concentrated and taken up in minimal amount of CH ₂ Cl ₂ . After filtering off Ν, Ν'-dicyclohexylurea, the solution was concentrated under vacuum and dried under vacuum to afford the title compound in quantitative yield as a white foam; TLC, R _f = 0.37 and 0.45, MeOH: CH ₂ Cl ₂ (5:95).

d. 2 (RS), 3 (SR) -L-phenylalanyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula IVb, R ¹ = CH ( CH ₃ ) CH ₃ , R ² = CH ₂ O, R ⁴ = H, n = 1).

A mixture of the product of Example 76c (501.3 mg, 0.898 mmol) and 50% water-wet 10% Pd / C (50 mg) in absolute EtOH (17 ml) was added overnight under hydrogen (1 atmosphere, 101 325 Pascal stirred, filtered, concentrated and dried under vacuum to afford the title compound in quantitative yield; TLC, R _f = 0.14, MeOH = CH ₂ Cl ₂ (5:95) R _f = 0.43 and 0.48 MeOHiNH ₄ OH saturated CH ₂ Cl ₂ (5:95).

e. 2 (RS), 3 (SR) - (4-ethoxycarbonylphenyl) aminecarbonyl-L-phenyl-alanyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VII b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = OCH ₂ -, R ³ = 4- [CH ₃ CH ₂ OC (O)] O-, R ⁴ = H, A = NHCO, n = 1).

By the method of Example 15a, material prepared by the procedure of Example 76d was given the opportunity to react with ethyl 4-isocyanatobenzoate to give the title compound isolated in 95% yield; TLC, R _f = 0.21 and 0.26, MeOH: CH ₂ Cl ₂ (5:95).

f. SfRSJ ^ -ethoxycarbonylphenyDaminocarbonyl-L-phenylalanyl-N-IS-dJ ^ -trifluoro-methyl-oxopentyl-1-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = OCH ₂ -, R ³ = 4- [CH ₃ CH ₂ OC (O)] O-, R ⁴ = H, A = NHCO, n = 1).

The product of Example 76e was oxidized by the method of Example 61c to afford the title product (94%) after purification by flash chromatography (gradient elution, Et ₂ O: pentane [11: 1] to Et ₂ O); HPLC, t _R = 10.26 and 13.52, column A, CH ₃ CN: H ₂ O (45:55), flow = 2.0 ml / min.

Analysis calculated for:

C ₃₀ H ₃₅ F ₃ N ₄ O ₆ -1.24 H ₂ O: C, 57.47; H, 6.03; N, 8.94

Found: C, 57.43; H, 6.02; N, 8,97

Exemplary embodiment 77

3 (RS) - [[4 - [(1-IMaphthylsulfoπyl) aminocarboπyl] phenyl ^ aminocarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 4- [1-naphthyl-S (O ₂ ) NHC (O)] 0 , R ⁴ = H, A = IMHCO, η = 1).

a. 1-naphthalenesulfonamide.

Ammonia was bubbled (-5 ° C) into a stirred solution of 1-naphthalenesulfonyl chloride (5.0 g, 22 mmol) and anhydrous Et ₂ O (400 mL) for 5 min. The resulting mixture was stirred at -78 ° C for 1 h, then allowed to warm to room temperature and stirred overnight. The Et ₂ O was removed in vacuo to leave a white powder, which was washed with water and dried under vacuum to give 3.2 g (70%) of the title compound as a white powder. Melting point 152 ... 153 ° C.

b. StRSJ-t ^ -Id-NaphthylsulfonyDaminocarbonylJphenylJ-aminocarbonylJ-L-valyl-N-tS-tiJJ-trifluoro ^ -methyl ^ -oxopentyl)] - L-prolinamidiFormellb.R ¹ = CH (CH ₃ ) CH ₃ , R ² = ( CH ₃ I ₂ CH-, R ³ = 4- [1-naphthyl-S (O ₂ ) NHC (O)] O, R ⁴ = H, A = NHCO, η = 1)

1-Naphthalenesulfonamide prepared according to Example 77a (0.64 g, 3.09 mmol) was added to a stirred solution of material prepared according to Example 16 (1.5 g, 2.84 mmol), DMAP (0.38 g, 3.1 mmol) WSCDI (0 , 58g, 3.08 mmol) and dry CH ₂ Cl ₂ (40 ml at room temperature under nitrogen.

The resulting reaction mixture was stirred at room temperature overnight before being washed (1N HCl), dried (MgSO ₄ ) and filtered. The filtrate was concentrated under vacuum to a gummy residue, which was purified by flash chromatography (CH ₂ Cl ₂ , then CH ₂ Cl ₂ : MeOH: AcOH [98: 1.9: 0.1]) to give 0.76 g (36 %) of the title compound in the form of a white powder; HPLC, t _R = 10.08 and 16.38, column A, CH ₃ CNiH ₂ O (30:70), flow rate = 2.5 ml /

Analysis calculated for:

C ₃₄ H ₃₈ F ₃ N ₅ O ₇ S-OOH ₂ O: C, 54.25; H, 5:49; N, 9,30

Found: C, 54.56; H, 5.68; N, 8,85

Embodiment 78

3 (RS) -N ² - (4-hydroxycarbonylphenyl) aminocarbonyl-l \ l ^{6-phenylmethoxycarbonyl-L-lysyl} [3- (1,1,1-trifluoro-4-methyl-2- oxopentyUR-prolinamide (Formula Ib , R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ ) ₄ NHC (O) OCH ₂ O, R ³ = 4-HOC (O) O, R ⁴ = H, A = IMHCO, η = 1)

a. 2 (RS), 3 (SR) -N ² - (4-ethoxycarbonylphenyl) -aminocarbonyl-N ⁶ -phenylmethoxycarbonyl-L-lysyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl )] - L-prolineamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ J ₄ NHC (O) OCH ₂ U, R ³ = 4- [EtOC (O)] O, R ⁴ = H, A = NHCO, η = 1).

By the method of Example 15a, material prepared by the procedure of Example 72a was allowed to react with 4-isocyanatobenzoate to afford the title compound, which after purification was purified by flash chromatography (gradient elution, CHCl ₃ to MeOH: CHCl ₃ [2:98], then [5:95] was isolated in 95% yield TLC, R _f = 0.41, MeOH: CHCl ₃ (2.5: 97.5).

b. 3 (RS) -N ² - (4-Ethoxycarbonylphenyl) aminocarbonyl-N ⁶ -phenylmethoxycarbonyl-L-lysyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl-proline amide (Formula Ib , R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ ) ₄ NHC (O) OCH ₂ O, R ³ = 4- [EtOC (O)] O, R ⁴ = H, A = NHCO, n = 1).

The product of embodiment has been oxidized 78a according to the procedure of Working Example 31 c in order, after purification by means of flash chromatography (gradient elution, CHCl ₃ to MeOH: CHCl ₃ [2.5: 97.5] to [5:95]), the title product (77 %); TLC, R _f = 0.48, MeOH: CHCl ₃ (2.5: 97.5).

c. 3 (RS) -N ² - (4-Hydroxycarbonylphenyl) aminocarbonyl-N ⁶ -phenylmethoxycarbonyl-L-lysyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl-proline amide (Formula Ib , R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ ) ₄ NHC (O) OCH ₂ O, R ³ = 4- [HOC (O)] O, R ⁴ = H, A = NHCO, n = 1).

Following the method of Example 14, material prepared according to the procedure of Example 78b was converted to the title product and isolated in 85% yield; HPLC, t _R = 4.71 and 6.76, column A, CH ₃ CN: H ₂ O (40:60), flow = 2.5 mL / min.

Analysis calculated for:

C ₃₃ H ₄₀ F ₃ N ₅ O ₈ -1.5 H ₂ O: C, 55.15; H, 6.03; N, 9,74

Found: C, 54.90; H, 5.92; N, 9,29

Embodiment 79

3 (RS) - (4-Hydroxycarbonylphenyl) carbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 4- [HOC (O)] O, R ⁴ = H, A = CO, η = 1

Following the method of Example 14, material prepared according to the procedure of Example 84c was converted to the title product and isolated in n% yield; HPLC, t _R = 3.48 and 5.31, column A, H ₂ O: CH ₃ CN (3: 1), flow rate = 2.0 ml / min.

Analysis calculated for:

C ₂₄ H ₃₀ F ₃ N ₃ O ₆ -I ₁ OH ₂ O: C, 54.23; H, 6.07; N, 7,91

Found: C, 54.46; H, 6.05; N, 7,69

Embodiment 80

3 (RS) -phenylsulphonyl-La-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] -L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = β, R ⁴ = H. A = S (O ₂ ), η = 1)

a. 2 (RS), 3 (SR) -phenylsulfonyl-La-aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = QR ⁴ = H, A = S (O ₂ ), η = 1).

NMM (0.24 g, 2.4 mmol) and benzenesulfonyl chloride (0.21 g, 1.2 mmol) were added to a solution of material (0.5 g, 1.1 mmol) prepared in Example 61 a in CH ₂ Cl ₂ ( 5 ml) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum; the residue was taken up in EtOAc and filtered; and the filtrate was concentrated under vacuum to give the crude product. The product was partially purified by flash chromatography (gradient, MeOH: CHCl ₃ [2.5: 97.5] to [5:95] and finally purified by flash chromatography (gradient, Et ₂ O: hexane (80:20) to Et ₂ O: hexane (90:10) to Et ₂ O) to give the title product (0.118g), TLC, R _f = 0.33, Et ₂ O.

b. 3 (RS) -phenylsulfonyl-La-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = O, R ⁴ = H, A = S (O ₂ ), η = 1).

The product of Example 80a was oxidized following the procedure of Example 31c to afford the title product after purification by flash chromatography (gradient, MeOH: CHCl ₃ [0: 100] to [2:98] to [5:95]) (42%). ); HPLC, t _R = 4.97 and 6.17, column A, H ₂ O: CH ₃ CN (1: 1), flow = 1.0 mL / min.

Analysis calculated for:

C ₂₁ H ₂₈ F ₃ N ₃ O ₅ SH ₂ O: C, 49.50; H, 5.93; N, 8,25

Found: C, 49.70; H, 6.24; N, 7,67

Embodiment 81

3 (RS) - [1- (Ethoxycarbonyl) cyclopent-1-yl] carbonyl-La-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = 1- [CH ₃ CH ₂ OC (O)] cyclopent-1-yl, R ⁴ = H , A = CO, η = 1)

a. 1- (ethoxycarbonyl) cyclopentane carboxylic acid.

To a solution of diethyl i-cyclopentanedicarboxylate (2.5 g, 11.68 mol) in EtOH (10 mL) was added dropwise over half an hour a solution of KOH (654 mg, 11.68 mmol) in EtOH (10 mL). The resulting mixture was stirred at room temperature for 96h, concentrated under vacuum and partitioned between H ₂ O and EtOAc. The aqueous layer was acidified with concentrated HCl and extracted with EtOAc. The EtOAc extracts were washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum to give the product (1.73 g) as a clear oil.

b. 2 (RS), 3 (SR) - [1-Ethoxycarbonyl) cyclopent-1-yl)] carbonyl-La-aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl) ] -L-prolinamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = 1- [CH ₃ CH ₂ OC (O)] - cyclopent-1-yl , R ⁴ = H, A = CO, η = 1).

Following the method of Example 50a with the following ratios of reagents to one equivalent of the product prepared according to the procedure of Example 81a: HOBT (3.3 equivalents), DCC (1.65 equivalents), TEA (1.5 equivalents) and material according to the preparation of Example 61 a (1.0 equivalent) as well as omitting the citric acid wash, the title product was prepared and isolated by 46% yield by suction pressure chromatography (gradient elution, Et ₂ O: hexane [1: 1] to Et ₂ O); TLC, R _f = 0.47, MeOH: CHCl ₃ (5:95). Analysis calculated for:

C ₂₄ H ₃₈ F ₃ N ₃ O _6: C, 55.27; H, 7:34; N, 8.06

Found: C, 54.74; H, 5.93; N, 7,88

c. 3 (RS) - [1- (Ethoxycarbonyl) cyclopent-1-yl)] carbonyl-Lo: aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamide (formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ , R ³ = 1- [CH ₃ CH ₂ OC (O)] - cyclopent-1-yl, R ⁴ = H, A = CO, η = 1).

The product of Example 81b was oxidized following the procedure of Example 33c to afford the title product (37%) after purification by flash chromatography (acetone: hexane [1: 4]); HPLC, t _R = 6.68 and 8.31, column A, H ₂ O: CH ₃ CN (70:30), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₄ H ₃₆ F ₃ N ₃ O ₆ -LIH ₂ O: C, 53.44; H, 7:13; N, 7,80

Found: C, 53.48; H, 6.97; N, 7,60

Embodiment 82 StRSJ-tTricycloO.S.I. ldec-i-y-sulfonyl-L-a-aminobutyryl-N-tS-dJJ-trifluoro-methyl-oxopenty-Dl-L-prolinamide (Formula

I b, R = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = 1-adamantyl, R ⁴ = H, A = S (O ₂ ), η = 1)

a. 1-adamantane sulfinyl chloride.

Aluminum trichloride (40g, 3 mol) was slowly added to thionyl chloride (200 ml, 2.7 mol) and the mixture was cooled to -20 ⁰ C. Then was added portionwise over 2 ¹ / 2h away adamantane added, after which the resulting mixture was stirred for 1 hour in length and was allowed to warm to room temperature. After removing the thionyl chloride under vacuum

the residue was diluted with CCI4 and the aluminum trichloride was decomposed with ice and water. The layers were separated and the organic layer was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated under vacuum. The residue was distilled under vacuum (1 torr, 133.3 pascals) on a Vigreaux column to give the product (28.8g, b.p. 118-128 ° C) as a waxy solid; TLC, R _f = 0.6 ... 0.4, EtOAc: hexane (15:85).

b. 2 (RS), 3 (SR) - (tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl) sulfonyl-la-aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy) 4-methylpentyl)] - L-prolinamide (formula VII R ¹ = CH (CH ₃ ) CH ₃ , R ² = »CH ₃ CH ₂ -, R ³ = 1-adamantyl, R ⁴ = H, A = S ( O), η = 1.

By the method of Example 20a, an opportunity was afforded by the procedure of Example 61a to react with material prepared according to the procedure of Example 82a to provide the title compound which, after purification, was purified by flash chromatography (gradient, Et ₂ O EtOAc [1: 1] to EtOAc) was isolated in 61% yield; TLC, R _f = 0.53, MeOH: CHCl ₃ (5:95).

Analysis calculated for:

C ₂₅ H ₄₀ F ₃ N ₃ O ₄ S 0.45 H ₂ O: C, 55.22; H, 7.58

Found: C, 55.05; H, 7.57

c. 2 (RS), 3 (SR) - (tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl) sulfonyl-la-aminobutyryl-N- [3- (1,1,1-trifluoro-2-hydroxy) 4-methylpentyl)] - L-prolineamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = 1-adamantyl, R ⁴ = H, A = S (O ₂ ), η = 1).

To a solution of the product of Example 82b (277mg, 0.515mmol) in acetone (25ml) was added, under refluxing conditions, dropwise over 1h a saturated acetone solution of KMnO ₄ (60ml). This mixture was stirred at reflux for 15 minutes, cooled, filtered through Celite® and concentrated under vacuum. The crude product was purified by flash chromatography (EtOAc: Et ₂ O [4: 6]) to give the title product (180 mg) as a solid, TLC, R f = 0.67 and 0.70, MeOH: CHCl ₃ (m.p. 1: 9)

 Analysis calculated for:

C ₂₅ H ₄₀ F ₃ N ₃ O ₅ S: C, 54.43; N, 7,31; N, 7,62

Found: C, 54.49; N, 7,33; N, 7,39

d. SfRSJ-iTricyclop.SII ^ Jdec-i-y-sulfonyl-La-aminobutyryl-N-IS-d ^ J-trifluoro-methyl-O-oxypenty-Dl-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = 1-adamantyl, R ⁴ = H, A = S (O ₂ ), η = 1).

The product of Example 82c was oxidized following the procedure of Example 33c to afford the title product (40%) after purification by flash chromatography (acetone: hexanes [15:85]); HPLC, t _R = 6.27 and 8.29, column A, H ₂ O: CH ₃ CN (1: 1), flow rate = 2.0 ml / min.

Analysis calculated for:

C ₂₅ H ₃₈ F ₃ N ₃ O ₅ SO ₁ OH ₂ O: C, 53.75; H, 7.04; N, 7,32

Found: C, 53.91; H, 7.11; N, 6,97

Embodiment 83

3 (RS) - [1- (hydroxycarbonyl) cyclopent-1-yl] carbonyl-L-α-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L - prolineamide (formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH ₃ CH ₂ -, R ³ = 1 - [HOClOHcyclopenMyl, R ⁴ = H, A = CO, η = 1) Following the method of Example 14, material prepared according to the procedure of Example 81c was converted to the title product and isolated in 79% yield; HPLC, t _R = 3.74 and 4.92, column A, H ₂ O = CH ₃ CN (3: 1), flow = 2.0 mL / min.

Analysis calculated for:

C ₂₂ H ₃₂ F ₃ N ₃ O ₆ -0.35 H ₂ O: C, 53.08; H, 6.62; N, 8.44

Found: C, 53.04; H, 6.58; N, 8,16

Embodiment 84

3 (RS) - (4-Methoxycarbonylphenyl) carbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ ) ₂ CH-, R ³ = 4- [CH ₃ OC (O)] O, R ⁴ = H, A = CO, η = 1)

a. 4-Methoxycarbonylbenzencarbonsäure.

Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over half an hour of time a mulled solution of Chromium (VI) oxide (299,25g, 2.99 mol) and water (925 ml) at 0 ⁰ C. , The resulting solution was added dropwise over 1 hour to a stirred solution of methyl 4- (hydroxymethyl) benzoate (92.5 g, 0.564 mol) and acetone (4.6 g) at 0 ° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The supernatant was decanted before extracting the black tar-like residue with acetone. The decanted supernatant and acetone extracts were pooled and concentrated under vacuum to give a dark brown residue, which was triturated with cold water (4 liters). The resulting precipitate was collected, washed three times with water (1 liter) and dried to give 94.6 g (94%) of the title compound as white crystals; Melting point 218 ... 221 ⁰ C.

b. 2 (RS), 3 (SR) - (4-methoxycarbonylphenyl) carbonyl-L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VII b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4- [CH ₃ OC (O)] O, R ⁴ = H, A = CO, η = 1).

WSCDI (10.27 g, 53.6 mmol) was added to a stirred solution of a compound prepared according to Working Example 3d (17.54 g, 47.8 mmol), the product of Example 84a (8.6 g, 47.8 mmol), HOBT (12 , 86g, 95,3mMol) and dry THF (400 ml) at 0 ⁰ C under nitrogen. The resulting reaction mixture was stirred at ⁰ ° C for one hour; then he was given the opportunity to warm to room temperature, whereupon it was stirred overnight. The THF was removed under vacuum to leave an oily residue which was dissolved in EtOAc. The EtOAc solution was washed (1N HCl, saturated aqueous NaHCO ₃ and brine), dried (MgSO ₄ ), filtered and concentrated under vacuum to give 24.45 g of the crude product as a dry white foam. Purification by flash chromatography (CHCl ₃ : MeOH [97: 3]) afforded the title compound (79%); HPLC, t _R = 4.62 and 5.80, column A, H ₂ O: CH ₃ CN (55:45); Flow rate = 3.0ml / min.

c. Sf S-1-methoxycarbonyl-phenyl-carbonyl-L-valyl-N-IS-di-J-trifluoro-methyl-oxopenty-Dl-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH -, R ³ = 4- [CH ₃ OC (O)] O, R ⁴ = H, A = CO, η = 1).

The product of Example 84b was oxidized by the method of Example 31c to give, after purification by flash chromatography (CHCl ₃ : MeOH [98: 2]), the title product (69%); HPLC, t _R = 4.51 and 6.82, column A, H ₂ O = CH ₃ CN (55:45), flow = 2.0 ml / min.

Analysis calculated for:

C ₂₅ H ₃₂ F ₃ N ₃ O ₆ -O ^ H ₂ O: C, 55.96; H, 6.19; N, 7.83

Found: C, 55.90; H, 6.30; N, 7,93

d. 3 (RS) - (4-Methoxycarbonylphenyl) carbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 4- (CH ₃ OCO) O, R ⁴ = H, A = CO, η = 1).

A preferred process using the oxidation described by DB Dess and JC Martin, J. Org. Chem., 48, 4155-4156 (1983) to prepare the title compound is as follows: A stirred solution of Dess-Martin periodinane (6.76g , 15.96 mmol) and a product prepared by the procedure of Example 84b (6.49 g, 12.25 mmol) in dry CH ₂ Cl ₂ (80 mL) under nitrogen was added TFA (1.82 g, 1.23 mL, 15.96 mmol). added. After stirring the reaction mixture at room temperature overnight, Et ₂ O (30 mL) was added and the mixture was poured into an aqueous solution of saturated NaHCO ₃ and Na ₂ S ₂ O ₃ (17.63 g, 111.51 mmol). After stirring for 15 minutes, the organic layer was separated, washed (saturated NaHCO ₃ , brine), dried (Na ₂ SO ₄ ), filtered, and concentrated to give the title product as a white foam (6.42 g, 99.4%). ; TLC, R _f = 0.67 and 0.76; MeOH = CHCl ₃ (3:97); HPLC, t _R = 4.64 and 6.84, column A, H ₂ O: CH ₃ CN (60:40), flow = 2.0 mL / min.

Embodiment 85

3 (RS) - {4-hydroxycarbonylphenyaminocarbonyl-L-phenylalanyl-N- [3- {1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolineamide (Formula Ib, R ¹ = CH ( CH ₃₎ CH _3, R ² = 0CH _2, R ³ = 4- [HOC (O)] B, R ⁴ = H, A = NHCO, n = 1) Following the method of embodiment 14 according to method of Working example 76f converted material into the title product and isolated by flash chromatography (gradient, MeOH: CH ₂ Cl [4:96] to [10:90]) in 48% yield; HPLC, t _R = 5.52 and 8.12, column A, CH ₃ CN: H ₂ O (35:65), flow rate = 2.0 ml / min.

Analysis calculated for:

C ₂₈ H ₃₁ F ₃ N ₄ O ₆ H ₂ O: C, 56.56; H, 5.59; N, 9.42

Found C, 56.58; H, 5.59; N, 9,22

Embodiment 86

3 (RS) - (4-Methoxycarbonylphenyl) methoxycarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formle Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 4- [CH ₃ OC (O)] OCH ₂ -, R ⁴ = H, A = OCO, η = 1)

a. (4-Methoxycarbonylphenyl) methyl 4-nitrophenyl carbonate.

Following the procedure of Example 7a, but omitting the pH 7.0 wash, methyl 4-hydroxymethylbenzoate was converted to the title compound, which was isolated by trituration with hexane, washed with hexanes: EtOAc (1: 1), and vacuum was dried to yield a 50% yield; TLC, R _f = 0.75, EtOAc: hexane (1: 1).

b. 2 (RS), 3 (SR) - (4-methoxycarbonylphenyl) methoxycarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH, R ³ = 4- [CH ₃ OC (O)] BCH ₂ , R ⁴ = H, A = OCO, η = 1).

The procedure of Example 7b was used to react with the product of Example 86a to afford the title compound which, after purification by flash chromatography (acetone: hexanes [2: 3]) in 48%, was allowed to react with the product of Example 3d. iger yield was isolated; TLC, R, = 0.63 and 0.68, MeOH = CHCl ₃ (1: 9).

Analysis calculated for:

C ₂₆ H ₃₆ F ₃ N ₃ O _7: C, 55.81; H, 6:48; N, 7.51

Found: C, 55.54; H, 6:39; N, 7,29

c. 3 (RS) - (4-Methoxycarbonylphenyl) methoxycarbonyl-L-valyl-N- [3- (1,1,1-trifluoroo-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4 CH ₃ OC (O) OCH ₂ , R ⁴ = H, A = OCO, η = 1).

The product of Example 86b was oxidized by the method of Example 33c to give, after purification by preparative TLC (EtOAc: Et ₂ O [3: 2]), the title product (10%); HPLC, t _R = 4.32 and 6.44, H ₂ O: CH ₃ CH (1: 1), flow = 2.0 ml / min.

Analysis calculated for:

C ₂₆ H ₃₄ F ₃ N ₃ O ₇ -O ^ oH ₂ O: C, 54.86; H, 6.25; N, 7,38

Found: C, 54.87; H, 6.25; N, 7.05

Embodiment 87

3 (RS) - [E-3- (4-Ethoxycarbonylphenyl) -1-oxoprop-2-enyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-mehtyl-2-oxopentyl )] - L-prolineamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = E-4- [CH ₃ CH ₂ OC (O)] - eCH = CH, R ⁴ = H, A = CO, η = 1)

a. Ethyl 4-formylbenzoate. ....

A mixture of 4-formylbenzoic acid (25g), concentrated sulfuric acid (2ml) and EtOH (19.5ml) was moderately heated in 100ml of 1,2-dichloroethane for 5 days under reflux conditions. The solvent was then stripped off and Et ₂ O added to the residue. The Et ₂ O solution was washed (saturated aqueous NaHCO ₃ ), dried (Na ₂ SO ₄ ), filtered and evaporated. The bulb-to-bulb distillation afforded 20.1 g (68%) of the Titelesters in the form of a clear liquid, boiling point 145 ... 150 ⁰ C (2900 Pascals, 22 torr).

b. E- (4-Ethoxycarbonyl) benzenpropensäure.

A mixture of the product of Example 87a (8.9g), malonic acid (10.4g) and piperidine (1ml) in 25ml of pyridine was heated on a steam bath for 3 hours. After evaporation of the solvent and slurrying of the residue in 200 ml of water, the pH was adjusted to 6 with acetic acid. The precipitate was collected and air dried. Crystallization of the material from EtOH gave 10.1 g (92%) of title acid in the form of sparkling white crystals, mp 220.5 ... 221 ⁰ C.

c. 2 (RS), 3 (SR) - [Er3- (4-Ethoxycarbonylphenyl) -1-oxoprop-2-enyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy- 4-methylpentyl)] - L-prolineamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CHa) ₂ CH-, R ³ = E- [4-CH ₃ CH ₂ OC (O) ] 0CH = CH, R ⁴ = H, A = CO, η = 1).

In accordance with the method of Example 32a, the material prepared according to the procedure of Embodiment 3d was given the opportunity to react with the product of Example 87b to give the title compound, which was isolated in 88% yield; TLC, R _f = 0.14 and 0.18, MeOH = CH ₂ Cl ₂ (5:95).

d. 3 (RS) - [E-3- (4-Ethoxycarbonylphenyl) -1-oxoprop-2-enyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl )] - L-proline amide (formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CHg) ₂ CH-, R ³ = E- [4-CH ₃ CH ₂ OC (O)] 0 -HC = CH, R ⁴ = H, A = CO, η = 1)

The product of Example 87c was oxidized by the method of Example 61c to give, after purification by flash chromatography (MeOH: CH ₂ Cl ₂ [2:98]), the title product (65%); TLC, R _f = 0.23, MeOH: CH ₂ Cl ₂ (5:95).

Analysis calculated for:

C ₂₈ H ₃₆ F ₃ N ₃ O _6: C, 59.25; H, 6:39; N, 7,40

Found: · C, 59,14; H, 6.75; N, 7.21

Embodiment 88

3 (RS) - (2-ethoxycarbonylphenyl) aminocarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 2- [CH ₂ CH ₂ OC (O)] 0 _f R ⁴ = H, A = NHCO, η = 1).

a. 2 (RS), 3 (SR) - (2-ethoxycarbonylphenyl) aminocarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ I ₂ CH-, R ³ = 2- [CH ₃ CH ₂ OC (O)] O, R ⁴ = H, A = NHCO, η = 1).

By the method of Embodiment 15a, the material prepared according to the procedure of Embodiment 3d was given an opportunity to react with ethyl 2-isocyanatobenzoate to afford the title compound, which after purification by flash chromatography (EtOAc: hexane [60:40]) in 66% Yield was isolated; TLC, R _f = 0.48 and 0.57, MeOH: CHCL ₃ (5:95).

b. 3 (RS) - (2-ethoxycarbonylphenyl) aminocarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 2- (CH ₃ CH ₂ OCO) O, R ⁴ = H, A = NHCO, η = 1).

Here, a modification of the procedure of Example 54b using the indicated ratios of the product of Example 88 a (1 equivalent), oxalyl chloride (2 equivalents), DMSO (4 equivalents), wherein the reaction mixture for adding these above additives to -45 was warmed (instead of diisopropylethylamine) at -20 ° C and cooled ^c C for the addition of the triethylamine. The work-up involved washing (1N HCl, saturated aqueous NaHCO ₃ , 10% aqueous NaOCl, brine). The title product was obtained after purification by flash chromatography (Et ₂ O: hexane [4: 1]) in 74% yield; HPLC, t _R = 6.95 and 10.46, column A, CH ₃ CN: H ₂ O (35:65), flow = 2.0 mL / min

 Analysis calculated for:

C ₂₆ H ₃₅ F ₃ N ₄ O ₆ -OJoH ₂ O: C, 54.78; H, 6.45; N, 9.83 Found: C, 54.73; H, 6:34; N, 9.51

Exemplary embodiment 89

3 (RS) -4 - [(4-Nitrophenyl) sulfonylaminocarbonyl] phenylcarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] -L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = "-" ⁴ ^ ⁰ ZU) S (O ₂ NHCOIe, R ⁴ = H, A = CO, η = 1) 4-Nitrobenzenesulfonamide (0.196 g, 0.97 mmol) was added under nitrogen at room temperature to a stirred solution of the product of Example 79 (0.5 g, 0.97 mmol), DMAP (0.12 g, 0.97 mmol) mmol) of DCC (0.22 g, 0.97 mmol) and dry CH ₂ Cl ₂ (30ml) was added. The resulting mixture was stirred overnight at room temperature and filtered. The filtrate was washed (1 N HCI), dried (MgSO ₄ filtered and concentrated under vacuum to a yellow residue, which was purified by flash chromatography (CHCl ₃ : MeOH: AcOH [90: 9.8: 0.2]) to give 0.29 g (43%) of the title compound as HPLC, t _R = 4.26 and 8.42, column A, H ₂ O: CH ₃ CN (4: 1), flow = 2.0 mL / min.

C ₃₀ H ₃₄ F ₃ N ₅ O ₉ is -H ₂ O: C, 50.34; H, 5.06; N, 9.78

Found: C, 50.03 H, 4.92; N, 9,43

Embodiment 90

StRSI-phenylmethoxycarbonyl-L-glutamyl-N-CS-fiI.I-trifluoro-methyl-Z-oxopentyl-L-prolineamide phenylmethyl ester (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = - (CH ₂ ) ₂ C (O) OCH ₂ O, R ³ = OCH ₂ -, R ⁴ = H, A = OCO, n = 1)

a. 2 (RS), 3 (SR) -phenylmethoxycarbonyl-L-glutamyl-N- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L -prolineamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ ) ₂ C (O) OCH ₂ O, R ³ = OCH ₂ -, R ⁴ = H, A = OCO, n = 1).

By the method of Embodiment 84b, CBZ-glutamic acid-gamma-benzyl ester was allowed to react with material prepared according to the procedure of Example 2 b to afford the title compound, which after purification by flash chromatography (gradient elution, hexane: Et ₂ O [1 : 3] to Et ₂ O) was isolated in 64% yield; TLC, R _f = 0.61, Et ₂ O.

b. 3 (RS) -phenylmethoxycarbonyl-L-glutamyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide-phenyimethyl ester (Formula Ib, R ¹ = CH ( CH ₃ ) CH ₃ , R ² = (CH ₂ J ₂ C (O) OCH ₂ O, R ³ = OCH ₂ -, R ⁴ = H, A = OCO, n = 1).

The product of embodiment 90a was oxidized by the method of embodiment 54b to give, after purification by flash chromatography (gradient, hexane: Et ₂ O [2: 8] to [1: 9]), the title product (30%); HPLC, t _R = 6.12 and 8.48, column A, CH ₃ CN: H ₂ O (1: 1), flow = 3.0 mL / min.

Analysis calculated for:

C ₃₁ H ₃₆ F ₃ N ₃ O ₇ -2 H ₂ O: C, 56.78; H, 6,15; N, 6,41

Found: C, 56.98; H, 5.74; N, 6,12

Embodiment 91

3S (or R) - (tricyclo [3.3.1.1.1 ³ ' ⁷ ] dec-1-yl) sulfonyl-L-valyl-N- [3- (1,1-J-trifluoro-4-methyl-2-oxo-benzyl)] - L-rolinamide (formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 1-adamantyl, R ⁴ = H, A = S (O ₂ ), η = 1)

a. 2 (RS), 3 (SR) - (tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl = sulfinyl-L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy) 4-methylpentyl)] - L-prolineamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ I ₂ CH, R ³ = 1-adamantyl, R ⁴ = H, A = S ( O), η = 1).

In accordance with the method of Example 20a, the material prepared according to the procedure of Embodiment 3d was given the opportunity to react with product of Example 82a to afford the title compound, which was isolated by flash chromatography (EtOAc = Et ₂ O [2: 3]); TLC, R _f = 0.75, MeOH: CHCl ₃ (1: 9).

b. 2 (RS), 3 (SR) - (tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl) sulfonyl-L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy) 4-methylpentyl)] - L-prolinamide (formula VIIb, R ¹ = CH (CH ₃₎ CH _3, R ² = (CHa) ₂ CH-, R ³ = 1-adamantyl, R ⁴ = H, A = S ( O ₂ ), η = 1).

Following the method of Example 82c, the product of Example 91 a was converted to the title compound and isolated after purification by flash chromatography (EtOAc: hexane [3: 2]) in 60% yield; TLC, R _f = 0.29 and 0.35, EtOAc: hexane (1: 1).

Analysis calculated for:

C ₂₆ H ₄₂ F ₃ N ₃ O ₅ -2.5 H ₂ O: C, 51.13; H, 7.75; N, 6.88

Found: C, 51.12; H, 7.03; N, 6,40

c. 3S (or R) -tricyclo [3.3.1 ³ ' ⁷ ] dec-1-yl) sulfonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] -L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CHa) ₂ CH-, R ³ = 1-adamantyl, R ⁴ = H, A = S (O ₂ ), η =).

The product of embodiment 91b was oxidized by the method of embodiment 33c to afford, after purification by flash chromatography (EtOAc: hexane [1: 1]), the title product (57%) as a substantially pure isomer; HPLC, t "= 3.01, column A, H ₂ O: CH ₃ CN (45:55), flow rate = 2.0 ml / min. Analysis calculated for:

C ₂₆ H ₄₀ F ₃ N ₃ O ₅ -O ^ H ₂ O: C, 54.70; H, 7,20

Found: C, 54.89; H, 7.17

Embodiment 92

3 (RS) - (4-Ethoxycarbonylphenyl) aminocarbonyl-L-phenylglycyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = O, R ³ = 4- [CH ₃ CH ₂ OC (O) Je, R ⁴ = H, A = IMHCO, η = 1)

a. 2 (RS), 3 (SR) -phenylmethoxycarbonyl-L-phenylglycyl-N- [3-1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VII b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = O, R ³ = OCH ₂ -, R ⁴ = H, A = OCO, n = 1).

By the method of Example 50a, material prepared according to the procedure of Example 76b was given the opportunity to react with CBZ-L-phenylglycine to give, after purification by flash chromatography (MeOH: CH ₂ Cl ₂ [5:95]), the title product (95%). to provide; TLC, R _f = 0.13 and 0.19, MeOH: CH ₂ Cl ₂ (5:95).

b. 2 (RS), 3 (SR) -L-phenylglycyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula IVb, R ¹ = CH ( CH ₃₎ CH _3, R ² = 0, R ⁴ = H, n = 1).

According to the method of Example 2 b was prepared according to the procedure of Example 92 a prepared material in 100% yield in the title product.

c. 2 (RS), 3 (SR) - (4-ethoxycarbonylphenyl) aminocarbonyl-L-phenylglycyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = O, R ³ = 4- [CH ₃ CH ₂ -OC (O)] B, R ⁴ = H, A = NHCO, η = 1).

Material prepared according to the procedure of Example 92b was given the opportunity to react with ethyl 4-isocyanatobenzoate by the method of Example 15a to afford the title product (86%); TLC, R _f = 0.24 and 0.27, MeOH: Et ₂ O (1:99).

d. 3 (RS) - (4-Ethoxycarbonylphenyl) aminocarbonyl-L-phenylglycyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = O, R ³ = 4- [CH ₃ CH ₂ OC (O)] O, R ⁴ = H, A = NHCO, η = 1).

The product of Example 92c was oxidized by the method of Example 31c to give the title product [82%] after purification by flash chromatography (gradient, Et ₂ O to CH ₃ CNiEt ₂ O (1:99); HPLC, t _R = 8.88 and 10.82, column A, CH ₃ CN = H ₂ O (45:55), flow = 2.0 ml / min.

Analysis calculated for:

C ₂₉ H ₃₃ F ₃ N ₄ O ₆ -0.64 H ₂ O: C, 56.77; H, 5.80; N, 8.75

Found: C, 56.62; H, 5.78; N, 8.78

Exemplary embodiment 93

SfRSI-phenylmethoxycarbonyl-L-tB-f-phenylsulfonylaminol-glutamic-N-tS-ii.ii-trifluoro-methyl-oxopentyl-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = O (O ₂ ) NHC (O) (CH ₂ ) ₂ , R ³ = OCH ₂ , R ⁴ = H, A = OCO, n = 1)

a. 3 (RS) -phenylmethoxycarbonyl-L-glutamyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = HOCO (CH ₂ I ₂ , R ³ = OCH ₂ , R ⁴ = H, A = OCO, n = 1).

Material prepared according to the procedure of embodiment 90b was converted to the title product by the method of embodiment 14; TLC, R _f = 0.27, MeOH: CHCl ₃ : AcOH (2.5: 95: 0.1).

b. 3 (RS) -phenylmethoxycarbonyl-L- [5- (phenylsulfonylamino) -glytamyl] -N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I b , R ¹ = CH (CH ₃ ) CH ₃ , R ² = OS (O ₂ ) NHC (O) (CH ₂ J ₂ , R ³ = OCH ₂ -, R ⁴ = H, A = OCO, n = 1) ,

By the method of Embodiment 77b, according to the procedure of Embodiment 93a, a prepared material was given an opportunity to react with benzenesulfonamide to recover after purification by flash chromatography (gradient, MeOH: Et ₂ O [2.5: 97.5] to [5: 95]) to give the title product (40%); HPLC, t "= 7.38 and 10.35, column A, H ₂ O: CH ₃ CN (65:35), flow rate = 2.5 ml / min.

Analysis calculated for:

C ₃₀ H ₃₅ F ₃ N ₄ O ₈ S -1.5 H ₂ O: C, 51.79; H, 5.51; N, 8:19

Found: C, 51.70; H, 5:24; N, 7,89

Embodiment 94

3 (RS) - [4- (phenylsulfonylaminocarbonyl) -phenYlcarbonyl] -L-valyl-N-t3- (1,1 _f 1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formally, b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ ) ₂ CH-, R ³ = -4- [e S (O ₂ ) NH-C (O)] e, R ⁴ = H, A = CO, η = 1) By the method of Embodiment 89, material prepared according to the procedure of Embodiment 79 was given an opportunity to react with benzenesulfonamide to be purified by flash chromatography (EtOAc: Et ₂ O: AcOH [25: 74.9: 0.1]). ) to give the title product (33%); HPLC, t _R = 3.71 and 5.65, column A, H ₂ O: CH ₃ CN (3: 1); Flow rate = 2.0ml / min.

Analysis calculated for:

C ₃₀ H ₃₅ F ₃ N ₄ O ₇ S-UBH ₂ O: C, 53.36; H, 5.59; N, 8,29

Found: C, 53.75; H, 5.64; N, 7,72

Embodiment 95

SIRSl - ^ - tfBromophenyOsulfonylaminocarbonylphenylcarbonyl-L-valyl-NO-fluoro-trifluoro-methyl-oxopenty-Dl-L-proline amide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) _Z CH -, R ³ = 4 - [(4-Br 0) S (O ₂ ) NHC (O)] O, R ⁴ = H, A = CO, η = 1)

a. 4-Bromobenzensulfonamid.

Following the procedure of Example 77a, 4-bromobenzenesulfonyl chloride (10g, 39.6 mmol) was converted to the title product and recovered as white crystals (8.45g, 92%); Melting point 163 ... 165 ⁰ C.

b. 3 (RS) - [4 - [(Bromophenyl) sulfonylaminocarbonyl] -phenylcarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl] -L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4 - [(4-Br-O) S (O ₂ ) NHC (O)] O, R ⁴ = H, A = CO, η = 1).

By the method of Embodiment 89, material prepared according to the procedure of Embodiment 79 was given an opportunity to react with the product of Example 95a to recover the title product (50%) after purification by recrystallization from hexane / Et ₂ O; HPLC, t _R = 5.25 and 7.84, column A, H ₂ O = CH ₃ CN (77.5: 22.5), flow = 2.0 ml / min.

Analysis calculated for:

C ₃₀ H ₃₄ BrF ₃ N ₄ O ₇ S-OJoH ₂ O: C, 48.36; H, 4.80; N, 7.52

Found: C, 48.61; H, 4.89; N, 7.18

Exemplary embodiment 96

3 (RS) -4- (1-naphthylsulfonylamino) -1,4-dioxobutyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 1-I \ laphthyl-S (O ₂ ) 1 \ IHC (O) (CH ₂ ) ₂ , R ⁴ = H, A = CO, η = 1) By the method of Embodiment 89, a material prepared according to the procedure of Embodiment 14 was given an opportunity to react with 1-naphthalenesulfonamide to be purified by flash chromatography (MeOH: CHCl _3). 5:95]) to afford the title product [46%], HPLC, t _R = 4.09 and 6.57, column A, H ₂ O: CH ₃ CN (60:40), flow rate = 2.0 ml / minute

Analysis calculated for:

C ₃₀ H ₃₇ F ₃ N ₄ O _{7 1} OH SO ₂ O: C, 54.29; H, 5:77; N, 8.44

Found: C, 54.33; H, 6.01; N, 8.09

Embodiment 97

3 (RS) - [2- (4-Aminocarbonylphenoxy) -1-oxoethyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 4- [H ₂ IMC (O)] OOCH ₂ , R ⁴ = H, A = CO , η = 1)

a. 4-Aminocarbonylphenoxyessigsäuremethylester.

A mixture of p-hydroxybenzamide (3.43g), methyl bromoacetate (2.37ml) and K ₂ CO ₃ (3.45g) was stirred in 25ml DMF for 12h. The reaction mixture was diluted with water (150 ml); the solid was filtered, washed with water and air dried. Crystallization from ethanol gave 3.3 g (63%) of the title compound as white crystals.

b. 4-Aminocarbonylphenessigsäure.

A mixture of the product of Example 97a (3.3g) in 0.5 N NaOH (30ml) was stirred for 3 hours. The solution was filtered and the filtrate made acidic (pH 1) with 1N HCl. The solid was filtered and air dried to afford 3.0 g (97%) of the title acid in the form of a white powder; Melting point 255 ... 256 ° C.

c. 2 (RS), 3 (SR) - [2- (4-Aminocarbonylphenoxy) -1-oxoethyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl) ] -L-prolinamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4- [H ₂ NC (O)] OOCH ₂ , R ⁴ = H, A = CO, η = 1).

By the method of Example 32a, material prepared according to the procedure of Example 5d was given the opportunity to react with material prepared according to Procedure of Example 97b to afford the title compound which was isolated in 33% yield; TLC, R _f = 0.27 and 0.31, MeOH: CH ₂ Cl ₂ (1: 9).

d. SfRSJ - ^^ - aminocarbonylphenoxyJ-i-oxoethyll-L-valyl-N-IS-d ^^ - trifluoro ^ -methyl ^ -oxopentyDl-L-prolineamide (formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4- [H ₂ NC (O)] OOCH ₂ , R ⁴ = H, A = CO, η = 1).

The product of Example 97c was oxidized by the method of Example 61c to give, after purification by flash chromatography (MeOH: CH ₂ Cl ₂ [4:96]), the title product (35%); TLC, R _f = 0.37, MeOH: CHCl ₃ (1: 9).

Analysis calculated for:

C ₂₅ H ₃₃ F ₃ N ₄ O ₆ -1.5 H ₂ O: C, 52.72; H, 6:37; N, 9,83

Found: C, 52.78; H, 6.03; N, 9,65

Exemplary embodiment 98

SlRSi-f ^ hydroxycarbonylphenyllmethoxycarbonyl-L-valyl-N-IS-fi.U-trifluoro-methyl-Z-oxopentyDl-L-proline amide (formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = ( CH ₃ I ₂ CH-, R ³ = 4- [HOC (O)] BCH ₂ , R ⁴ = H, A = OCO, η = 1) By the method of Embodiment 14, material prepared according to the procedure of Embodiment 86c was incorporated in the Titled product and isolated by preparative TLC (IVIeOHiCHCl ₃ [ISiSS]) in 45% yield HPLC HPLC = 2.27 and 3.02, column A, H ₂ OiCH ₃ CN (60:40), flow = 2.0 ml / minute

Analysis calculated for:

C ₂₅ H ₃₂₃ N ₃ O ₇ H ₂ O: C, 51.91; H, 6.26; N, 7.25

Found: C, 51.75; H, 5.63; N, 7,15

Embodiment 99

3 (RS) - [4- [4- (2-amino-2-oxoethyl) phenoxy] -1-oxobutyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl] 2-oxopentyl)] - L-prolineamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH, R ³ = 4- [H ₂ NC (O) CH ₂ ] 0O - (CH ₂ ) ₃ , R ⁴ = H, A = CO, η = 1)

a. 4- (4-Aminocarbonylphenoxy) butanoic acid ethyl ester.

A mixture of p-hydroxyphenylacetamide (3.8g), ethyl 4-bromobutyrate (3.6ml) and K ₂ CO ₃ (3.45g) was stirred in DMF (30ml) for 12h. The mixture was diluted with water (100 ml); the solid was filtered and air dried. Crystallization of the solid from ethanol gave 4 g (60%) of the title compound as white crystals; Melting point 144.5 ... 145.5 ° C.

b. 4- (4-Aminocarbonylphenoxy) butanoic acid.

A mixture of the product of Example 99a (3.97g) in 1N NaOH (20ml) was stirred at room temperature overnight. The solution was filtered and acidified with 1N HCl. The solid was filtered and dried under high vacuum to give 3g (82%) of the title compound as a white powder; Melting point 162.5 ... 164 ⁰ C.

c. 2 (RS), 3 (SR) - [4- [4- (2-Amino-2-oxoethyl) phenoxy] -1-oxobutyl] -L-valyl-N- [3- (1,1,1-trifluoro 2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4- [H ₂ NC ( O) CH ₂ ] O (CH ₂ ) ₃ , R ⁴ = H, A = CO, η = 1).

In accordance with the method of Example 32a, the material prepared according to the procedure of Example 5d was given the opportunity to react with the product of Example 99b to give the title compound, which was isolated in 71% yield; TLC, R _f = 0.28 and 0.31, MeOH: CHCl ₃ (1: 9).

d. 3 (RS) - [4- (2-Amino-2-oxoethyl) phenoxy] -1-oxobutyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl )] - L-prolineamide (formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ I ₂ CH-, R ³ = 4- [H ₂ NC (O) CH ₂ ] O ( CH ₂ ) ₃ , R ⁴ = H, A = CO, η = 1).

The product of Example 99c was oxidized following the procedure of Example 61c to give, after purification by flash chromatography (MeOH: CH ₂ Cl ₂ [4:96]), the title product (32%); HPLC, t _R = 2.11 and 3.01, SaUIeB ^ ₂ O = CH ₃ CNiTHFiTFA (SSiSSnSiCl), flow = 2.0 ml / min.

Analysis calculated for:

C ₂₈ H ₃₉ F ₃ N ₄ O ₆ SH ₂ O: C, 56.65; H, 6.79; N, 9,43

Found: C, 56.83; H, 6.98; N, 9,24

Embodiment 100 _v

3 (RS) -E- [3- (4-hydroxycarbonylphenyl) -1-oxoprop-2-enyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl) ] -L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = E-4- [HOC (O)] CH = CH-, R ⁴ = H, A = CO, η = 1) Following the method of Example 14, material prepared according to the procedure of Example 87d was converted to the title product in 88% yield, HPLC, t _R = 2.6 and 3.4, column B, H ₂ O: CH ₃ CN: THF: TFA (55: 35: 15: 0.1), flow = 1.5 ml / min.

Analysis calculated for:

C ₂₆ H ₃₂ F ₃ N ₃ O ₆ -0.35 H ₂ O: C, 57.21; H, 6.03; N, 7.96

Found: C, 57.40; H, 6.40; N, 7,38

Embodiment 101

3 (RS) - [2- (4-ethoxycarbonylphenoxy) -1-oxoethyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 4- [CH ₃ CH ₂ OC (O)] OOCH ₂ , R ⁴ = H, A = CO, η = 1)

a. Ethyl 4- [2-oxo-2- (phenylmethoxy) ethoxy] benzoate.

A mixture of ethyl p-hydroxybenzoate (4.98g), benzyl bromoacetate (4.75ml) and K ₂ CO ₃ (4.14ml) was stirred in 30ml DMF for 15h. The reaction mixture was diluted with water (200 ml) and extracted with a 1: 1 ether: hexane mixture. The combined organic extracts were washed (water, brine), dried (Na ₂ SO 4), filtered and evaporated to leave 9.3 g (99%) of the title compound as a heavy oil; TLC, R _f = 0.71, Et ₂ O: hexane (1: 1).

b. Ethyl 4- (2-hydroxy-2-oxoethoxy) benzoate.

A solution of the product of Example 101a (2.0g) in EtOH (50ml) was hydrogenated at 170,000 pascals (10psi) using 10% Pd / C (200mg). After 20 minutes, the reaction was complete and the reaction mixture was filtered through a pad of Celite® and concentrated under vacuum. The residue was crystallized from methyl tert -butyl ether / hexane to give 900 mg (63%) of the title compound as fine white needles; Melting point 129 ... 130 ° C.

c. 2 (RS), 3 (SR) - [2- (4-ethoxycarbonylphenoxy) -1-oxoethyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyI) -L-prolinamide (Formula VII b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4- [CH ₃ CH ₂ OC (O)] OOCH ₂ , R ⁴ = H, A = CO, η = 1).

By the method of Embodiment 32a, an opportunity of reacting with the product of Embodiment 101b was obtained according to the procedure of Embodiment 5d to afford the title compound which was isolated in 92% yield; TLC, R _f = 0.47 and 0.53, MeOH: CH ₂ Cl ₂ (1: 9).

d. 3 (RS) - [2- (4-ethoxycarbonylphenoxy) -1-oxoethyl] -L-valyl-N- [3- {1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH, R ³ = 4- [CH ₃ CH ₂ OC (O) J-OOCH ₂ , R ⁴ = H, A = CO, η = 1).

The product of Example 101c was oxidized by the method of Example 61c to afford the title product (41%) after purification by flash chromatography (MeOHiCH ₂ Cl ₂ [2:98]); TLC, R _f = 0.37, MeOH: CHCl ₃ (1: 9). Analysis calculated for:

C ₂₇ H ₃₆ F ₃ N ₃ O _7: C, 56.74; H, 6.35; N, 7,35

Found: C, 56.40; H, 6.50 N, 7.12

Embodiment 102

3tRS) -t3- (4-ethoxycarbonylphenyl) -1-oxopropyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib , R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CHj) ₂ CH, R ³ = 4- [CH ₃ CH ₂ OC (O) WCHz) ₂ -, R ⁴ = H, A = CO, η = 1)

3. 4-ethoxycarbonylbenzenepropanoic acid.

A solution of 4-carbethoxycinnamic acid (4.9g) in EtOH (120ml) was hydrogenated over 5% Rh / C (485mg) at atmospheric pressure for 21h. The solution was filtered and stripped off. The residue was crystallized from cyclohexane to afford 2.23 g (46%) of the title compound as white crystals; Melting point 108.5 ... 110.5 ⁰ C.

b. 2 (RS), 3 (SR) - [3- (4-Ethoxycarbonylphenyl) -1-oxopropyl] -L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl) ] -L-prolinamide (Formula VII b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4- [CH ₃ CH ₂ OC (O)] O (CH ₂ J ₂ -, R ⁴ = H, A = CO, η = 1).

By the method of Example 32a, a material prepared according to the procedure of Example 5d was given the opportunity to react with the product of Example 102a to produce the title compound which, after purification, was purified by flash chromatography (MeOH: CH ₂ Cl ₂ [4:96 ]) was isolated in 83% yield; TLC _f Rf = 0.33 and 0.38, MeOH: CH ₂ Cl ₂ (5:95).

c. 3 {RS) - [3- (4-Ethoxycarbonylphenyl) -1-oxopropyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide {Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 4- [CH ₃ CH ₂ OC (O)] O (CH ₂ ) ₂ -, R ⁴ = H, A = CO, η = 1).

The product of embodiment 102b was oxidized following the procedure of embodiment 84d to yield the TTtel product (97%).

Analysis calculated for:

C ₂₈ H ₃₈ F ₃ N ₃ O ₆ -0.65 H ₂ O: C, 57.85; H, 6.81; N, 7.23

Found: C, 57,89; H, 6.83; N, 6.98

Example of Alignment 103

3 (RS) -4-Hydroxybenzoyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4- (HO) B, R ⁴ = H, A = CO, η = 1)

a. 2 (RS), 3 (SR) -4-hydroxybenzoyl-L-valyl-N- [3- (1,1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolinamide (Formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4- (HO) O, R ⁴ = H, A = C0, n = 1).

By the method of Embodiment 84b, material prepared according to the procedure of Embodiment 5d was given an opportunity to react with 4-hydroxybenzoic acid to afford the title compound which, after purification by flash chromatography (EtOAc: Et ₂ O [15:85]) in 65% Yield was isolated; TLC, R _f = 0.43, EtOAc: Et ₂ O (15:85).

Analysis calculated for:

C ₂₃ H ₃₂ F ₃ N ₃ O ₅ -0.6 H ₂ O: C, 55.43; H, 6.71; N, 8.43

Found: C, 55.76; H, 6.62; N, 8.03

b. 3 (RS) -4-Hydroxybenzoyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃₎ CH _3, R ² = (CH) ₂ CH-, R ³ = 4 (HO) 0, R ⁴ = H, A = CO, η = 1).

The product of Example 103a was oxidized by the method of Example 33c and with the following modified work-up: The crude residue was dissolved in MeOH and stirred with aqueous K ₂ CO ₃ (5 mL) for 16 h at room temperature. After the mixture was partially concentrated under vacuum, it was acidified with concentrated HCl and extracted with EtOAc. The EtOAc solution was washed (brine), dried (Na ₂ SO ₄ ), filtered and concentrated to a residue which was purified by flash chromatography (EtOAc: Et ₂ O [1: 9]) to afford the title compound in 38% Yield yield; HPLC, t _R = 3.54 and 4.92, column A, CH ₃ CN = H ₂ O (35:65), flow = 2.0 mL / min

 Analysis calculated for:

C ₂₃ H ₃₀ F ₃ N ₃ O ₅ -IH ₂ O: C, 54.47; H, 6:44; N, 6,29

Found: C, 54.83; H, 6:49; N, 7,89

Embodiment 104 '

3 (RS) - [4 - [(4-Chlorophenyl) sulfonylaminocarbonyl] phenylcarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolineamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH, R ³ = 4 - [(4-CIO) S (O ₂ ) NHC (O)] O-, R ⁴ = H, A = CO, η = 1).

By the method of Embodiment 77b, material prepared according to the procedure of Embodiment 79 was given an opportunity to react with 4-chlorobenzenesulfonamide to obtain the titled product (66%) after purification by flash chromatography (MeOH: CH ₂ Cl ₂ [3:97]) thereunder; HPLC, t _R = 4.26 and 6.07, column A,

Analysis calculated for: 0: C., 51.23; H, 5.13; N, 7,60 C ₃₀ H ₃₄ CIF ₃ N ₄ O ₇ SO ₂ H ₂ C 51.23; H 5 11 · N, 7.69 Found:

Embodiment 105

3 (RS) - [3- (4-hydroxycarbonylphenyl) -1-oxopropyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (formula Ib, R ¹ = CH (CH ₃₎ CH _3, R ² = (CHa) ₂ CH-, R ³ = 4- [HOC (O)] 0 _{(CH2) 2),} R ⁴ = H, A = CO. η = 1) Material converted by the method of Embodiment 14 according to the procedure of Embodiment 102c into the title product in 81% yield; HPLC, t _R = 2.6 and 3.4 column B, H ₂ OICH ₃ CNiTHFiTFA (55: 35: 15: 0.1).

Analysis calculated for:

C ₂₆ H ₃₄ F ₃ N ₃ O _6: C, 57.66; H, 6,33; N, 7,76

Found: C, 56.98; H, 6:49; N, 7,35

Embodiment 106

StRSi-ES - ^ - Et ^ chlorophenyldsulfonylaminocarbonyl-phenyll-i-oxopropyn-L-valyl-N-IS-ti.ii-trifluoro-niethyl-oxopenty-OR-pro-amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₂ ) ₂ CH-, R ³ = 4 - [(4-CW) S (O ₂ ) NHC (O) MCH ₂ J ₂ , R ⁴ = H, A = CO, n = 1)

By the method of Example 77b, material prepared according to the procedure of Embodiment 105 was allowed to react with 4-chlorobenzenesulfonamide to afford the title product (90%) after purification by flash chromatography (MeOH = CH ₂ Cl ₂ [5:95]) ; HPLC, t _R = 3.96 and 5.73, column B, H ₂ O: CH ₃ CN: THF: TFA (55: 35: 15: 0.1), flow = 3.0 mL / min.

Analysis calculated for:

C ₃₂ H ₃₈ CIF ₃ N ₄ O ₇ S-UH ₂ O: C, 51.33; H, 5.59; N, 7.51

Found: C, 51.72; H, 5.40; N, 7,24

Embodiment 107

SIRS1-E-IS - ^ - EIChlorophenylsulfonylaminocarbonyl-phenylM-oxoprop-a-enyl-L-valyl-N-ES-dJJ-trifluoro-methyl-a-oxo-pentyl)] - L-prolineamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = E-4 - [(4-CIO) S (O ₂ ) NHC (O)] O-CH = CH-, R ⁴ = H, A = C0, n = 1)

By the method of Example 77b, material prepared according to the procedure of Embodiment 100 was given an opportunity to react with 4-chlorobenzenesulfonamide to obtain after purification by flash chromatography (MeOH: CH ₂ Cl ₂ [5:95]) the titled product (97%) thereunder; HPLC, t _R = 4.73 and 6.68, column B, H ₂ OiCH ₃ CNiTHFiTFA (SS = SSiISiCl), flow = 3.0 ml / min.

Analysis calculated for:

C ₃₂ H ₃₆ CIF ₃ N ₄ O ₇ S-UH ₂ O: C, 51.67; H, 5.33; N, 7.53

Found: C, 51.72; H, 5.40; N, 7.24

Embodiment 108

3 (RS) - [1- [4 - [[(4-bromophenyl) sulfonyl] [phenylmethyl] aminocarbonyl] phenyl] -1-oxomethyl] -L-valyl-N- [3- (1,1,1-trifluoro -4-methyl-2-oxopentyl JR-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 4 - [(Br 0) S (O _{2) N, H2} 0 c) C (O)] 0-, R ⁴ = H, A = CO, n = 1)

a. 4-Bromo-N- (phenylmethyl) benzenesulfonamide.

4-Bromobenzenesulfonyl chloride (14.05 g, 55 mmol) was added to a stirred solution of benzylamine (5.36 g, 50 mmol) and pyridine (400 ml) under nitrogen at room temperature. The resulting reaction mixture was stirred for 1 h, then poured onto ice / water (800 mL) to form a yellow precipitate, which was filtered and recrystallized from EtOH / water to give 9.44 g (53%) of the title compound whitish needles, melting point 116 ... 117 ⁰ C, to give.

Analysis calculated for:

C ₁₃ H ₁₂ BrNO ₂ S: C, 47.87; H, 3.71; N, 4.29

Found: C, 48.02; H, 3.78; N, 4,25

b. 1,1-dimethylethyl 4 - benzoate [[(4-bromophenyl) sulfonyl] [phenylmethyl] aminocarbonyl].

DMAP (1.81 g, 14.84 mmol) was added to a stirred solution of the product of Example 108a (4.4 g, 13.49 mmol) and CH ₂ Cl ₂ (150 mL) at room temperature. To the resulting solution were successively added WSCDI (2.84 g, 14.84 mmol) and terephthalate mono t-butyl ester (3.0 g, 13.49 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum to leave a residue, which was dissolved in EtOAc. The EtOAc solution was washed (20% aqueous citric acid solution, brine, water), dried (MgSO ₄ ), filtered and concentrated under vacuum to leave an oily residue. This residue was dissolved in warm EtOH and allowed to cool. The forming white crystals were filtered, washed with cold EtOH and dried under high vacuum to give 5.72 g (80%) of the title compound as white crystals; Melting point 120 ... 122 ° C. Analysis calculated for:

C ₂₅ H ₂₄ BrNO ₅ S: C, 56.61; H, 4.56; N, 2.64

Found: C, 56.84; H, 4.68; N, 2.60

c. 4 - benzoic acid [[(4-bromophenyl) sulfonyl] [phenylmethyl] aminocarbonyl].

The product of embodiment 108 b (5,30g, 1OmMoI) at 0 ⁰ C to TFA (50 ml) was added and dissolved immediately upon addition. After about 10 minutes, a white precipitate formed; Stirring was continued for half an hour before the mixture was filtered. The collected solid was washed with water and recrystallized from hot absolute EtOH to afford 4.0 g (84%) of the title compound as a white powder; Melting point 193 ... 194 ° C.

d. 2 (RS), 3 (SR) [1- [4 - [[(4-Bromophenyl) sulfonyl] - [phenylmethyl] aminocarbonyl] phenyl-1-oxomethyl] -L-valyl-N- [3- (1, 1,1-trifluoro-2-hydroxy-4-methylpentyl)] - L-prolineamide (formula VIIb, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 4- [[(4-BrO) S (O) ₂ )] [OCH _Z ] -NCO] O, R ⁴ = H, A = CO, η = 1.

WSCDI (0.44 g, 2.3 mmol) was stirred under nitrogen) ° C of a stirred solution of the product of Working Example 108c 1.0 g, 2.1 mmol), material prepared according to Working Example 5d (0.85 g, 2 3 mmol), HOBT (0.28 g, 2.1 mmol) and dry THF The resulting reaction mixture was stirred at 0 ° C for 15 min then allowed to warm to room temperature whereupon it was stirred for 4 h was removed under vacuum to leave a brownish residue, which was dissolved in EtOAc The EtOAc solution was washed (1N HCl, saturated NaHCO ₃ , brine), dried (MgSO ₄ ), filtered and concentrated in vacuo to leave a residue A (1.27 g) portion of this residue was recrystallized from methyl t-butyl ether / hexane to give 0.64 g (49% overall yield) of the title compound as a white powder; TLC, R _f = 0.59 and 0.64, CHCl ₃ : CH ₃ OH (95: 5), HPLC, t _R = 14.34 and 15.26, acid le B, H ₂ O: CH ₃ CN: THF: TFA (55: 35: 15: 0.1), flow = 3.0 ml / min.

e. 3 (RS) - [1- [4 - [[(4-bromophenyl) sulfonyl] [phenylmethyl] aminocarbonyl] phenyl] -1-oxomethyl] -L-valyl-N- [3- (1,1,1-trifluoro 4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ J-CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4 - [[(4 -BrO) S (O ₂ )] N (CH ₂ O) C (O)] O, R ⁴ = H, A = CO, η = 1).

A solution of the product of Example 108d (300 mg, 0.364 mmol) in CH ₂ Cl ₂ (2 mL) was added to a stirred mixture of Dess-Martin periodinane (1.54 g, 3.63 mmol) and dry CH ₂ Cl ₂ ( IOmI) under nitrogen at room temperature. To the resulting mixture was added TFA (0.41 g, 3.63 mmol); whereupon the mixture cleared up immediately; 10 minutes later it was cloudy. Stirring was continued overnight before EtOAc (50 mL) was added, whereupon the resulting mixture was poured into 4 g Na ₂ S ₂ O ₃ containing saturated aqueous NaHCO ₃ (100 mL). The biphasic mixture was stirred vigorously for 10 minutes. The organic layer was separated, washed (saturated NaHCO ₃ [100 ml], brine [10 10mM]), dried (MgSO ₄ ), filtered, concentrated under vacuum and dried under strong vacuum to give 0.24 g (80%) of the title compound in the form to give a white powder; TLC, R _f = 0.62 and 0.75, CHCl ₃ : MeOH (95: 5); HPLC, t "= 14.88 and 21.56, column B, H ₂ O: CH ₃ CN: THF: TFA (55: 35: 15: 0.1), flow = 3.0 ml / min. Analysis calculated for:

C ₃₇ H ₄₀ BrF ₃ N ₄ O ₇ SO ₂ OH ₂ O: C, 53.78; H, 4.94; N, 6.78. Found: C, 53.84; H, 4.98; N, 6.45

Exemplary embodiment 109

SRIoderSI ^ tricycloiS.SII ^ ldec-i-yl-sulfonyl-L-valyl-N-IS-dI.I-trifluoro-methyl-oxo-pentyl-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ZCH-, R ³ = 1-adamantyl, R ⁴ = H, A = S (O ₂ ), η = 1) From the flash chromatography described in Example 91c, the title compound became substantially the other pure isomer (84%) recovered; HPLC, t _R = 3.89, column A, H ₂ O: CH ₃ CN (45:55), flow rate = 2.0 ml / min.

Analysis calculated for:

C ₂₆ H ₄₀ F ₃ N ₃ O ₅ SO ^ H ₂ O: C, 54.57; H, 7:22; N, 7,34

Found: . C, 54.52; H, 7:15; N, 7,33

Embodiment 110

3S (or R) - [4- (phenylsulfonylaminocarbonyl) phenylaminocarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolineamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 4- [O (O ₂ ) NHC- (O)] O, R ⁴ = H, A = NHCO, η = 1) The two diastereomers of Example 58 were separated by MPLC on a LiChroprep® RP-8 column (Merck, size B40-63 | Lim) using MeOH: H ₂ O (50:50) as eluent collected fractions were analyzed by HPLC and the appropriate fractions were pooled and lyophilized to give the title product, HPLC, t _R = 4.5, column B, H ₂ O: CH ₃ CN: THF: TFA (55:35: 1). 15: 0.1), flow rate = 2.0 ml / min.

Exemplary embodiment 111

SS, or RJ-phenylmethoxycarbonyl-L-phenylglycyl-N-f S -fi-trifluoro-methyl-a-oxo-benzyl-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = O, R ³ = 0CH ₂ -, R ⁴ = H, A = OCO, n = 1)

Following the method of Example 61c, the product prepared by the procedure of Example 92a was oxidized to give, after purification by flash chromatography (MeOH: CH ₂ Cl ₂ [1.5: 98.5]), the title product (80%) as a to yield substantially pure isomer; TLC, R _f = 0.26, pentane: MeOH: Et ₂ O (25: 1: 99).

Analysis calculated for:

C ₂₇ H ₃₀ F ₃ N ₃ O _5: C, 60.78; H, 5.67; N, 7,88

Found: C, 60.64; H, 5.85; N, 7,96

Embodiment 112

3R (or Sl-phenylmethoxycarbonyl-L-phenylglycyl-N-IS-dU-trifluoro-methyl-oxopentyl-U-L-proline amide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = O, R ³ = 0CH ₂ -, R ⁴ = H, A = OCO, n = 1)

From the flash chromatography described in Example III, the title product (83%) was recovered as the other substantially pure isomer; TLC, R _f = 0.30, pentane: MeOH: Et ₂ O (25: 1: 99).

Analysis calculated for:

C ₂₇ H ₃₀ F ₃ N ₃ O _5: C, 60.78; H, 5.67; N, 7,88

Found: C, 59.43; H, 5.65; N, 7.48

Exemplary embodiment 113

3R (or S) - [4 - [(4-Bromophenyl) sulfonylaminocarbonylphenylcarbonylH-valyl-N-β-d, 1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 4- [4- (Br 0) S (O ₂ ) NHC (C)] e, R ⁴ = H, a = CO, η = 1) The product of embodiment 95b (0.5 g, 0.7 mmol) was purified by MPLC on a LiChroprep®RP-8 column (Merck, size Β40-63μΓη) using of MeOH: H ₂ O (60:40) as eluent chromatographies The collected fractions were evaluated by HPLC, pooled and lyophilized to give two products The title product (0.147 g) was recovered as a substantially pure isomer; t _R = 12.38, column B, H ₂ OiCH ₃ CN: THF: TFA (55: 35: 15: 0.1), flow = 3.0 ml / min.

Embodiment 114

3S (or R) - [4 - [(4-bromophenyl) sulfonylaminocarbonyl] -phenylcarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L- prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ J ₂ CH-, R ³ = 4 - [(4-BrB) S (O ₂ ) NHC (O) W, R ⁴ = H, A = CO, η = 1) The other product recovered in the separation described in Example 113 was the title product (0.065 g) which was recovered as a substantially pure isomer; t _R = 8.44, column B, H ₂ O: CH ₃ CN: THF: TFA (55: 35: 15: 0.1), flow = 3.0 ml / min.

Exemplary embodiment 115

3S (or R) - [4 - [(4-chlorophenyl) sulfonylaminocarbonyl] phenyl carbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-Prolineamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ I ₂ CH-, R ³ = 4 - [(4-CW) S (O ₂ ) NHC (O)] B, R ⁴ = H, A = CO, η = 1) A portion of material (544.8 mg) prepared according to procedure of Example 104 was dissolved in H ₂ O: CH ₃ CN: THF (2.2 mL: 3.3 mL). 0.5 ml) and purified by MPLC on a Lobar® size B LiChroprep® RP-8 column using H ₂ O: CH ₃ CN: THF: TFA (55: 32.5: 12.5: 0.1) After analysis by HPLC, the appropriate fractions were pooled, concentrated under vacuum and dried under high vacuum at 43 ° C to afford the title compound (255mg) as a white amorphous solid, HPLC, t _R = 5.76, column B , H ₂ O: CH ₃ CN: THF: TFA (55: 32.5: 12.5: 0.1), flow = 3.0 ml / min

 Analysis calculated for:

C ₃₀ H ₃₄ CIF ₃ N ₄ O ₇ SI ^ H ₂ O: C, 50.71; H, 5.19; N, 7.89 Found: C, 50.88; H, 4,87; N, 7,70

Embodiment 116

3R (or S) - [4 - [(4-chlorophenyl) sulfonylaminocarbonyl] phenyl] carbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-Prolineamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = (CH ₃ ) ₂ CH-, R ³ = 4 - [(4-CIB) S (O ₂ ) NHC (O) RR ⁴ = H, A = CO, η = 1) A portion of material prepared according to procedure of embodiment 104 (573.8 mg) was dissolved in H ₂ OiTHF ( ₂ mL: 3 mL) and analyzed by MPLC on a Lobar® size B LiChroprep® RP 8 column using THF: H ₂ O ¹ TFA (41: 59: 0.1) separated as eluent. After analysis by HPLC, the appropriate fractions were pooled and lyophilized to afford the title compound (51.8 mg) as a substantially pure isomer (99: 1 by HPLC); HPLC, t _R = 8.8, column B, H ₂ O: CH ₃ CN: THF: TFA (55: 32.5: 12.5: 0.1), flow = 3.0 ml / min.

Embodiment 117

3S (or R) -phenylmethoxycarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = BCH ₂ , R ⁴ = H, A = OCO, η = 1)

A portion of material prepared according to the procedure of Example 11 (10 g, 0.02 mol) was separated by flash chromatography into its individual and substantially optically pure isomers, using chromatography using 1 kg of silica gel and Et ₂ O: hexane (80 : 20). The pooling of the appropriate fractions afforded the title compound (3.17g) as a substantially pure isomer; HPLC, t _R = 5.65, column A, H ₂ O: CH ₃ CN (55:45), flow = 2.0 ml / min

 Analysis calculated for:

C ₂₄ H ₃₂ F ₃ N ₃ O ₅ -H ₂ O: C, 55.47; H, 6.46; N, 8.08

Found: C, 55.50; H, 6.77; N, 7.99

Exemplary embodiment 118

3R (or S) -phenylmethoxycarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, R ¹ = CH ( CH ₃₎ CH _3, R ² = CH (CH ₃₎ CH _3, R ³ = BCH _2, R ⁴ = H, A = OCO, η = 1

The pooling of the appropriate fractions from the separation described in Example 117 afforded the title compound (3.67g) as the other substantially pure isomer.

Analysis calculated for:

C ₂₄ H ₃₂ F ₃ N ₃ O _5: C, 57.71; H, 6:46; N, 8.41

Found: C, 57.61; H, 6:34; N, 7,96

Exemplary embodiment 119

3S (or R) - [(4-Carboxyphenyl) aminocarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] -L-prolinamide (Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 4- (HOOC) B, R ⁴ = H, A = NHCO, η = 1)

A portion of material prepared by the procedure of Example 16 (500 mg) was separated by MPLC on a Lobar® size B LiChroprep® RP-8 column using MeOH: H ₂ O (1: 1) as eluent. After analysis by HPLC, the appropriate fractions were pooled to afford the title compound (150 mg) as an essentially isomer; HPLC, t _R = 6.58, column A, CH ₃ CNiH ₂ O (25:75), flow rate = 2.0 ml / min.

Embodiment 120 *

iR (or S - [(4-carboxyphenyl) aminocarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ib, i ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 4- (HOOC) O, R ⁴ = H, A = NHCO, η = 1) By combining the appropriate fractions from In Example 119, the title compound was recovered as a highly enriched isomer (220 mg) in a ratio of 90.4: 9.5 with the isomer described in Working Example 119; HPLC, t _R = 11.09, column A, CH ₃ CN: H ₂ O (25:75), flow = 2.0 ml / min.

Example 121

((RS) - [4 - [(4-Chlorophenyl) sulfonylaminocarbonyl] phenylcarbonyl] L -valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -rolanamide ( Formula Ib, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 4 - [(4-CIO) -S (O ₂ ) NHCO] O, R ⁴ = H , A = CO, η = 1) A preferred method of converting the material η prepared by the procedure of Embodiment 5d to the title compound is as follows:

i. 1,1-Dimethylethyl 4 - [(4-chlorophenyl) sulfonylaminocarbonyl] benzoate.

A 5-liter, 3-neck round bottom flask was equipped with a mechanical stirrer and a nitrogen inlet. CH ₂ Cl ₂ (2I) was charged to the reaction flask followed by terephthalic acid mono-t-butyl ester (127.5g, 0.574 mol), DMAP (70.06g,), 574mol) and 4-chlorobenzenesulfonamide (110.04g, 0.574 mol ) were added in the order mentioned, wherein CH ₂ Cl ₂ 400ml) was used to shut washing the solids. WSCDI (110.10g, 0.574 mol) was added portionwise over 10 min, using CH ₂ Cl ₂ (100 mL) to wash off the solid. After stirring the reaction mixture overnight at room temperature, it was concentrated to dryness under vacuum. The residue was partitioned between EtOAc and water. The EtOAc solution was washed (20% aqueous citric acid, saturated aqueous NaHCO ₃ , brine), dried (Na ₂ SO ₄ ) and concentrated under vacuum to a white solid. After drying in iinem vacuum oven at 5O ⁰ C, the title product (227 g, 100%) was obtained in a sufficiently pure state to be jm used directly for the next step; TLC, R _f = 0.43, MeOH: CHCl ₃ (15:85). (Further purification was Tiittel's recrystallization from EtOH: water possible, melting point above 300 ° C). 3. 4 - [(4-Chlorophenyl) sulfonylaminocarbonyl] benzene-carboxylic acid.

A 3-necked 3-neck round bottom flask was equipped with a mechanical stirrer and a CaCl ₂ drying tube. TFA 1300g) was added and cooled to ⁰ ° C, whereupon the product of Example 121a (79.5g, 0.20 mole) was added. Initially, the solid dissolved and gave a clear solution. After 10 ... 15 minutes, a strong product precipitate formed and it became difficult to stir the reaction mixture. Strong agitation with the mechanical stirrer was required to drive the reaction to completion. The reaction mixture was stirred at 0 ... 5 ° C for 1 h before being poured onto 1,500 ml of ice / water and stirred for 2 h. The resulting solid was filtered and dried. The recovered white solid (61.5 g, 91%) was recrystallized from 1600 mL of absolute EtOH / 1600 mL H ₂ O to afford the title product (54 g, 80%) as white needles; Melting point = 286-288 ° C, TLC, R _f = 0.7, VleOH: CHCl ₃ : AcOH (10: 90: 1)

;. 2 (RS), 3 (SR) - [4 - [(4-chlorophenyl) sulfonylaminocarbonyl] phenylcarbonyl] (-L-valyl-N- [3- 1,1,1-trifluoro-2-hydroxy-4-methylpentyOR- prolinamide (Formula VII b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 4 - [(4CI-0) S (O ₂ ) NHCO] O, R ⁴ = H, A = CO,

A 250 ml, 3-neck round bottom flask was fitted with a magnetic stirrer and nitrogen inlet. To the reaction flask contained CH ₂ Cl ₂ (125ml) was the product of Example 121 b (5.45g, 16.07 mmol), DMAP [1.96g, 16.07 mmol) and according to Embodiment 5d prepared material (6.20g , 16.87 mmol) using CH ₂ Cl ₂ [20 mL] to wash off the solids; then WSCDI (2.24 g, 16.87 mmol) was added using CH ₂ Cl ₂ (5 mL) to wash off the solid. After stirring for 5 hours, the reaction mixture was washed (1N HCl, saturated aqueous NaHCO ₃ , brine), dried (Na ₂ SO ₄ ) and concentrated in vacuo to afford a crude product (11.0g, 100%) as a white solid , A portion of this crude product (3.39g) was dissolved in MeOH (40ml) and diluted with water (9ml). The resulting solution was saturated with K ₂ CO ₃ and stirred at room temperature overnight. After most of the MeOH was removed under vacuum, the residue was partitioned between EtOAc and water. The EtOAc solution was washed (saturated aqueous NaHCO ₃ , brine), dried (Na ₂ SO ₄ ) and concentrated to afford a substantially pure title product (3.13 g, 92%); TLC, R _f = 0.38 and 0.46, MeOH = CHCl ₃ = AcOH (5: 95: 1); HPLC, t _R = 6.20 and 6.25, column A, H ₂ O: CH ₃ CN: THF: TFA (55: 35: 15: 0.1), flow = 3.0 mL / min

 d. 3 (RS) - [4 - [(4-chlorophenyl) sulfonylaminocarbonyl] -phenylcarbonyl] -L-valyl-N- [3- (1,1, '1-trifluoro-4-methyl-2-oxopentyl)] - L -

prolinamide (formula I b, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 4 - [(4-CIO) S (O ₂ ) NHCO] O, R ⁴ = H, A = CO, η = 1). To a stirred solution of Dess-Martin periodinane (636 g, 1.50 mol) in CH ₂ Cl ₂ (5 liters) was added product (351 g, 0.50 mol) in THF (500 mL) according to the procedure of Example 121c. whereupon the resulting suspension was diluted with CH ₂ Cl ₂ (2 liters) and then TFA (171 g, 1.50 mol) was added. After stirring the reaction overnight at room temperature, the CH ₂ Cl ₂ was removed in vacuo, the residue was diluted with EtOAc and treated with a 1: 1 mixture of saturated aqueous NaHCO ₃ and saturated aqueous Na ₂ S ₂ O ₃ . After dissolution of the entire solid, the aqueous layer was separated and the EtOAc layer was washed (a mixture of saturated aqueous NaHCO ₃ : saturated aqueous Na ₂ SO ₃ [1: 1], saturated aqueous NaHCO ₃ , brine) dried (Na ₂ SO ₄ ) and concentrated under vacuum. The residue was dissolved in MeOH (1.5 liters) and treated with 1N HCl (1.5 liters) and the MeOH was removed in vacuo. The remaining aqueous suspension was extracted with CH ₂ Cl ₂ , and the combined

CH ₂ Cl ₂ extracts were washed (brine), dried (Na ₂ SO ₄ ) and concentrated in vacuo to give, after purification by flash chromatography (gradient, Et ₂ O to Et ₂ O: MeOH [95: 5]) the title product (37 %); HPLC, t _R = 6.68 and 9.27, column

B = IS = O ₁ I), flow = 2.0 ml / min.

Embodiment 122

3 (RS) -N ² , N ^e -di (phenylmethoxycarbonyl) -L-lysyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L- prolinamide (formula Ic, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = BCH ₂ , R ⁴ = H, R ⁵ = OCH ₂ OCONH (CH ₂ J ₄ , R ⁶ = H, A = OCO, η = 1)

Following the method of Example 54b, the product of Example 28a was oxidized to give, after purification by flash chromatography (hexane: Et ₂ O [1: 1], then Et ₂ O, then Et ₂ O = EtOAc [3: 1]) the title product ( 56%); HPLC, t _R = 4.19 and 6.02, column A, CH ₃ CN: H ₂ O (60:40), flow = 1.5 mL / min.

Analysis calculated for:

C ₃₈ H ₅₀ F ₃ N ₅ O ₈ -O ^ H ₂ O: C, 59.21; H, 6.67; N, 9.03

Found: C, 58.93; H, 6.62; N, 8.75

Embodiment 123

StRSI-ti ^ -Oioxo ^ -thenylsulfonylaminotbutyl-L-leucyl-L-valyl-NO-ti.ii-trifluoro-methyl-oxo-pentoxyd-L-proline amide (Formula IcR ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ , R ³ = 0S (O ₂ ) NHCO (CH ₂ ) ₂ , R * = H, R ⁵ = (CH ₂ J ₃ CH ₃ , R ⁶ = H, A = CO, η = 1)

A solution of the product of Example 24 (0.5g, 0.87mmol) benzenesulfonamide (0.14g, 0.87mmol, DMAP (0.11g, 0.87mmol) and DCC (0.18g, 0.87 The reaction mixture was filtered and concentrated in vacuo to give a crude product. The product was purified by flash chromatography on Baker pH 5.0 silica gel (gradient, 0.1 mmol) in CH ₂ Cl ₂ (20 ml). CHCl ₃ to MeOH: CHCl ₃ [2:98] to MeOH: CHCl ₃ [5:95]) to give the title product (0.37 g); HPLC, t _R = 3.84 and 5.03, column A , H ₂ O = CH ₃ Cn (65:35), flow = 1.0 ml / min

 Analysis calculated for:

C ₃₂ H ₄₆ F ₃ N ₅ O ₈ S: C, 52.23; H, 6.57; N, 9,52

Found: C, 51.94; H, 6.29; N, 9.37

Embodiment 124

3 (RS) - [4- (Methylsulfonylamino) -1,4-dioxobutyl] -L-leucyl-L-valyl-IM- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl) ] -L-prolinamide (formula I c, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ ,

R ³ = CH ₃ S (O ₂ ) NHCO (CH ₂ ) ₂ , R ⁴ = H, R ^s = (CH ₂ J ₃ CH ₃ , R ⁶ = H, A = CO, η = 1) A solution of the product of Example 24 (0.5g, 0.87mmol), methanesulfonamide (0.082g, 0.87mmol), DMAP (0.11g, 0.87mmol) and DCC (0.18g, 0.87mmol) in CH ₂ Cl ₂ (20 ml) was stirred for four days at room temperature. The reaction mixture was filtered and concentrated under vacuum to give a crude product, which was purified by flash chromatography on Baker pH 5.5 silica gel (gradient, CHCl ₃ , MeOH: CHCl ₃ [1:99] to [2.5: 97.5]. ) was partially cleaned. The partially purified product was partitioned between EtOAc and a mixture of aqueous 1N HCl and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated to give the title product (0.28g); HPLC, t _R = 5.99 and 8.95, column A, H ₂ OiCH ₃ CN (65:35), flow = 1.0 mL / min

 Analysis calculated for:

C ₂₇ H ₄₄ F ₃ N ₅ O ₈ S: C, 49.46; H, 6.76; N, 10.68

Found: C, 49.07; H, 6.79; N, 10,43

Embodiment 125

3 (RS) -N ² - [1,4-dioxo-4- (phenylsulfonylamino) butyl] -N ⁶ -phenyl-methoxycarbonyl-L-lysyl-L-valyl-N- [3- (1,1,1- trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide (Formula Ic, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH- (CH ₃ ) CH ₃ , R ³ = O (O ₂ ) NHCO (CH ₂ ) Z, R ⁴ = H, R ⁵ = OCH ₂ OCONH (CH ₂ J ₄ , R ⁶ = H, A = CO, η = 1)

A solution of the product of Example 27 (493 mg, 0.67 μmol), benzenesulfonamide (117 mg, 0.745 mmol), DMAP (91 mg, 0.745 mmol) and DCC (153 mg, 0.745 mmol) in CH ₂ Cl ₂ (20 ml). was stirred at room temperature for 24 hours. The solution was diluted with EtOAc, washed (water), dried (MgSO ₄ ), filtered and concentrated under vacuum. The crude product was purified by flash chromatography on Baker pH 5.5 silica gel (CH ₃ OH: CHCl ₃ [2.5: 97.5]) to afford the title product (243 mg) as a white powder; TLC, R _f = 0.50, CH ₃ OH: CHCl ₃ : AcOH (5: 94: 1). Analysis calculated for:

C ₄ OH ₆₃ F ₃ N ₆ Oi ₀ -OJSH ₂ O: C, 54.56; H, 6.24; N, 9.54 Found: C, 54.52; H, 6.23; N, 9,48

Embodiment 126

3 (RS) - [1,4-dioxo-4 - [(tricyclo 3.3.1!) Idec-i-y-sulfonylaminol-butyl-L-leucyl-L-valyl-N-ia-di-i-trifluoro] - methyl ^ -oxopentyl)] - L-prolinamide (formula Ic, R ¹ = CH (CH ₃ ) CH ₃ , R ² = CH (CH ₃ ) CH ₃ ,

R ³ = (1-adamantyl) S (Oz) NHCO (CH ₂ ) 2, R ⁴ = H, R ⁵ = (CH ₂ ) ₃ CH ₃ , R ⁶ = H, A = CO, η = 1)

a. 1-Adamantansulfinamid.

Slowly concentrated ammonium hydroxide (300 ml) was added to the product of Example 82a (10.0 g, 45.7 mmol) and the mixture was heated to reflux for 3 hours. After distillation of the ammonium hydroxide, the residue was taken up in water and extracted with Et ₂ O. The Et ₂ O layer was washed (brine), dried (Na ₂ SO ₄ ),

filtered and concentrated under vacuum. The crude product was purified by suction chromatography on silica gel (Et 2 O to EtOAc) to give the product (4.2 g) as a white solid; Melting point 139 ... 141 ⁰ C (literature 141 ... 142 ⁰ C).

b. 1-Adamantansulfonamid.

To a solution of the product of Example 126a (4.0 g, 20%, OmMoI) in acetone (150 ml) under reflux was added a saturated acetone solution of KMnO ₄ until a pale violet color persisted. The solution was cooled, filtered through Celite® and concentrated under vacuum to give the product (3.2g) as a solid; (

Melting point = 191 ... 193 ⁰ C (literature 197 ... 198 ⁰ C); TLC, R _f = 0.80, EtOAc.

c. 3 (RS) - [1,4-dioxo-4 - [(tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl) sulfonylamino] butlyl] -L-leucyl-L-valyl-N- [3- ( 1,1,1-trifluoro-4-methyl-2-oxopentyDR-prolinamide (formula Ic, R ¹ = CH (CH ₃₎ CH _3, R ² = CH (CH ₃₎ CH _3, R ³ = (1-adamantyl ) S (O ₂ ) NHCO (CH ₂ ) 2, R ⁴ = H, R ⁵ = (CHz) ₃ CH ₃ , R ⁶ = H, A = CO, η = 1).

A solution of the product of Example 24 (300 mg, 0.51 mmol), DMAP (62 mg, 0.51 mmol), WSCDI (99 mg, 0.51 mmol) and the product of Example 126b (110 mg, 0.51 mmol). in CH ₂ Cl ₂ (30 ml was stirred at room temperature for 16 h.) The CH ₂ Cl ₂ solution was washed (1N HCl, brine), dried (MgSO ₄ ), filtered and concentrated in vacuo The crude product was purified by preparative TLC. MeOHiCHCl ₃ ] [1: 9]) to give the title product as a solid; TLC, R _f = 0.56, MeOH: CHCl ₃ (5:95); HPLC, t _R = 4.23 and 7.05, column A, H ₂ O: CH ₃ CN (1: 1), flow rate = 2.0 ml / min.

Analysis calculated for:

C ₃₆ H ₅₆ F ₃ N ₅ O ₈ -1.2 H ₂ O: C, 54.22; H, 7:38; N, 7:78

Found: C, 54.28; H, 7,84; N, 7,71

Claims (14)

Invention claim: R1 corresponds to an alkyl group having 1 to 5 carbon atoms and preferably 2 to 5 carbon atoms; R2 and R5 are each independently selected from: (I) an alkyl group of 1 to 10 carbon atoms; (II) an alkyl group having 1 to 6 carbon atoms substituted by at least one member selected from: (a) hydroxy; (b) amino; · (C) alkylamino having 1 to 6 carbon atoms; m (d) dialkylamino, wherein each alkyl group contains 1 to 6 carbon atoms; (e) alkanoyl of 1 to 6 carbon atoms; (f) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbon atoms; (g) aralkanoyl with 8 to carbon atoms; (h) amido which may be attached to the alkyl group with one of its nitrogen or carbon atoms; (i) alkylcarbonylamino wherein the alkyl group contains from 1 to 6 carbon atoms; (j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 6 carbon atoms; (k) arylcarbonylamino, wherein the aryl group contains 6, 10 or 12 carbon atoms; (I) aralkylcarbonylamino, wherein the aralkyl group contains 7 to 13 carbon atoms; (m) arylaminocarbonyl wherein the aryl group contains 6, 10 or 12 carbon atoms; (n) aralkylaminocarbonyl wherein the aralkyl group contains 7 to 13 carbon atoms; (o) carboxy; (ρ) aryloxycarbonyl wherein the aryl group contains 6, 10 or 12 carbon atoms; (q) aralkoxycarbonyl, wherein the aralkoxy group contains 7 to 13 carbon atoms; (r) alkanoyloxy of 1 to 6 carbon atoms; (s) aroyloxy wherein the aryl moiety contains 6.10 or 12 carbon atoms; (t) aralkanoyloxy of 8 to 14 carbon atoms; (u) alkylsulfonamido wherein the alkyl group contains from 1 to 6 carbon atoms; (v) aralkylsulfonamido wherein the aralkyl group contains 7 to 13 carbon atoms; (w) arylsulfonamido wherein the aryl group contains 6, 10 or 12 carbon atoms; (x) acylsulfonamido (ie, acylaminosulfonyl and sulfonylaminocarbonyl) including acylsulfonamido, wherein the acyl group, when forming the terminal portion of the acylsulfonamide, contains from 1 to 7 carbon atoms, and further that in the presence of an aryl in the acylsulfonamide, that aryl is further replaced by fluorine, chlorine , Bromine, iodine and nitro-selected member may be substituted; (y) alkoxycarbonyl, wherein the alkoxy group contains up to 6 carbon atoms; (z) aralkoxycarbonylamino, wherein the aralkoxy group contains from 8 to 13 carbon atoms (eg, benzyloxycarbonylamino); (aa) aryloxycarbonylamino, wherein the aryloxy group contains 6, 10 or 12 carbon atoms; (bb) alkoxycarbonylamino, wherein the alkyloxy group contains 1 to 6 carbon atoms; (cc) aryl of 6, 10 or 12 carbon atoms (e.g., phenyl, biphenyl, naphthyl); (dd) aryl having 6, 10 or 12 carbon atoms and substituted by 1 to 3 under chlorine, bromine, iodine, fluorine, trifluoromethyl. Hydroxy, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (1 to 6 carbon atoms), carboxy, 5-tetrazolo and acylsulfonamido (ie acylaminosulfonyl and sulfonylaminocarbonylOd to 15 carbon atoms), and provided that when the acylsulfonamide contains an aryl, said aryl may be further substituted by a member selected from fluoro, chloro, bromo, iodo and nitro; (ee) cycloalkyl of 3 to 15 carbon atoms (eg, cyclohexyl, adamantyl, norbornyl); (ff) alkylureido, wherein the alkyl group contains up to 6 carbon atoms; (gg) aralkylureido, wherein the aralkyl group contains from 8 to 13 carbon atoms; (hh) arylureido, wherein the aryl group contains 6, 10 or 12 carbon atoms; and (III) an aryl group having 6 carbon atoms, e.g. As phenyl. R3 is selected from: (I) an alkyl group having 1 to 12 carbon atoms; (II) an alkyl group having 1 to 12 carbon atoms and 1 to 4 heteroatoms, each of which is independently selected from nitrogen and oxygen; (III) an alkyl group having 1 to 12 carbon atoms and optionally 1 to 4 heteroatoms, each independently selected from nitrogen and oxygen and substituted on at least one carbon or nitrogen by 1 to 3 members independently selected under: For carbon: (a) hydroxy, provided that it can not be located on a carbon atom directly attached to A; (b) amino, provided that it may not be located on a carbon atom directly attached to A; (c) alkylamino of 1 to 6 carbon atoms, provided that it may not be located on a carbon atom directly attached to A; (d) dialkylamino, wherein each alkyl group contains from 1 to 6 carbon atoms, and provided that it may not be located on a carbon atom directly attached to A; (e) alkanoyl of 1 to 6 carbon atoms; (f) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbon atoms; (g) aralkanoyl of 8 to 13 carbon atoms; (h) amido, which may be attached to the alkyl group via either one of its nitrogen atoms or one of its carbon atoms; (i) alkylcarbonylamino wherein the alkyl group contains from 1 to 6 carbon atoms; (j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 6 carbon atoms; (k) arylcarbonylamino, wherein the aryl group contains 6, 10 or 12 carbon atoms; (k) - (1) Arylcarbonylamino wherein the aryl group contains 6, 10 or 12 carbon atoms and is substituted by one of carboxy, alkoxycarbonyl of 1 to 3 alkoxy carbon atoms, 5-tetrazolo and acylsulfonamido (ie, acylaminosulfonyl and sulfonylaminocarbonyl) of 1 to 15 Carbon atoms, and provided that in the presence of an aryl in the acylsulfonamide, the aryl may be further substituted by a member selected from fluoro, chloro, bromo, iodo and nitro; (I) aralkylcarbonylamino, wherein the aralkyl group contains 7 to 13 carbon atoms; (I) - (I) Aralkylcarbonylamino, wherein the aralkyl group contains 7 to 13 carbon atoms and is represented by carboxy, alkoxycarbonyl of 1 to 3 alkoxy carbon atoms, 5-tetrazolo and acylsulfonamido (ie, acylaminosulfonyl and sulfonylaminocarbonyl) of 1 to 15 carbon atoms selected member being substituted, and provided that in the presence of an aryl in the acylsulfonamide, the aryl may be further substituted by a member selected from fluorine, chlorine, bromine, iodine and nitro; (m) arylaminocarbonyl wherein the aryl group contains 6, 10 or 12 carbon atoms; (n) aralkylaminocarbonyl, wherein the aralkyl group contains 7 to 13 carbon atoms; (o) carboxy; (ρ) aryloxycarbonyl wherein the aryl group contains 6, 10 or 12 carbon atoms; (q) aralkoxycarbonyl, wherein the aralkoxy group contains 7 to 13 carbon atoms; (r) alkanoyloxy of 1 to 6 carbon atoms; (s) aroyloxy, wherein the aryl moiety contains 6.10 or 12 carbon atoms; (t) aralkanoyloxy of 8 to 13 carbon atoms; (u) alkylsulfonamido wherein the alkyl group contains from 1 to 6 carbon atoms; (u) - (1) cycloalkylsulfonamido wherein the cycloalkyl moiety contains from 3 to 15 carbon atoms (eg, cyclohexyl, adamantyl, norbornyl); (v) aralkylsulfonamido wherein the aralkyl group contains 7 to 13 carbon atoms; (w) arylsulfonamido wherein the aryl group contains 6, 10 or 12 carbon atoms; 1) SIRSJ-fW-Id-naphthylsulfonyDaminocarbonynylphenylaminocarbonyl-L-valyl-N-ts-ilibrethyltrifluoro-methyl-oxopentyl) -L-prolinamide; 1) 3 (RS) - [(4-Carboxyphenyl) aminocarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] -L-prolinamide; 1) SSfoderRl-phenylmethoxycarbonyl-L-valyl-N-O-d-yl-trifluoro-methyl-oxopenty-Dl-L-proline amide; From 1 to 2 five- or six-membered rings, at least one of which is aromatic, and optionally having up to 3 carbon atoms of the aromatic ring (s) on any carbon atom with one of fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, alkoxy 1 to 2 carbon atoms, alkanoyl with (1) alkyl straight or branched chain may be; 2) SfRSK ^ -tW-BromophenyOsulfonylaminocarbonylphenylcarbonylJ-L-valyl-N-tS-n, i-trifluoro-methyl-oxopentyl) -L-prolinamide; ' 2) 3 (RS) - [(2-carboxyethyl) carbonyl] -L-norleucyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L- prolinamide; 2) 3 (RS) - [(phenylmethoxy) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide; 2- (phenylsulfonylaminocarbonyl) ethyl, 2 - [(1-adamantyl) sulfonylaminocarbonyl] ethyl and 2 - [(1-naphthyl) sulfonylaminocarbonyl] ethyl were selected: (y) an alkyl group having 2 or 10 carbon atoms and substituted by methoxycarbonyl; (z) an alkyl group having 2 to 5 carbon atoms and substituted by aralkoxycarbonyl, wherein the aralkoxy Proportion contains 7 carbon atoms;
(aa) an alkyl having 5 carbon atoms and substituted by aryloxycarbonylamino, wherein the aryloxy moiety Further, provided that any nitrogen may be substituted by an alkyl group of 1 to 6 carbon atoms, as well as provided that A is attached to a carbon of the aromatic heterocyclic group if A is OCO or NHCO; (IX) an alkenyl group of 2 to 10 carbon atoms having at least one double bond; (X) an alkenyl group of 2 to 10 carbon atoms having at least one double bond and substituted by a member which has been selected from (a) aryl of 6 or 10 carbon atoms; (b) aryl having 6 or 10 carbon atoms substituted by 1 to 3 members independently of one another from chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), Alkoxycarbonyl (2 to 6 carbon atoms), carboxy, acyl sulphoneamido (1 to 15 carbon atoms), and 5-tetrazoles; and (c) ureidocarbonyl.
R ^{4 and} R ⁶ 1 are each hydrogen;
η = 1, and A is under -C, -N-C-, -O-C- and -S- selected. * M H 0 2'- R ³ .A R ¹ OH I!
CO.NH _e CH.CH «CF ₃ to form a first compound of formula I a, I b or I c. 2. The method according to item 1, characterized in that in the compound according to item 1 R ¹ corresponds to an alkyl group having 3 carbon atoms; R ² and R ⁵ are each independently selected from the group consisting of: (I) an alkyl group having 1 to 4 carbon atoms; (II) an alkyl group having 1 to 4 carbon atoms substituted by at least one member selected from: (e) alkanoyl of 1 to 3 carbon atoms; (f) Arylcarbonyl wherein the aryl contains 6 or 10 carbon atoms (g) aralkanoyl of 8 carbon atoms; (h) Amido attached to the alkyl group with either one of its nitrogen atoms or one of its carbon atoms can be connected; (i) alkylcarbonylamino wherein the alkyl group contains from 1 to 2 carbon atoms; (j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 2 carbon atoms; (k) arylcarbonylamino, wherein the aryl group contains 6 carbon atoms; (I) aralkylcarbonylamino, wherein the aralkyl group contains 7 carbon atoms; (m) arylaminocarbonyl wherein the aryl group contains 6 carbon atoms; (η) aralkylaminocarbonyl wherein the aralkyl group contains 7 carbon atoms; (o) carboxy; (ρ) aryloxycarbonyl wherein the aryl group contains 6 carbon atoms; (q) aralkoxycarbonyl wherein the aralkoxy group contains 7 carbon atoms; (r) alkanoyloxy of 1 to 2 carbon atoms; (s) aroyloxy, wherein the aryl moiety contains 6 carbon atoms; (t) aralkanoyloxy of 8 carbon atoms; (u) alkylsulfonamido wherein the alkyl group contains from 1 to 6 carbon atoms; (ν) aralkylsulfonamido wherein the aralkyl group contains 7 to 13 carbon atoms; (w) arylsulfonamido wherein the aryl group contains 6 or 10 carbon atoms; (χ) acylsulfonamidomiti to 15 carbon atoms; (y) alkoxycarbonyl wherein the alkoxy group contains from 1 to 2 carbon atoms; (z) aralkoxycarbonylamino wherein the aralkoxy group contains 7 carbon atoms; (aa) aryloxycarbonylamino, wherein the aryloxy group contains 6 carbon atoms; (bb) alkoxycarbonylamino, wherein the alkyloxy group contains 1 to 3 carbon atoms; (cc) aryl having 6 or 10 carbon atoms; (dd) aryl having 6 or 10 carbon atoms and substituted by 1 to 3 members which are chlorine, bromine, iodine, fluorine, Trif luoromethyl. Hydroxy, alkyl (1 to 2 carbon atoms), alkoxy (1 to 2 carbon atoms), alkoxycarbonyl (2 to 3 carbon atoms), carboxy, 5-tetrazolo and acylsulfonamido (1 to 15 carbon atoms are selected '; (ee) cycloalkyl of 3 to 15 carbon atoms (ff) alkylureido, wherein the alkyl group contains 1 to 2 carbon atoms; (gg) aralkylureido, wherein the aralkyl group contains 7 carbon atoms; (hh) arylureido, wherein the aryl group contains 6 or 10 carbon atoms; and (III) an aryl group of 6 carbon atoms. R ³ is selected from the group consisting of: (I) an alkyl group having 1 to 12 carbon atoms; (II) an alkyl group having 1 to 12 carbon atoms and 1 to 4 heteroatoms, each independently selected from nitrogen and oxygen; (III) an alkyl group having 1 to 12 carbon atoms and optionally 1 to 4 heteroatoms, each independently selected from nitrogen and oxygen, and at least one carbon or nitrogen atom substituted by 1 to 3 members independently of one another selected from the group consisting of: For carbon: (e) alkanoyl of 1 to 6 carbon atoms; (f) arylcarbonyI wherein the aryl contains 6, 10 or 12 carbon atoms; (g) aralkanoyl of 8 to 13 carbon atoms; (h) Amido attached to the alkyl group with either one of its nitrogen or carbon atoms can; (i) alkylcarbonylamino "wherein the alkyl group contains 1 to 6 carbon atoms; (j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 6 carbon atoms; (k) arylcarbonylamino, wherein the aryl group contains 6 or 10 carbon atoms; (k) - (1) arylcarbonylamino wherein the aryl group contains 6 or 10 carbon atoms and is substituted by a member selected from carboxy, alkoxycarbonyl having 1 to 3 alkoxy carbon atoms, 5-tetrazolo and acylsulfonamido having 1 to 15 carbon atoms; (I) aralkylcarbonylamino, wherein the aralkyl group contains 7 to 13 carbon atoms; (I) - (I) aralkylcarbonylamino wherein the aralkyl group contains 7 to 13 carbon atoms and is substituted by a member selected from carboxy, alkoxycarbonyl having 1 to 3 alkoxy carbon atoms, 5-tetrazolo and acylsulfonamido having 1 to 15 carbon atoms; (m) arylaminocarbonyl wherein the aryl group contains 6 or 10 carbon atoms; (n) aralkylaminocarbonyl wherein the aralkyl group contains 7 to 13 carbon atoms; (o) carboxy; (ρ) aryloxycarbonyl; wherein the aryl group contains MO carbon atoms; (q) aralkoxycarbonyl wherein the aralkoxy group contains 7 to 13 carbon atoms; (r) alkanoyloxy of 2 to 3 carbon atoms; (s) aroyloxy, wherein the aryl moiety contains 6 or 10 carbon atoms; (t) aralkanoyloxy of 8 to 13 carbon atoms; (u) alkylsulfonamido wherein the alkyl group contains from 1 to 6 carbon atoms; (u) - (1) cycloalkylsulfonamido wherein the cycloalkyl moiety contains from 3 to 15 carbon atoms; (v) aralkylsulfonamido wherein the aralkyl group contains 7 to 13 carbon atoms; (w) arylsulfonamido wherein the aryl group contains 6 or 10 carbon atoms; (x) acylsulfonamido having 1 to 15 carbon atoms; (y) alkoxycarbonyl wherein the alkoxy group contains from 1 to 3 carbon atoms; (z) aralkoxycarbonylamino, wherein the aralkoxy group contains from 8 to 13 carbon atoms; (z) - (1) aralkylaminocarbonyloxy wherein the aralkyl group contains 7 to 13 carbon atoms; (z) - (2) aryloxy, wherein the aryl contains 6, 10 or 12 carbon atoms; (z) - (3) aryloxy wherein the aryl contains 6, 10 or 12 carbon atoms and is substituted by a member selected from aminocarbonylalkyl of 1 to 3 alkyl carbon atoms, alkoxycarbonyl of 2 to 4 carbon atoms and carboxy; (aa) aryloxycarbonylamino, wherein the aryloxy group contains 6 or 10 carbon atoms; (aa) - (1) arylaminocarbonyloxy wherein the aryl group contains 6 or 10 carbon atoms; (bb) alkoxycarbonylamino, wherein the alkyloxy group contains 1 to 6 carbon atoms; (bb) - (D Alkoxycarbonylamino wherein the alkoxy group contains from 1 to 6 carbon atoms and optionally to one Carbon of an aromatic heterocyclic group as described under R ³ is bound in (gg); (bb) - (2) alkoxycarbonylamino, wherein the alkoxy group contains 1 to 6 carbon atoms "substituted by an aliphatic heterocyclic group as described under R ³ in (ff); (bb) - (3) aryloxyalkylcarbonylamino, wherein the aryl contains 6 or 10 carbon atoms and the alkyl contains 1 to 6 carbon atoms;
(bb) - (4) alkylaminocarbonyloxy wherein the alkyl group contains 1 to 6 carbon atoms; (cc) aryl of 6 or 10 carbon atoms; (Cc) - (D aryloxy having 6 or 10 carbon atoms; (dd) aryl having 6, 10 or 12 carbon atoms and substituted by 1 to 3 members independently of one another are selected from chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, aminocarbonylalkyl (2 to 6 carbon atoms aminocarbonyl, 5 Tetrazole and acylsulfonamidod to 15 carbon atoms); (dd) - (1) Aryloxy having 6, 10 or 12 carbon atoms and substituted by 1 to 3 members independently selected from chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxy ( 1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, acylsulfonamido (1 to 15 carbon atoms), aminocarbonylalkyl (2 to 6 carbon atoms), aminocarbonyl and 5-tetrazolo; (ee) cycloalkyl of 3 to 15 carbon atoms; (ee) - (1) cycloalkyloxy of 3 to 15 carbon atoms; (ff) an aliphatic heterocyclic group of at least SA atoms having up to 5 carbon atoms and 1 to 2'- R ² O (2) no carbon of an alkyl must be bonded directly to two heteroatoms; 3) SfRSi - ^ - ft ^ chlorophenylsulfonylaminocarbonylphenylcarbonylJ-L-valyl-N-IS-UJ-trifluoro-methyl ^ -oxopentyl)] - L-prolinamide; 3) 3 (RS) -N ² - [(2-carboxyethyl) carbonyl] -N ⁶ - [(phenylmethoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1, 1,1-trifluoro-2-oxopentyl)] - L-prolinamide; 3) 3 (RS) - [(4- (ethoxycarbonyl) phenyl) aminocarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide ; 3. The method according to item 1, characterized in that in the compound according to item 1 R ^{1 is} isopropyl; R ² is selected under: (I) an alkyl group having 2 to 3 carbon atoms; (II) (q) ethyl substituted by aralkoxycarbonyl wherein the aralkoxy group contains 7 carbon atoms; (w) butyl substituted by an arylsulfonamido wherein the aryl moiety has 6 carbon atoms; (x) ethyl substituted with acyl sulphoneamido having 7 carbon atoms; (z) butyl substituted by aralkyloxycarbonylamino wherein the araloxy moiety contains 7 carbon atoms; (cc) methyl substituted by an aryl of 6 carbon atoms; and (III) aryl of 6 carbon atoms,
R ³ is selected under: (I) branched alkyl of 4 carbon atoms; (II) an alkyl group having 5 carbon atoms and 2 oxygen atoms; (III) - (k) ethyl substituted by arylcarbonylamino, wherein the aryl moiety contains 6 carbon atoms; (I) ethyl substituted by an aralkylcarbonylamino wherein the aralkyl moiety contains 13 carbon atoms; (n) ethyl substituted by aralkylaminocarbonyl wherein the alkyl contains 7 carbon atoms; (o) an alkyl group containing 2 or 10 carbon atoms and substituted by carboxy; (w) an alkyl group having 5 carbon atoms and substituted by arylsulfonamido, wherein the aryl moiety (3) no heteroatom may be bonded directly to a sulfur, nitrogen or oxygen atom; and 3 carbon atoms and carboxy was selected; (aa) aryloxycarbonylamino, wherein the aryloxy group contains 6, 10 or 12 carbon atoms; (aa) - (1) arylaminocarbonyloxy wherein the aryl group contains 6, 10 or 12 carbon atoms; (bb) alkoxycarbonylamino wherein the alkyloxy group contains up to 6 carbon atoms; (bb) M1) alkoxycarbonylamino wherein the alkoxy group contains from 1 to 6 carbon atoms and optionally on carbon to a carbon of an aromatic heterocyclic group as described in (gg) under R ³ is bonded; (bb) - (2) alkoxycarbonylamino, wherein the alkoxy group contains 1 to 6 carbon atoms substituted by an aliphatic heterocyclic group according to the description given in (ff) under R ³ ; (bb) - (3) aryloxyalkylcarbonylamino wherein the aryl contains 6 or 10 carbon atoms and the alkyl has 1 to 6 carbon atoms; (bb) - (4) alkylaminocarbonyloxy wherein the alkyl group contains up to 6 carbon atoms; (cc) aryl of 6, 10 or 12 carbon atoms (e.g., phenyl, naphthyl, biphenyl); (cc) - (1) aryloxy of 6, 10 or 12 carbon atoms; (dd) aryl having 6, 10 or 12 carbon atoms and substituted by 1 to 3 members, independently of one another among chloro, bromo, iodo, fluoro, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxide to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, aminocarbonylalkyl (2 to 6 carbon atoms), aminocarbonyl, 5-tetrazolo and acylsulfonamido (ie, acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbon atoms), and provided that when the acylsulfonamide contains an aryl, then said aryl is further substituted by a member selected from fluorine, chlorine, bromine, iodine and nitro can be; (dd) - (1) aryloxy having 6, 10 or 12 carbon atoms and substituted on carbon by 1 to 3 members independently selected from chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, aminocarbonylalkyl (2 to 6 carbon atoms), aminocarbonyl, 5-tetrazolo, acylsulfonamido (ie acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbon atoms), and under Provided that in the presence of an aryl in the acylsulfonamide, the aryl may be further substituted by a member selected from fluorine, chlorine, bromine, iodine and nitro; (ee) cycloalkyl of 3 to 15 carbon atoms (e.g., cyclohexyl, adamantyl, norbornyl); (ee) - (1) cycloalkyloxy of 3 to 15 carbon atoms; (ff) an aliphatic heterocyclic group of at least 4 atoms having 1 to 5 carbon atoms and 1 to -3- £ f * l OSJ (x) acylsulfonamido (i.e., acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbon atoms) including acylsulfonamido wherein the acyl group contains from 1 to 7 carbon atoms when it is the terminal portion of the acylsulfonamide and provided that in the presence of an aryl in the acylsulfonamide the aryl is further substituted by a member selected from fluoro, chloro, bromo, iodo and nitro can; . (y) alkoxycarbonyl wherein the alkoxy group contains from 1 to 6 carbon atoms; (z) aralkoxycarbonylamino wherein the aralkoxy group contains from 8 to 13 carbon atoms (e.g. Benzyloxycarbonylamino); (z) - {1) aralkylaminocarbonyloxy wherein the aralkyl group contains 8 to 13 carbon atoms; (z) - (2) aryloxy wherein the aryl contains 6, 10 or 12 carbon atoms; (z) - (3) aryloxy wherein the aryl contains 6, 10 or 12 carbon atoms and is substituted by a member selected from aminocarbonyl, aminocarbonylalkyl having 1 to 3 alkyl carbon atoms, alkoxycarbonyl having 1 to 4) SSfoderRJ-W-K ^ bromophenyldsulfonylaminocarbonylphenylcarbonyl-L-valyl-N-O-d ^ J-trifluoro-methyl-aoxopentyl)] - L-prolinamide; and 4) SIRSJ-K-d-dimethylsulfonylaminocarbonyldiphenylaminocarbonyl-L-valyl-N-IS-di (i-trifluoro-methyl-oxopentyl) -L-prolinamide; 4) 3 (RS) -f (4-carboxyphenyl) aminocarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide; 4. Method according to item 1, characterized in that the compound according to item 1 is selected from the group consisting of: 4 carbon atoms and one sulfur atom; and ethyl substituted by an aromatic heterocyclic one Compound having 5 carbon atoms and one nitrogen atom; (jj) - (D is an alkyl group having 5 carbon atoms and substituted by an arylureido wherein the aryl moiety contains 6 carbon atoms and wherein the aryl moiety is further represented by ethoxycarbonyl or carboxy is substituted;
(zz) propyl substituted by aryloxy wherein the aryl contains 6 carbon atoms; a branched alkyl group with 4 heteroatoms, each independently selected from nitrogen and oxygen, which may be substituted at any nitrogen atom by a member selected from methyl, an alkanoyl group having 2 to 6 carbon atoms, an aryloxycarbonyl group having 6 or 10 aryl groups; Carbon atoms, an aralkoxycarbonyl group having 7 aralkyl carbon atoms and an alkoxycarbonyl group having 2 to 3 carbon atoms, provided that A must be bonded to a carbon of the aliphatic heterocyclic group when A is OCO or NHCO; (VIII). an aromatic heterocyclic group having (a) 1 to 15 carbon atoms and 1 to 4 heteroatoms, of each of which was independently selected from sulfur, nitrogen and oxygen, thus having (b) 4 heteroatoms, each independently selected from nitrogen and oxygen, wherein the aliphatic heterocyclic group may optionally contain 1 or 2 double bond (s), the aliphatic heterocyclic group being attached to any nitrogen having an alkyl group of 1 to 6 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms, an aryloxycarbonyl group having 6, 10 or 12 aryl carbon atoms, an aralkoxycarbonyl group having tbisi alkylaromatic carbon atoms or an alkoxycarbonyl group having 1 to 6 alkyl carbon atoms; (ff) - (1) an aliphatic heterocyclic oxy group in which the oxy bond is connected directly to a carbon of an aliphatic heterocyclic group of at least 5 atoms having 1 to 5 carbon atoms and 1 to 4 heteroatoms, each independently wherein the aliphatic heterocyclic group may optionally contain 1 or 2 double bond (s) and wherein the aliphatic heterocyclic group is attached to any nitrogen having an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms, an aryloxycarbonyl group with 6, 10 or ^ aryl carbon atoms ^ of an aralkoxycarbonyl group having from T to 13 aralkyl carbon atoms or an alkoxycarbonyl group having from 1 to 6 alkyl carbon atoms; (gg) an aromatic heterocyclic group having (1) 1 to 15 carbon atoms and 1 to 4 heteroatoms, of each independently selected from sulfur, nitrogen and oxygen; and having (2) from 1 to 2 five- or six-membered rings, at least one of which is aromatic and optionally substituting up to 3 carbon atoms of the aromatic ring (s) with a member which was selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl-containing alkyl, alkoxy of 1 to 2 carbon atoms, alkanoyl of 2 to 3 carbon atoms, carboxy, aminocarbonylalkyl (2 to 6 carbon atoms) and aminocarbonyl, and further provided that any nitrogen atom may be substituted by an alkyl group having 1 to 6 carbon atoms; (gg) - (1) an aromatic heterocyclic oxy group in which the oxy bond is directly connected to a carbon atom of an aromatic heterocyclic group which in turn contains (1) 1 to 15 carbon atoms and 1 to 4 heteroatoms, each of which is independently selected from sulfur, nitrogen and oxygen and which (2) contains 1 to 2 five- or six-membered rings, at least one of which is aromatic and optionally wherein up to 3 carbon atoms of the aromatic ring (s) with one member which was selected from fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, alkoxy having 1 to 2 carbon atoms, alkanoyl having 2 to 3 carbon atoms, carboxy, aminocarbonylalkyl (2 to 6 carbon atoms) and aminocarbonyl, and further provided that any nitrogen atom may be substituted by an alkyl group having 1 to 6 carbon atoms; (hh) alkylureido wherein the alkyl group contains from 1 to 6 carbon atoms; (hh) - (1) cycloalkylureido wherein the alkyl group contains from 3 to 15 carbon atoms; (ii) aralkylureido, wherein the aralkyl group contains from 7 to 13 carbon atoms; (jj) arylureido, wherein the aryl group contains 6 or 10 carbon atoms; (jj) - (1) arylureido, wherein the aryl group contains 6 or 10 carbon atoms and is substituted by 1 to 3 members independently selected from chlorine, bromine, iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms ), Alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy, acylsulfonamido (1 to 15 carbon atoms), aminocarbonylalkyl (2 to 6 carbon atoms, aminocarbonyl and 5-tetrazolo; For nitrogen: (a) alkyl of 1 to 3 carbon atoms; (b) alkanoyl of 2 to 6 carbon atoms; (c) arylcarbonyl.wobeidasAryiejO or ^ carbon atoms; (d) aralkanoyl of 8 to 13 carbon atoms; (e) formyl; (f) an aliphatic heterocyclic amino group wherein the amino bond is directly attached to a carbon of an aliphatic heterocyclic group as defined in (ff) for the carbon substituents; (g) an aromatic heterocyclic amino group wherein the amino bond is attached directly to a carbon of an aromatic heterocyclic group as defined in (gg) for the carbon substituents; (IV) an aryl group having 6 or 10 carbon atoms; (V) an aryl group having 6 or 10 carbon atoms, suitably substituted by 1 to 3 members independently selected from fluoro, chloro, bromo, iodo, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , Alkoxycarbonyl having 2 to 6 carbon atoms, carboxy, Alkylcarbonylamino having 1 to 6 alkyl carbon atoms, 5-tetrazolo and Acylsülfonamido having 1 to 15 carbon atoms were selected; (VI) a cycloalkyl group of 3 to 15 carbon atoms; (VI) - (I) a cycloalkyl group having 3 to 15 carbon atoms, substituted by a member selected from carbon and alkoxycarbonyl, wherein the alkoxy group in the case of alkoxycarbonyl contains 1 to 4 carbon atoms; . (VII) an aliphatic heterocyclic group of at least 5 atoms having 1 to 5 carbon atoms and 1 to (4) alkenyls of IX and X may not be 1,1-disubstituted for R ³ , and a carbon of a double bond may not be bonded directly to an oxygen or nitrogen atom, characterized in that it comprises oxidizing a compound of formula VII a, VIIb or VIIc R ¹ OH II
C0.NH _e CH "CHoCF ₃ ** Vila CH) 4 heteroatoms, each independently selected from nitrogen and oxygen (e.g., morpholine, piperazine), which may be substituted on any nitrogen with a member selected from an alkyl group of 1 to 6 carbon atoms, an alkanoyl group A group having 1 to 6 carbon atoms, an aryloxycarbonyl group having 6, 10 or 12 aryl carbon atoms, an aralkoxycarbonyl group having 7 to 13 aralkyl carbon atoms and an alkoxycarbonyl group having 2 to 7 carbon atoms, provided that when A is OCO or NHCO, A is attached to a carbon atom of must be bonded to aliphatic heterocyclic group; (VIII) an aromatic heterocyclic group having (a) 1 to 15 carbon atoms and 1 to 4 heteroatoms, each independently selected from sulfur, nitrogen and oxygen, and having (b) 1 to 3 five- or six-membered rings, of which is at least one aromatic and optionally having up to 3 carbon atoms of the aromatic ring (s) on any carbon atom containing one of fluoro, chloro, bromo, iodo, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms , Alkanoyl having 2 to 6 carbon atoms and carboxy group, and further provided that any nitrogen may be substituted by an alkyl group having 1 to 6 carbon atoms, as well as provided that A is attached to a carbon of the aromatic heterocyclic group must be bound when A is OCO or NHCO; (IX) an alkenyl group of 2 to 10 carbon atoms having at least one double bond; and (X) an alkenyl group of 2 to 10 carbon atoms having at least one double bond substituted by a member selected from (a) aryl with 6 or 10 carbon atoms; (b) aryl of 6 or 10 carbon atoms substituted by 1 to 3 members independently represented by chlorine, bromine iodine, fluorine, hydroxy, trifluoromethyl, alkyl (1 to 6 carbon atoms), alkoxide to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), carboxy , 5-tetrazolo and acylsulfonamido (ie acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbon atoms), and provided that in the presence of an aryl in the acylsulfonamide, the aryl is further selected from fluoro, chloro, bromo, iodo and nitro may be substituted; and lf \ I Iroirlnrarhnnul R ⁴ and R ⁶ are independently (selected from each other under hydrogen, or methyl; η is 0,1 or 2; A is under 0 0 0 O -0-C and so selected; or optionally their acid and base addition salts; and provided that: 4 heteroatoms, each independently selected from nitrogen and oxygen (eg, morpholine, piperazine), wherein the aliphatic heterocyclic group may optionally contain one or two double bonds and wherein the aliphatic heterocyclic group on any nitrogen having an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, an aryloxycarbonyl group having 6, 10 or 12 aryl carbon atoms, an aralkyloxycarbonyl group having 7 to 13 aralkyl carbon atoms or an alkoxycarbonyl group having 1 to 6 carbon atoms may be substituted; (ff) - (i) an aliphatic heterocyclic oxy group wherein the oxy bond is connected directly to a carbon atom of the aliphatic heterocyclic group, said aliphatic heterocyclic group consisting of at least 5 atoms having 1 to 5 carbon atoms and 1 to 4 heteroatoms each of which is independently selected from nitrogen and oxygen (eg, morpholine, piperazine), wherein the aliphatic heterocyclic group may optionally contain 1 or 2 double bonds, and wherein the aliphatic heterocyclic group is on each nitrogen atom having an alkyl group of 1 to 6 carbon atoms , an alkanoyl group having 1 to 6 carbon atoms, an aryloxycarbonyl group having 6, 10 or 12 aryl carbon atoms, an aralkyloxycarbonyl group having 7 to 13 aralkyl carbon atoms or an alkyloxycarbonyl group having 1 to 6 alkyl carbon atoms can; (gg) an aromatic heterocyclic group having (1) 1 to 15 carbon atoms and 1 to 4 heteroatoms, of each independently selected from sulfur, nitrogen and oxygen, and having (2) from 1 to 3 five- or six-membered rings, at least one of which is aromatic, and optionally having up to 3 carbon atoms of the aromatic ring (s) may be substituted with a member of the group consisting of fluoro, chloro, bromo, iodo, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, carboxy, aminocarbonylalkyl (2 to carbon atoms and aminocarbonyl, and further provided that any nitrogen atom may be substituted by an alkyl group having from 1 to 6 carbon atoms; (gg) - (1) an aromatic heterocyclic oxy group, wherein the oxy bond directly to a carbon atom of an aromatic heterocyclic group having (1) 1 to 15 carbon atoms and 1 to 4 heteroatoms each of which is independently selected from sulfur, nitrogen and oxygen and having (2) from 1 to 3 five- or six-membered rings, at least one of which is aromatic, and optionally-up to 3 carbon atoms of the one or more aromatic rings / rings may be substituted with a member of the group consisting of fluorine, chlorine, bromine, iodine, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyl of 2 to 6 carbon atoms, carboxy, aminocarbonylalkyl (2 to »6 carbon atoms) and aminocarbonyl, and further provided that any nitrogen atom may be substituted by an alkyl group of 1 to 6 carbon atoms; (hh) alkylureido wherein the alkyl group contains from 1 to 6 carbon atoms; (hh) - (1) cycloalkylureido wherein the alkyl group contains from 3 to 15 carbon atoms; (ii) alkylureido wherein the aralkyl group contains 7 to 13 carbon atoms; (jj) arylureido, wherein the aryl group contains 6, 10 or 12 carbon atoms; (jj) - (1) arylureido, wherein the aryl group contains 6, 10 or 12 carbon atoms and is substituted by 1 to 3 members independently selected from chloro, bromo, iodo, fluoro, hydroxy, trifluoromethyl, alkyl (1 to 6 Carbon atoms), alkoxy (1 to 6 carbon atoms), alkoxycarbonyl (2 to 6 carbon atoms), aminocarbonyl, 5-tetrazolo and acylsulfonamido (ie acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbon atoms) including acylsulfonamide, with the acyl group present in the final portion of the acylsulfonamide contains from 1 to 7 carbon atoms and further provided that in the presence of an aryl in the acylsulfonamide, the aryl may be further substituted by a member selected from fluoro, chloro, bromo, iodo and nitro; For nitrogen: (a) alkyl of 1 to 3 carbon atoms; (b) alkanoyl of 2 to 6 carbon atoms; (c) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbon atoms; (d) aralkanoyl of 8 to 14 carbon atoms; (e) formyl; (f) an aliphatic heterocyclic group in which the amino bond is connected directly to a carbon of an aliphatic heterocyclic group as defined in (ff) for the carbon substituents; (g) an aromatic heterocyclic group in which the amino bond is attached directly to a carbon of the aromatic heterocyclic group defined in (gg) for the carbon substituents; (IV) an aryl group of 6, 10 or 12 carbon atoms; (V) an aryl group having 6, 10 or 12 carbon atoms, suitably substituted by 1 to 3 members independently selected from fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy 1 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, carboxy, alkylcarbonylamino having 1 to 6 alkyl carbon atoms, 5-tetrazolo and acylsulfonamido (ie acylaminosulfonyl and sulfonylaminocarbonyl) having 1 to 15 carbon atoms, and provided that in the presence of an aryl in acylsulfonamide, the aryl may be further substituted by a member selected from fluorine, chlorine, bromine, iodine and nitro; (VI) a cycloalkyl group having 3 to 15 carbon atoms (eg, cyclohexyl, adamantyl, norbornyl); (VI) - (I) a cycloalkyl group having 3 to 15 carbon atoms (ζ, Cyclo, cyclohexyl, adamantyl, norbornyl) substituted by a member selected from carboxy and alkoxycarbonyl wherein the alkoxy group contains 1 to 4 carbon atoms; (VII) an aliphatic heterocyclic group of at least 5 atoms having 1 to 5 carbon atoms and 1 to 5) SSI or R1-K-tt ^ chlorophenylsulfonylaminocarbonylphenylcarbonyn-L-valyl-N-O-dJJ-trifluoro-methyl-Z-oxopentyl)] - L-prolinamide. 5) SfRSI-W-f-phenylsulfonylaminocarbonyldiphenylaminocarbonyl-L-valyl-N-IS-d, J-trifluoro-methyl-oxopentyl) - L-prolineamide; 5. The method according to item 4, characterized in that the compound according to item 1 is selected from the group consisting of: 5) 3 (RS) - [(4-phenylbutyl) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide; 5 carbon atoms and substituted by 2 aryloxy groups, each containing 6 carbon atoms; (zzz) methyl or propyl which is substituted by an aryloxy group having 6 carbon atoms, where the aryloxy Group is further substituted by aminocarbonyl; and methyl substituted by aryloxy of 6 carbon atoms, wherein the aryloxy group is further substituted by ethoxycarbonyl; (IV) an aryl group having 6 or 10 carbon atoms; (V) an aryl group having 6 carbon atoms substituted by a member selected from fluoro, hydroxy, carboxy, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, methylcarbonylamino, an acylsulfonamide having 2 carbon atoms, an acylsulfonamide having 7 carbon atoms, an acylsulfonamide having 11 carbon atoms, an acylsulfonamide having 14 carbon atoms; an aryl group having 6 carbon atoms and substituted by 2 chlorine atoms; and an aryl group having 6 carbon atoms and substituted by a chlorine and an amino group; (VI) a cycloalkyl having 10 carbon atoms; (VI) - (I) a cycloalkyl having 5 carbon atoms and substituted by carboxy or ethoxycarbonyl; and (X) an alkenyl group having 2 carbon atoms and substituted by a member selected from Carboxy, carboxyphenyl, ethoxycarbonyl, ureidocarbonyl, acylsulfonamido, and 4-carboxyphenyl. R ⁴ is hydrogen; R ⁵ is selected under; (I) n-butyl; (II) (q) aralkoxycarbonyl-substituted ethyl wherein the aralkoxy contains 7 carbon atoms; and (II) (z) aralkyloxycarbonylamino substituted butyl, wherein the aralkyl group contains 7 carbon atoms; A corresponds to the above definition; and η _ = 1._ 5 carbon atoms and substituted by two aryl groups, each containing 6 carbon atoms; (dd) a member selected from an alkyl of 1 or 2 carbon atoms and substituted with an aryl 6. The method according to item 5, characterized in that the compound is selected according to point 1 under: 6) 3 (RS) - (4-hydroxycarbonylphenyl) aminocarbonyl-L-alpha-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 6) 3 (RS) -2 [2- (Tricyclo [3.3.1.1. ^{3 '7]} dec-1-yl) ethoxycarbonyl] -L-valyl-N- [3- (4-methyl-1,1,1 trifluoro-2-oxopentyl)] L-prolinamide; 6 carbon atoms, wherein the aryl is further substituted by carboxy; Methyl substituted with an aryl of 6 carbon atoms, the aryl being further substituted by methoxycarbonyl; Ethyl substituted by an aryl of 6 carbon atoms, wherein the aryl is further substituted by ethoxycarbonyl; and ethyl substituted by an aryl having 6 carbon atoms, wherein the aryl further substituted by an acylsulfonamide having 7 carbon atoms; (ee) ethyl substituted with a cycloalkyl with 1 carbon atoms; (ff) ethyl substituted by an aliphatic heterocyclic compound having 4 carbon atoms, a Nitrogen atom and an oxygen atom;
(gg) an alkyl of 1 to 2 carbon atoms and substituted by an aromatic heterocyclic compound with Contains 6 carbon atoms and the alkyl group is methyl;
(cc) methyl or butyl substituted by aryl of 6 carbon atoms !; and a branched alkyl group with Contains 6 carbon atoms;
(bb) ethyl substituted by an alkoxycarbonylamino wherein the alkyl group contains 4 carbon atoms; such as an alkyl of 5 carbon atoms and substituted by an alkyloxycarbonylamino wherein the alkoxy group contains 2 carbon atoms and on the terminal carbon via a direct link to Carbon atom of an aromatic heterocyclic group having 5 carbon atoms and 1 nitrogen atom is substituted;
(bb) - (3) a propyl group substituted by an aryloxyalkylcarbonylamino, wherein the aryl group Contains 6 carbon atoms;
(x) ethyl substituted by an acylsulfonamide which is protected by 2- (methylsulfominocarbonyl) ethyl, 7. The method according to item 1, characterized in that said acid addition salt is a salt formed with hydrochloric, hydrobromic, sulfuric, nitric, citric, malic, fumaric or acetic acid. 7) 3 (RS) - [Z- (4-aminocarbonylamino-1,4-dioxo-2-butenyl)] - L -valyl-N- [3- (1,1,1-trifluoro-4-methyl-2 -oxopentyl)] - L-prolinamide; 7) 3 (RS) -t (4-methoxyphenyl) carbonyl] -L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide; 8. The method according to item 1, characterized in that said base addition salt is a salt formed with an alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, alkaline earth hydroxide or an organic amine salt. 8) StRSI-IW-tfi-naphthylsulfonyaminocarbonylphenyl-amyl-carbonyl-L-valyl-N-tS-f1-trifluoro-methyl-oxopentyl) -L-prolinamide; 8) 3 (RS) -N ² , N 1 -dilfiphenylmethoxylcarbonyl-L-lysyl-N-tS 1 -methyl-i, -i-trifluoro -oxopenty-D-L-proline amide; 9. The method according to item 8, characterized in that it is an oxidation using one of the following group selected member includes: (a) oxalyl chloride, dimethyl sulfoxide and a tertiary amine in methylene chloride; (b) acetic anhydride and dimethylsulfoxide; (c) chromium trioxide-pyridine complex in methylene chloride; and (d) Dess-Martin periodinane in methylene chloride. 9) 3 (RS) -N ² - (4-hydroxycarbonylphenyl) aminocarbonyl-N ⁶ -phenylmethoxycarbonyl-L-lysyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 9) 3 (RS) - [(phenylmethoxy) carbophenyl] -L-phenylalanyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L-prolinamide; A process according to item 9, characterized in that said oxidation comprises the use of Dess-Martin periodinan in methylene chloride. 10) 3 (RS) - (4-hydroxycarbonylphenyl) carbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 10) 3 (RS) - [2- (methoxycarbonyl) ethylcarbonyl] -L-norleucyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L- prolinamide; 11. The method according to item 8, characterized in that it further comprises forming a second compound of formula la, I b or I c with a carboxy group in R ² , R ³ or R ⁵ from said first compound of formula I. a, I b and I c respectively, wherein said first compound in R ² , R ³ or R ^{5 contains} a carboxylic acid ester group and wherein said method involves converting said carboxylic acid ester group to the corresponding carboxy group. 11) 3 (RS) - (4-hydroxycarbonylphenyl) aminocarbonyl-L-phenylalanyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 11) 3 (RS) - [(2-carboxyethyl) carbonyl] -L-norleucyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L- prolinamide; 12. The method according to item 11, characterized in that it involves the conversion of said carboxylic ester group into the corresponding carboxy group by hydrolysis. 12) 3 (RS) -4 - [(4-Nitrophenyl) sulfonylaminocarbonyl] phenylcarbonyl-L-valyl-N-t3 -d, 1,1-trifluoro-4-methyl-2-oxopentyl)] - L-proline amide; 12) 3 (RS) - [(phenylmethoxy) carbonyl] -L-alpha-glutamyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl)] - L- prolinamide phenylmethyl ester; 13. The method according to item 8 or 11, characterized in that it further comprises forming a third compound of formula I a, I b or I c with a sulfonylaminocarbonyl group in R ² , R ³ or R ⁵ from said first or the said second compound of the formula Ia, Ib or Ic, wherein said first or said second compound in R ² , R ³ or R ^{5 contains} a carboxy group and this by linking said carboxy group with the amino Group of a sulfonamide takes place. 13) SiRSl-phenylmethoxycarbonyl-L-tB-iphenylsulfonylamino-glutamyl-N-tS-d ^^ - trifluoro ^ -methyl ^ -oxo-pentyl-L-proline amide; 14) 3 (RS) - [4- (phenylsulfonylaminocarbonyl) phenylcarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolineamide; 15) SiRSl-W - ^ - Bromophenyllsulfonylaminocarbonylphenylcarbonyl-L-valyl-N-O-dI-trifluoro-methyl-oxopentyl) -L-prolinamide; 16) 3 (RS) -4- (1-Naphthylsulfonylamino) -1,4-dioxobutyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamid; 17) 3 (RS) - (4-hydroxycarboylphenyl) methoxycarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl) -L-prolineamide; 18) 3 (RS) -E- [3- (4-Hydroxycarbonylphenyl) -1-oxo-prop-2-enyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2 -oxopentyl)] - L-prolinamide; 19) 3 (RS) - [4 - [(4-Chlorophenyl) sulfonylaminocarbonyl] phenylcarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamid; 20) 3 (RS) - [3- (4-Hydroxycarbonylphenyl) -1-oxopropyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamid; 21) 3 (RS) - [3- [4 - [(4-Chlorophenyl) sulfonylaminocarbonyl] phenyl] -1-oxopropyl] -L-valyl-N- [3- (1,1,1-trifluoro-methyl-2 -oxopentyl)] - L-prolinamide; 22) 3 (RS) -E- [3- [4 - [(4-Chlorophenyl) sulfonylaminocarbonyl] phenyl] -1-oxo-propyl-2-enyl] -L-valyl-N- [3- (1,1,1 -trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 23) 3S (or R) - [4- (phenylsulfonylaminocarbonyl) phenylaminocarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-methyl-2-oxopentyl)] - L- prolinamide; 24) 3S (or R) - [4 - [(4-Bromophenyl) sulfonylaminocarbonylphenylcarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide ; 25) SSIorRl - ^ - ^ - chlorophenylsulfonylaminocarbonylphenylcarbonylJ-L-valyl-N-IS-dJJ-trifluoro-methyl-oxopentyl) -L-prolineamide; 26) 3S (or R) - [(4-carboxyphenyl) aminocarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] -L-prolineamide; 27) 3 (RS) - [1,4-dioxo-4- (phenylsulfonylamino) butyl] -L-leucyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2- oxopentyl)] - L-prolinamide; 28) 3 (RS) - [4- (Methylsulfonylamino) -1,4-dioxobutyl] -L-leucyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl )] - L-prolinamide; and 29) SIRSl-N ^ II ^ -Dioxo ^ -phenylsulfonylaminoibutyl-N-phenylmethoxycarbonyl-L-lysyl-L-valyl-N-IS-dJJ-trifluoro-methyl-2-oxopentyl)] - L-prolinamide. 13) 3 (RS) -N ² - [2- (methoxycarbonyl) ethylcarbonyl] -N ⁶ - [(phenylmethoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1,1 ,1- trifluoro-2-oxopentyl)] - L-prolinamide;
14) 3 (RS) -N ² - [(2-carboxyethyl) carbonyl] -N ⁶ - [(phenylmethoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1, 1,1-trifluoro-2- oxopentyl)] - L-prolinamide;
15 3S (or R) -N ² , N ⁶ -Di [(phenylmethoxy) carbonyl] -L-lysyl-L-valyl-N- [3- (4-methyl-1,1,1-trifluoro-2-oxopentyl) ] -L-prolinamide; 16) SIRSHi-naphthylcarbonyO-L-valyl-N-tS-d 1-trifluoro-methyl-oxopenty-Dl-L-proline amide; 17) SfRSl - ^ - i-methylsulfonylaminocarbonyldiphenylaminocarbonyl-L-valyl-N-O-di-trifluoro-methyl-oxopentyl) -L-prolinamide; ο ^ « 20) SiRSJ-phenoxycarbonyl-L-valyl-N-f S -d Y y -trifluoro-methyl-oxopenty DJ-L-proline amide; 21) 3 (RS) - [2- {2-pyridyl) ethoxycarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-pro-aminamide; 22) SIRSJ - ^ - IPhenylsulfonylaminocarbonyl-phenylaminocarbonyl-L-valyl-N-IS-di (trifluoro-methyl-oxopentyl)] - L-prolinamide; 23) 3 (RS) - [2- (3-thiophenyl) ethoxycarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolineamide; 24) SiRSJ-iPhenylmethoxycarbonyD-L-alpha-aminobutyryl-N-tS-dJ ^ -trifluoro ^ -methyl ^ -oxopentyDl-L-proline amide; 25) SiRSi ^ phenoxycarbonylJ-L-alpha-aminobutyryl-N-IS-II.IJ-trifluoro ^ -methyl ^ -oxopentyDl-L-proline amide; 26) SfRSJ-N, di-dimethylethoxycarbonyD-N-phenylmethoxycarbonyl-L-lysyl-N-IS-di (i-trifluoro-1-methyl-1-oxopentyl) -L-prolineamide; 27) aiRSi - ^ - ITricycloO.S.I.I ^ l-dec-i-y-Dethoxycarbonyl-L-alpha-aminobutyryl-N-fS-dJ ^ -trifluoro ^ -methyl ^ -oxopentyl)] - L-prolineamide; 28) 3 (RS) - (4-hydroxycarbonylphenyl) aminocarbonyl-L-alpha-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 29) 3 (RS) -N ⁶ -phenylmethoxycarbonyl-N ² -phenylsulfonyl-L-lysyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 30) 3 (RS) - [Z- (4-aminocarbonylamino-1,4-dioxo-2-butenyl)] - L -valyl-N- [3- (1,1- _r- 1-trifluoro-4-methyl -2-oxopentyl)] - L-prolinamide; 31) SIRSJ-phenylaminocarbonyl-L-valyl-N-tS-d 1-trifluoro-methyl-oxo-pentyl-L-proline amide; 32) SIRSH ^ -td-naphthylsulfonyDaminocarbonylphenylaminocarbonyl-L-valyl-N-O-dJ.i-trifluoro-1-methyl-oxopentyl) -L-prolinamide; 33) 3 (RS) -N ² - (4-hydroxycarbonylphenyl) aminocarbonyl-N ⁶ -phenylmethoxycarbonyl-L-lysyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 34) 3 (RS) - (4-hydroxycarbonylphenyl) carbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 35) 3 (RS) - (tricyclo [3.3.1.1 ³ ' ⁷ ] dec-1-yl) sulfonyl-L-alpha-aminobutyryl-N- [3- (1,1,1-trifluoro-4-methyl-2 -oxopentyl)] - L-prolinamide; 36) 3 (RS) - (4-methoxycarbonylphenyl) carbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 37) 3 (RS) - (4-hydroxycarbonylphosphine) aminocarbonyl-L-phenylalanyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 38) 3 (RS) - (4-methoxycarbonylphenyl) methoxycarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 39) 3 (RS) - [E-3- (4-ethoxycarbonylphenyl) -1-oxo-2-ynyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2 -oxopentyl)] - L-prolinamide; 40) 3 (RS) - (2-ethoxycarbonylphenyl) aminocarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 41) 3 (RS) -4 - [(4-Nitrophenyl) sulfonylaminocarbonyl] phenylcarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide ; 42) SiRSl-phenylmethoxycarbonyl-L-glutamyl-N-fS-iiJJ-trifluoro-methyl-oxopentyl-J-L-proline-amide. phenylmethyl; 43) SSioderRMTricycloO.S.I. ldec-i-yDsulfonyl-L-valyl-N-tS-dJ.I-trifluoro-methyl-oxopentyDl-L-proline amide; 44) 3 (RS) -phenylmethoxycarbonyl-L- [5- (phenylsulfonylamino) glutamyl] - N - [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolineamide; 45) 3 (RS) - [4- (phenylsulfonylaminocarbonyl) phenylcarbonyl] -L-valyl-N- [3-d, 1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolineamide; 46) 3 (RS) - [4 - [(4-Bromophenyl) sulfonylaminocarbonyl] -phenylcarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 47) 3 (RS) -4- (1-Naphthylsulfonylamino) -1,4-dioxobutyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamid; 48) 3 (RS) - [2- (4-aminocarbonylphenoxy) -1-oxoethyl] -L-valyl-N- [3-d, 1,1-trifluoro-4-methyl-2-oxopentyl)] - L- prolinamide; 49) 3 (RS) - (4-hydroxycarbonyl-phenyl) -methoxycarbonyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 50) SfRSJ-W-W-d-amino ^ -oxoethylene-phenoxyl-i-oxobutyl-L-valyl-N-IS-di-i-trifluoro-methyl-oxo-pentyl-L-proline amide; 51) 3 (RS) -E- [3- (4-hydroxycarbonylphenyl) -1-oxo-prop-2-enyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2 -oxopentyl)] - L-prolinamide; 52) 3 (RS) - [2- {4-ethoxycarbonylphenoxy) -1-oxoethyl] -L-valVI-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamid; 53) 3 (RS) - [3- (4-ethoxycarbonylphenyl) -1-oxopropyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamid; 54) 3 (RS) -4-hydroxybenzoyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 55) 3 (RS) - [4 - [(4-Chlorophenyl) sulfonylaminocarbonyl] phenylcarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamid; 56) 3 (RS) - [3- (4-Hydroxycarbonylphenyl) -1-oxopropyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L -prolinamid; 57) 3 (RS) - [3- [4 - [(4-Chlorophenyl) sulfonylaminocarbonyl] phenyl] -1-oxopropyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl -2-oxopentyl)] - L-prolinamide; 58) SfRSKE-O-W - ^ - chlorophenyldsulfonylaminocarbonylphenyll-i-oxoprop-enyl-L-valyl-N-O-II.l-trifluoro-1-methyl-2-oxopentyl) - L-prolineamide; 59) 3 (RS) - [I- [4 - [[(4-Bromophenyl) sulfonyl] [phenylmethyl] aminocarbonyl] phenyl] -1-oxomethyl] -L-valyl-N- [3- (1,1,1 -trifiuoro-4-methyl-2-oxopentyl)] - L-prolinamide; 60) 3R (or S) - (tricyclo [3.3.1.i] ldec-i-y-sulfonyl-L-valyl-N-O-d ^ J-trifluoro-methyl-oxopenty-Dl-L-proline amide; 61) SSfoderRi-W-IPhenylsulfonylaminocarbonyliphenylaminocarbonyl-L-valyl-N-fS-f1-trifluoro-methyl-oxopentyl) -L-prolinamide; 62) 3S (or R) -phenylmethoxycarbonyl-L-phenylglycyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-proline amide; 63) 3S (or R) - [4 - [(4-Bromophenyl) sulfonylaminocarbonyl] phenylcarbonyl] -L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 64) SSI or RJ - ^ - tf ^ chlorophenyldsulfonylaminocarbonyl-phenylcarbonyl-L-valyl-N-IS-dJJ-trifluoro-methyl-oxopentyl) -L-prolineamide; 65) SSioderRl-phenylmethoxycarbonyl-L-valyl-N-IS-di-trifluoro-methyl-oxopentyDl-L-proline amide; 66) SStoderRl-K ^ carboxyphenyaminocarbonyl-L-valyl-N-tS-di-i-trifluoro-methyl-oxopentyDJ-L-proline amide; 67) SiRSJ-WK ^ chlorophenyldsulfonylaminocarbonylphenylcarbonyl-L-valyl-N-IS-d ^ J-trifluoro- ^ methyl ^ - oxopentyl)] - L-prolinamide; t 68) 3 (RS) -N ² , N ⁶ -Di (phenylmethoxycarbonyl) -L-lysyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl)] - L-prolinamide; 69) 3 (RS) - [1,4-dioxo-4- (phenylsulfonylamino) butyl] -L-leucyl-L-valyl-N- [3- (1,1,1-trifluoro-O-4-methyl-2-) oxopentyl)] - L-prolinamide; 70) 3 (RS) - [4- (Methylsulfonylamino) -1,4-dioxobutyl] -L-leucyl-L-valyl-N- [3- (1,1,1-trifluoro-4-methyl-2-oxopentyl )] - L-prolinamide; 71) SIRS1-N4-dioxo-1-phenylsulfonylamino-1-butylbutyl-N-phenylmethoxycarbonyl-L-lysyl-L-valyl-N-IS- (1-trifluoro-1-methyl-2-oxo-pentyl) -L-prolinamide; and 72) SfRSI-tiADioxo ^ -KricycloO.S.I.I ^ ldec-i-yDsulfonylaminol-butyil-L-leucyl-L-valyl-N-tS-di (i-trifluoro-1-methyl-2-oxopentyl)] - L-prolinamide. 14. Method according to item 13, characterized in that it uses a linking method which is selected using a member of the following group: (a) i-ethyl-S-f S -dimethylaminopropyllcarbodiimide hydrochloride and 4-dimethylaminopyridine in methylene chloride; and (b)!, S-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in methylene chloride.