HU0400321A2 - Fluoropyrrolidine derivatives as dipeptidyl-dipeptidase inhibitors, and pharmaceutical compositions containing them - Google Patents

Fluoropyrrolidine derivatives as dipeptidyl-dipeptidase inhibitors, and pharmaceutical compositions containing them Download PDF

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HU0400321A2
HU0400321A2 HU0400321A HU0400321A HU0400321A2 HU 0400321 A2 HU0400321 A2 HU 0400321A2 HU 0400321 A HU0400321 A HU 0400321A HU 0400321 A HU0400321 A HU 0400321A HU 0400321 A2 HU0400321 A2 HU 0400321A2
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amino
2s
hz
compound
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HU0400321A
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Curt Dale Haffner
James Martin Lenhard
Darryl Lynn Mcdougald
Amarjit Sab Randhawa
Steven Michael Reister
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Smithkline Beecham Corp.
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Priority to PCT/US2002/020471 priority patent/WO2003002531A2/en
Publication of HU0400321A2 publication Critical patent/HU0400321A2/en

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    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/262-Pyrrolidones
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    • C07D207/10Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D451/02Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Abstract

The present invention relates to compounds of formula (I) as well as to zeolites, solvates and pharmaceutically active functional derivatives thereof. In the formula (I), X is fluorine or hydrogen; R1 and R2 are independently (i) hydrogen, (ii) alkyl; or (iii) optionally substituted aryl or heteroaryl; or (iv) form together a ring system of 3 to 14 membered, optionally one or more heteroatoms and optionally one or more unsaturated bonds; when R 1 and R 2 are as defined in (iii) above, R 3 is hydrogen or alkyl; when R 1 and R 2 are as defined in (i), (ii) or (iv), R 3 is a group of formula (III) wherein n is an integer from 0 to 5; m is an integer from 0 to 12; Y is an oxygen atom, a chemical bond or an alkylene, alkylene, alkenylene or alkynylene group, or a group of the formula -S (O) p, and in the latter formula p is 0, 1 or 2; R4 is R5 when Y is a chemical bond or a sulfur or oxygen atom, or an alkylene, alkenylene or alkynylene group; group; and R 4 is R 6 when Y is sulphinyl or sulfonyl, wherein R 6 is optionally substituted alkyl, aryl, alkylalkyl, heteroaryl, amino, alkylamino, arityamino, heteroarylamino, cycloalkylamino, or hydroxy. The compounds of the present invention inhibit dipeptidyl peptidases such as dipeptidyl peptidase II (DPP-II) and dipeptidyl peptidase IV (DPP-IV) enzymes and are useful in the preparation of pharmaceutical compositions. HE

Description

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FLUORPIRROLIDINE ORIGINS AS DIPEPTIDIL DIPEPTIDAS F INHIBITORS TT LZfcHT TfWlh / uca ye 'c / txkQ-Q rrnwi = K.

FIELD OF THE INVENTION The present invention relates to dipeptidyl peptidases such as dipeptidyl peptidase II (DPP-II) and dipeptidyl peptidase IV (DPP-IV) inhibitors, to the preparation of such compounds and to the use of such compounds in the preparation of pharmaceutical compositions.

Dipeptidyl peptidase IV (DPP-IV) is a so-called post-proline / alanine cleavage serine protease found in various tissues of the body, including the kidneys, liver and intestines. It is believed that DPP-IV regulates a number of physiologically important peptides, including, but not limited to, GLP1, GIP, GLP2, GRP, vasoactive, i.e., vascular intestinal peptide, histidine methionine peptide, PYY, P-substance, beta-casomorphine, NPY,

PACAP38, prolactin, chorionic gonadotropin (middle fetal gonadotropin), aprotinin, corticotropin-like intermediate lobe peptide, pituitary adenylyl cyclase activating peptide, (Tyr) melanostatin, LD78beta (3-70), RANTES, eotaxin prochipase, enterostatin, vasostatin 1 , endomorphine, morphiceptin, skeletal derived derivative, macrophage-derived chemokine, granulocyte chemotactic protein-2 and GHRH / GRF activity. As regards the value of DPP-IV therapy, DPP-IV is assumed to play a role in a wide variety of metabolic, gastrointestinal, viral and inflammatory diseases, including, but not limited to, diabetes (diabetes), obesity, hyperlipidemia, dermatology. or mucosal membrane disorders, psoriasis (shingles), intestinal distress, constipation, autoimmune disorders such as cerebrovascular disease, complement mediated diseases (such as glomerulonephritis, fat metabolism and tissue damage), psychosomatic, depressive and \ t neuropsychiatric diseases, such as anxiety, depression, insomnia, schizophrenia, epilepsy, cramps and chronic pain, HIV infection, allergic diseases, inflammatory diseases, ulcers your inflammation

99770-5194 MR · · «· · · · · ······ · • · * · · · · ß *

-2 <transplant rejection, hypertension, congestive heart failure, tumors and stress-induced abortions such as cytokine-mediated mouse miscarriages. For example, DPP-IV, also known as CD26, mediates T cell activation and HIV infection (see Ohtsuki et al., 2000). DPs that select DPP-IV / CD26 mother5 are preferentially infected and depleted in HIV-infected patients (see also Ohtsuki et al., 2000). DPP-IV inhibitors exhibit anti-inflammatory effects on animal models used for articular inflammation (see Tanaka et al., 1997). In addition, in the case of inhibition of DPP-IV, it can be stated that survival after cardiac transplantation is enhanced (see Korom et al. 1997).

year). In vitro studies suggest that DPP-IV / CD26 expression correlates with tumor development of malignant melanomas (see Van den Oord's 1998 publication). In addition, DPP-IV is believed to be able to regulate metabolism by cleaving the last proline / alanine bond at the amino terminus of the polypeptides (see Mentlein, 1999). Examples of such polypeptides include glucagon-like peptides (GLP) and Y neuropeptide (NPY).

More specifically, GLPs help to metabolize glucose and thus control GLPs are likely to be useful in the treatment of metabolic disorders such as diabetes. Diabetes, such as type 2 diabetes [this type of disease is also referred to as non-insulin dependent diabetes mellitus (NIDDM) or diabetes associated with maturity], results in elevated blood sugar levels in view of the absolute or relative insufficiency of insulin. Type 2 diabetes is the most common form of diabetes, in 90% of cases this type of illness occurs, for example, 16 million people in the United States suffer from such a disease. Most drugs used to treat type 2 diabetes produce variable, sometimes normal amounts of insulin, but cause abnormalities in the liver and muscle cells that are resistant to them. Insulin is bound to the receptors of cells, but if glucose does not get inside the cells, this state is called insulin resistance. Many substances used to treat type 2 diabetes are unable to select enough insulin to overcome insulin resistance. GLP-1 enhances insulin secretion. so the

GLP-1 regulation correlates with regulation of insulin secretion. In addition, GLP-1 reduces hepatic glucose production, gastric emptying, and food intake (see Deacon et al., 1995). In addition, GLP-2 maintains the integrity of the intestinal mucosal epithelium for gastric motility, nutrient absorption, · · ··· · · · · · · · · · · · ·

- the effects of crypt cells proliferation and apoptosis, and the permeability of the intestines (see Drucker's 2001 publication).

DPP-IV inhibitors preserve the functionality of GLP-1 over a longer period of time (see Balka's 1999 publication). Thus, DPP-IV inhibitors may promote saturation, weight loss and anti-diabetic effects of GLP-1 (see Deacon et al., 1995, Holst and Deacon, 1998). For example, the inhibitory effect of the known compound NVP-DPP728 on DPP-IV increases the concentration of GLP-1 (2-36 amide) in blood plasma and increases oral glucose tolerance in obese Zucker rats (see Diabetology, 42). , 1324-1331). GLP-1 administered subcutaneously as well as intravenously is rapidly degraded starting with the amino end group II. patients with type 2 diabetes and healthy subjects (see Diabetes, 44, 1126 (1995)).

In addition, DPP-IV inhibitors preserve the effect of GLP-2 over extended periods of time and can thus be used to treat intestinal malfunctions and mucosal membranes (see Hartmann, B. et al., 2000).

Although DPP-IV is the most dominant protease control GLP, similar substrate or inhibitor specificity can be observed in related proteases. Examples of such serine proteases include, but are not limited to, dipeptidyl peptidase II (DPP-II), dipeptidyl peptidase-IV beta, dipeptidyl peptidase 8, dipeptidyl peptidase 9, aminopeptidase P, fibroblast activating alpha protein ( seplase), prolyl tripeptidyl peptidase, prolyl-oligopeptidase (endoproteinase Pro-C), attractin (soluble dipeptidylaminopeptidase), acylaminoacyl peptidase (N-acyl peptide hydrolase; fMet aminopeptidase) and lysosomal Pro-X carboxypeptidase (angiotensinase C, prolyl carboxypeptidase). Proline cleavage metallopeptidases with similar substrate or inhibitor specificity for DPP-IV include membrane Pro-X carboxypeptidase (carboxypeptidase P), angiotensin converting enzyme (peptidyl dipeptidase A multipeptidase), collagenase 1 (interstitial collagenase; matrix). metalloproteinase 1; MMP-1; Mcol-A) ADAM 10 (alpha-secretase, myelin-related dysintegrin-metalloproteinase), nephrilizin (adriopeptidase; CALLA; CD10; endopeptidase 24.11; enkephalinase), macrophage elastase (metalloelastase, matrix metalloproteinase 12; MMP-12 ), matrilysin (matrix metalloproteinase 7, MMP-7) and neurolysin (endopeptidase 24.16;

microsomal endopeptidase; mitochondrial oligopeptidase). For a list of these compounds, see the web-site: http://merops.iapc.bbsrc.ac.uk/.

In addition, other non-mammalian proteases may also exhibit substrate or inhibitor-4 specificity for DPP-IV in addition to the serine peptidases of the mammals and the metallopeptidases which cleave the proline. Non-limiting examples of such non-mammalian serine proteases include: prolylaminopeptidase (prolyl iminopeptidase), IgAl-specific serine-type prolyl-endopeptidase (IgA protease, Neisseria, Haemophilus), dipeptidylaminopeptidase A (STE13). ) (Saccharomyces cerevisiae), dipeptidylaminopeptidase B (fungus), prolyl-oligopeptidase homolog (Pyrococcus sp.), Oligopeptidase B (Escherichia coli alkaline proteinase II; protease II), dipeptidylaminopeptidase B1 (Pseudomonas sp.), Dipeptidyl peptidase IV (bacteria), dipeptidylaminopeptidase (Aureobacterium), dipeptidyl peptidase IV (insect), dipeptidyl peptidase V, allergen Tri t 4 (Trichophyton tonsurans), selected alanyl DPP (Aspergillus oryzae), peptidase II-mes (Prosopis velutina) and bamboo serine proteinase (Pleioblastus hindsii). Non-limiting examples of non-mammalian metallopeptidases cleaving proline include penicillolysin (fungic acid metalloendopeptidase), proline-specific peptidyl dipeptidase (Streptomyces), coccolizine (gelatinase, Enterococcus faecalis), aminopeptidase Ey (yolk egg yolk) (apdEg.p). Gallus gallus domesticus), metalloproteases of gametolosin [Chlamydomonas cell wall degrading protease] and serpentine proline cleavage. For these compounds see http://merops.iapc.bbsrc.ac.uk/.

Dipeptidyl peptidase II (DPP-II) is a serine protease that binds to the so-called lysosomes in cells and is thought to play a role in their degradation and protein conversion. The order of DPP-II selection is as follows: kidney »here> or = heart>brain> or = lung>spleen> skeletal muscle> or = liver [Araki, H. et al.

J. Biochem. (Tokyo) 129: 279-288 (2001). This expression suggests that there is a potential for use in renal failure or lysosomal disorders. The substrate-specificity studies indicated that purified DPP-II specifically hydrolyzed alanine or proline residues at acidic pH values (4.5-5.5). THE

DPP-II exhibits significant sequence homology and substrate specificity for so-called idle cell proline dipeptidase and prolyl carboxy peptidase, suggesting that overlap between these proteases is possible [Araki, H. et al., J. Biochem. (Tokyo) 129: 279-288 (2001).

The present invention relates to novel DPP-II and / or DPP-IV inhibitors for their preparation and to their use in the preparation of pharmaceutical compositions. Although not intended to be limiting in any way, it is believed that the compounds of the present invention can be used to treat a variety of metabolic, gastrointestinal, viral and inflammatory diseases. Such diseases include, but are not limited to, the following diseases: diabetes (diabetes), obesity,

-5hyperlipidemia, dermatological or mucosal membrane disorders, psoriasis, intestinal distress, constipation, autoimmune disorders such as brain • spinal cord inflammation, complement mediated diseases such as glomerulonephritis, fatty tissue disorders and tissue damage, as well as psychosomatic, depressive and neuropsychiatric diseases such as anxiety, depression, insomnia, schizophrenia, epilepsy, cramps and chronic pain, HIV infection, allergic diseases, inflammatory diseases, arthritis, graft rejection, hypertension, congestive heart failure, tumors and stress-induced abortions such as cytokine mediated mouse miscarriages.

Compared to other dipeptidyl peptidase inhibitors, the compounds of the invention exhibit improved stability, efficacy, duration of action and / or safety / toxicity profile.

The invention thus relates to the compounds of formula (I) and to their salts, solvates and pharmaceutically active functional derivatives. In the formula (I), X is fluoro or hydrogen; R 1 and R 2 are independently hydrogen, alkyl or optionally substituted aryl or heteroaryl; or together form a ring system of 3 to 14-membered, optionally one or more heteroatoms and optionally one or more unsaturated bonds. When R 1 and R 2 are optionally substituted aryl or heteroaryl, then R 3 is hydrogen or alkyl. In other cases, R 3 is a group of formula (III) and in this group n is an integer from 0 to 5, m is an integer from 0 to 12, Y is an oxygen atom, a chemical bond or an alkylene, alkenylene or alkynylene group, or S (O) p- and p is 0, 1 or 2; R 4 is R 5 when ha

Y represents a bond or a sulfur or oxygen atom or an alkylene, alkenylene or alkynylene group, whereby R5 is optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl or heterocyclyl; and R 4 is R 1, ha

Y is sulphinyl or sulfonyl, wherein R 1 is optionally substituted alkyl, aryl, alkylalkyl, heteroaryl, amino, alkylamino, arylamino, heteroarylamino, cycloalkylamino or hydroxy.

Although we do not wish to limit ourselves to these substituents, preferred optional substituents include one or more halogen or alkyl, alkoxy, aryloxy, haloalkyl, cyano, alkylsulfonyl, or aryl. More preferably, the optional substituents include one or more fluorine or chlorine atoms, or haloalkyl containing 1 to 6 carbon atoms, alkoxy of 1-6 carbon atoms, phenoxy, benzoxy, 1-6 carbon atoms. , cyano, C1-6alkylsulfonyl, phenyl or benzyl.

In a preferred embodiment, the compounds of the present invention contain both aryl and R 3 are hydrogen at R 1 and R 2 . Preferably, each aryl is phenyl. More preferably, each phenyl group is substituted with a halogen atom. More preferably, the halogen atom is a fluorine atom, more preferably a fluoro at the 4-position.

In another preferred embodiment, the compounds of the present invention contain alkyl at both R 1 and R 2 , and R 3 at position III.

Preferably, each alkyl group is C 1-6 alkyl. More preferably, each alkyl group is methyl. Preferably, n is 0, m is 1 and Y is -S (O) p . In another preferred embodiment, p is 0, R 4 is R 3 and R 5 is optionally substituted aryl. Preferably, R 3 is phenyl substituted with alkoxy. More preferably, this alkoxy group is methoxy. In a further preferred embodiment, p is 1 or 2, R 4 is R 6 and the latter is optionally substituted aryl. Preferably, R 1 is phenyl substituted with alkoxy. More preferably, the alkoxy group is methoxy. More preferably, p is 2.

In a further preferred embodiment, the amino group represented by the formula (I) is in the cis position relative to the nitrile group. In another preferred embodiment, the amino group depicted is trans-positioned relative to the nitrile group depicted.

Preferably, X is hydrogen. Preferably, the fluorine atom represented by the formula (I) is cis-positioned relative to the nitrile group also shown.

Particularly preferred are the compounds of the invention as well as their salts, solvates and pharmaceutically acceptable derivatives thereof, wherein X is fluorine or hydrogen; R 1 and R 2 are both optionally substituted aryl or heteroaryl; and R 3 is hydrogen or alkyl.

Particularly preferred are the compounds of the present invention as well as their salts, solvates and pharmaceutically acceptable functional derivatives thereof, of formula (I):

X is fluoro or hydrogen;

R 1 and R 2 are both (i) alkyl, or

-7 * (ii) form a ring system having from 3 to 14 members, optionally one or more heteroatoms and optionally one or more unsaturation;

R 3 is a group of formula (III) and n is an integer from 0 to 5;

m is an integer from 0 to 12;

Y is O or alkylene, alkenylene or alkynylene or -S (O) p - and in the latter p is 0 or 2;

R4 is R $ when Y represents an oxygen or sulfur atom or an alkylene, alkynylene alkenilénvagy, whereby R5 is optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl or heterocyclyl; and R 1 is R 6 when Y is a sulfinyl or sulfonyl group, wherein R 1 is optionally substituted alkyl, aryl, cycloalkyl, heteroaryl, amino, alkylamino, arylamino, heteroarylamino, cycloalkylamino or OH.

Preferably p is 1 or 2. More preferably p is 2. Preferably R 1 and R 2 represent an aryl alkyl group. More preferably, R 1 and R 2 are both C 1-6 alkyl. More preferably, R 'and R 2 are both methyl.

Particularly preferred compounds of the invention are compounds of formulas (IV), (V), (VI), (VII) and (VIII).

Particularly preferred are the compounds listed below.

(2S, 4S) -l - [(2S) -2-amino-3,3-difenilpropanoil] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - [(2S) -2-amino-3,3-bis (4-fluorophenyl) propanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - [(2S) -2-amino-5- (4-fluorophenyl) -3,3-dimethylpentanoyl] -4-fluoro-2-pyrrolidinecarbonitrile hydrochloride;

(2S, 4R) -l - [(2S) -2-amino-4- (4-fluorophenyl) -3,3-dimethylbutanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - {(2R) -2-Arino-3 - [(4-methoxybenzyl) thio] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(3-phenylpropyl) thio] butanoyl} -4-fluoropyrrolidine-2-carboxyl nitrile hydrochloride;

(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(2-phenylethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - ((2R) -2-amino-3 - {[3- (4-fluorophenyl) propyl] thio} -3-methylbutanoyl) -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

-8 (25.45) -1 - {(2R) -2-amino-3 - [(4-methoxybenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(2S, 4S) -1 - {(2R) -2-amino-3 - [(4-methoxybenzyl) sulfinyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(2S, 4S) -1 - ((2R) -2-amino-3-methyl-3 - {[4- (trifluoromethyl) benzyl] thio} butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - [(2S) -2-amino-2- (1-vinylcyclopentyl) ethanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - [(2S) -2-amino-5- (4-methoxyphenyl) -3,3-dimethylpentanoyl] -4-fluoropyrrolidine-210-carbonitrile hydrochloride;

(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(3-phenylpropyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile;

(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(4-methylbenzyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile;

(2S, 4S) -1 - ((2R) -2-amino-3 - {[4- (benzyloxy) benzyl] sulfonyl} -3-methylbutanoyl) -4-fluoropyrrolidine-2-carbonitrile;

(25.45) -1 - {(2R) -2-amino-3 - [(4-cyanobenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile;

(25.45) -1 - ((2R) -2-amino-3-methyl-3 - {[4- (methylsulfonyl) benzyl] sulfonyl} butanoyl) -4-fluoro-pyrrolidine-2-carbonitrile;

(25.45) -1 - {(2S) -2-amino-2- [1- (4-fluorobenzyl) cyclopentyl] ethanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - ((2S) -2-amino-2- {1- [4- (trifluoromethyl) phenyl] cyclopentyl} ethanoyl) -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(2S, 4S) -l - {(2 S} -2-amino-2- [l- (4-fluorobenzyl) cyclopropyl] ethanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - {(2R) -2-amino-3- (benzylsulfonyl) -3-methylbutanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(2S, 4S) -1 - {(2R) -2-amino-3 - [(3-methoxybenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-230carbonitrile hydrochloride;

(25.45) -1 - {(2R) -2-amino-3 - [(1,1'-biphenyl-4-ylmethyl) sulfonyl] -3-methylbutanoyl} -4-fluoropinoline-2-carbonitrile hydrochloride;

(25.45) -1 - {(2R) -2-amino-3 - [(2-methoxybenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

-9 (25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(pyridin-3-ylmethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile;

(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(pyridin-2-ylmethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(2S, 4S) -l - {(2R) -2-amino-3-methyl-3 - [(pyridin-4-ylmethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - {(2R) -2-amino-3 - [(4-fluorobenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(3-phenoxybenzyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-210-carbonitrile hydrochloride;

(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(3-phenoxybenzyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - ((2R) -2-amino-3 - {[(5-chloro-1,1-dioxido-1-benzothien-3-yl) methyl] sulfonyl} -3-methylbutanoyl) -4- fluoropyrrolidine-2-carbonitrile hydrochloride;

(2S, 4S) -l - {(2R) -2-amino-3 - [(2, l, 3-benzoxadiazol-5-ylmethyl) thio] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride ;

(25.45) -1 - {(2R) -2-Amino-3-methyl] -3 - [(pyridin-4-ylmethyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - [(2S) -2-amino-3-pyridin-4-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride; 20 (2S, 4S) -1 - [(2S) -2-amino-3-pyridin-3-ylpropanoyl-4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(2S, 4S) -1 - [(2S) -2-amino-3-piperidin-4-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride;

(25.45) -1 - [(2S) -2-amino-3-piperidin-3-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride;

(2S, 4S) -l - [(2S) -2-amino-3-piperidin-2-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride;

(2S, 4S) -1 - {(2S) -2-amino-3- [1- (isopropylsulfonyl) piperidin-4-yl] propanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - {(2S) -2-Amino-3- [1- (4-methyl-phenylsulfonyl) -piperidin-4-yl] -propanoyl} -4-fluoro-pyrrolidine-2-carbonitrile hydrochloride;

(2S, 4S) -1 - {(2S) -2-amino-3- [1- (isopropylsulfonyl) piperidin-3-yl] propanoyl} -4-fluoropyrrolidine · -2-carbonitrile hydrochloride;

(2S, 4S) -1 - {(2S) -2-amino-3- [1- (4-methylphenylsulfonyl) pipendin-3-yl] propanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

• «

- 10 (25.45) -1 - [(2S) -2-amino-3- (1-benzothien-3-yl) propanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;

(25.45) -1 - {(2S) -2-amino-3-methyl-3- [4- (trifluoromethyl) phenyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride; and (3R) -3-amino-4 - [(2S, 4S) -2-cyano-4-fluoropyridin-1-yl] -2-methyl-4-oxobutan-2-sulfonic acid.

The present invention further relates to pharmaceutical compositions comprising as active ingredient a compound of the invention or, preferably, carrier and / or other excipients commonly used in the pharmaceutical industry.

Thus, the pharmaceutical compositions of the present invention may inhibit so-called post-proline / alanine cleavage proteases, preferably a serine protease, more preferably a dipeptidyl peptidase, more preferably DPP-II or DPP-IV.

As mentioned, the following diseases can be treated or prevented with the pharmaceutical compositions of the invention: metabolic disorders, gastrointestinal disorders, viral diseases, inflammatory diseases, diabetes, obesity, hyperlipidemia, dermatological or mucosal membrane disorders, psoriasis, intestinal distress, constipation, autoimmune disorders such as cerebrovascular inflammation, complement mediated diseases such as glomerulonephritis, fat metabolism and tissue damage, as well as psychosomatic, depressive and neuropsychiatric diseases such as anxiety, depression, insomnia, schizophrenia, epilepsy, spasms and chronic pain, and HIV infection , allergic diseases, inflammatory diseases, arthritis, transplant rejection, hypertension, k ongestive heart failure, tumors and stress-induced abortions.

The pharmaceutical compositions of the present invention are preferably useful for the prevention or treatment of diabetes, i.e. diabetes.

The invention further relates to the use of the compounds of the present invention for the preparation of pharmaceutical compositions for inhibiting so-called post-proline / analin cleavage proteases. Preferably, such proteases include serine proteases, more preferably dipeptidyl peptidases, most preferably DPP-Π or DPP-IV.

In particular, the compounds of the present invention are therefore useful for the preparation of pharmaceutical compositions for the treatment or prevention of, for example, the following diseases: metabolic disorders, gastrointestinal disorders, viral diseases, inflammatory diseases, diabetes, obesity, hyper 11 * lipidemia, dermatological or mucosal membrane disorders, psoriasis ; epilepsy, cramps and chronic pain, and HIV infection, allergic diseases, inflammation diseases, arthritis, rejection of transplants, hypertension, congestive heart failure, tumors and stress-induced abortions.

In another aspect of the invention, a compound of the invention relates to the use of 10 as an active therapeutic agent. The purpose of this application is to inhibit serine protease. Preferably, such diseases can be treated or prevented by such use: metabolic disorders, gastrointestinal disorders, viral diseases, inflammatory diseases, diabetes, obesity, hyperlipidemia, dermatological or mucosal membrane disorders, psoriasis, intestinal distress, constipation, autoimmune disorders such as cerebrovascular inflammation , complement mediated diseases such as glomerulonephritis, fatty tissue disorders and tissue damage, as well as psychosomatic, depressive and neuropsychiatric diseases such as anxiety, depression, insomnia, schizophrenia, epilepsy, spasms and chronic pain, and HIV infection, allergic diseases , inflammatory diseases, arthritis, transplant rejection, hypertension, congestive heart failure, tumors and stress-induced abortions.

The term alkyl means straight or branched, saturated aliphatic hydrocarbon groups which may be substituted or mono- or polysubstituted. Examples of alkyl groups include, but are not limited to, methyl, ethyl, η-propyl, isopropyl, η-butyl, tert-butyl, n-pentyl or isobutyl.

As used herein to denote preferred number of carbon atoms such as C x -Cyalkilcsoport is used, which refers to an alkyl group as defined above containing the indicated number of carbon atoms. Similar terminology is used for further preferred ranges.

The term alkylene refers to a divalent, straight or branched aliphatic hydrocarbon group which may be substituted by one or more substituents.

- 12 w enssel. Examples of alkylene include, but are not limited to, methylene, i.e., CH2.

The term alkenyl refers to a straight or branched chain aliphatic hydrocarbon group containing one or more carbon-carbon double bonds which may be mono- or polysubstituted. By way of example, the vinyl group may be mentioned without limitation.

The term alkenylene refers to a divalent straight or branched aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, which may be mono- or polysubstituted. In the case of the alkenylene group, by way of example, the vinylene group, i.e., -CH = CH, may be mentioned without limitation.

The term alkynyl refers to a straight or branched chain aliphatic hydrocarbon group containing one or more triple bonds, which may be mono- or polysubstituted. Examples of alkynyl include, but are not limited to, ethinyl.

The term alkynylene refers to a divalent, straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond, which may be mono- or polysubstituted. Examples of alkynylene include, but are not limited to, the ethynylene group, -C = C-.

The term aryl refers to an aromatic ring system such as optionally substituted benzene ring systems such as phenyl. The term also includes fused ring systems consisting of one or more optionally substituted benzene rings, such as an anthracene, phenanthrene or naphthalene ring system. Also contemplated as such include ring systems which are mono- or polysubstituted or optionally alkylene-linked groups, such as C1-6 alkylene, through which the aryl group is attached to the rest of the molecule. Exemplary aryl groups include, but are not limited to, phenyl, benzyl, 2-naphthyl, 1-naphthyl, and biphenyl, as well as substituted derivatives thereof.

The term heteroaryl refers to monocyclic aromatic ring systems or bicyclic aromatic ring systems consisting of two or more aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur and / or oxygen atoms, and the nitrogen atoms in the ring are N-oxides or sulfur atoms in the ring.

V · »9 • · · ·· ♦ *«

-13 * can form sulfur oxides and sulfur oxides, and eventually the rings may be optionally substituted, or, if possible, multiple. The term "heteroaryl", as used herein, refers to cyclic groups which may be substituted once or more, or may include an alkylene linking group such as C 1-6, through which the heteroaryl group is attached to the rest of the molecule. Examples of heteroaryl include, but are not limited to, furan, thiophene, pyrene, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, and the like. pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole and indazole, and their substituted derivatives.

The term cycloalkyl refers to mono- or bicyclic hydrocarbon ring systems which may be optionally substituted with one or more substituents or optionally an alkylene linking group through which the cycloalkyl group is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. When substituted, the preferred substituent position for cycloalkyl groups according to the invention is 1-position. To illustrate this type of substitution, without limitation, reference can be made to general formula (IX) or, more generally, to general formula (X), wherein R is attached in this manner.

The term cycloalkyl includes bridged or condensed ring systems, such as hydrazane, decalin, or adamantyl rings. For simplicity, the term cycloalkyl extends to fused systems formed by a cycloalkyl group and an aryl group, for example a cycloalkyl group such as a cyclohexyl25 group is fused to an aromatic ring such as a benzene ring to form the (XI) moiety.

The term heterocyclic refers to heterocyclic rings, preferably 3- to 12-membered rings, which may be saturated or singly or multiply unsaturated. Such heterocyclic rings contain one or more heteroatoms, such as nitrogen, sulfur and / or oxygen, with the addition of heteroaromatic substituents such as N-oxide and sulfur oxide and sulfur dioxide. The heterocyclic group may optionally be mono- or polysubstituted or optionally contain an alkylene linking group such as C1-6 alkylene to which the heterocyclic group is attached to the rest of the molecule.

- 14 * dik A ring may optionally be condensed with one or more other heterocyclic rings or rings, aryl rings or rings or cycloalkyl rings or rings. Examples of such heterocyclic groups include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran and tetrahydrothiophene.

The term "halogen" means fluorine, chlorine bromine or iodine.

The term haloalkyl refers to alkyl groups as defined above substituted by at least one halogen atom. Examples of haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl independently of one or more halogen atoms, such as fluorine, chlorine, bromine, and the like. or iodine substituted. The term haloalkyl is to be understood to include groups such as perfluoroalkyl such as trifluoromethyl.

The term haloalkoxy refers to -OR a , wherein R a is haloalkyl as defined above.

The term alkoxy refers to the group -OR a , wherein R a is an alkyl group as defined above.

The term "aryloxy" refers to the group -OR5 wherein Rj is an aryl group as defined above.

By way of example, and as is described throughout the specification, the term "aryl" includes optionally substituted aryloxy groups as the term aryl includes optionally substituted aryl groups. Such an optional substitution is valid for all the terms used. Furthermore, as defined above, the term aryl refers to aryl groups attached via an alkylene group. Thus, for example, in the case of the aryloxy group and the like, the term "alkylene group" is used as the term. By way of example, non-limiting examples of aryloxy include -OR b , wherein R 1 is benzyl.

The term heteroaryloxy refers to -OR b , where

R b is heteroaryl as herein defined.

The term alkoxycarbonyl refers to the group -C (O) OR a wherein R a is an alkyl group as defined above.

- 15 ·· <

The term "aryloxycarbonyl" refers to the group -C (O) OR a wherein R a is an aryl group as defined above.

The term heteroaryloxycarbonyl refers to the group -C (O) OR a wherein R a is a heteroaryl group as defined above.

The term alkoxythiocarbonyl refers to the group -C (S) OR a wherein R a is an alkyl group as defined above.

The term aryloxythiocarbonyl refers to the group -C (S) OR a wherein R a is an aryl group as defined above.

The term heteroaryloxythiocarbonyl refers to the group C (S) OR a , wherein R a is a heteroaryl as defined above.

The term "oxo" refers to = O.

The term "mercaptoporph" refers to the -SH group.

The term "thio" refers to the group -S-.

The term "sulfinyl" refers to the group -S (O) -.

The term "sulfonyl" refers to the group -S (O) 2.

The term "alkylthio" refers to the group ~ SR wherein R is alkyl as herein defined.

The term "arylthio" refers to the group -SR a , wherein R a is an aryl group as defined above.

The term "heteroaryl" refers to the group -SR a , wherein

R a is heteroaryl as defined above.

The term "alkylsulfinyl" refers to the group -S (O) R a wherein R a is an alkyl group as defined above.

The term "arylsulfinyl" refers to the group -S (O) R a wherein R a is an aryl group as defined above.

The term "heteroarylsulfinyl" refers to the group -S (O) R a wherein R a is a heteroaryl as defined above.

The term "alkylsulfonyl" refers to the group -S (O) 2 R a , wherein R a is an alkyl group as defined above.

The term "cikloalkilszulfonilcsoport" -S (O) 2 is meant the group wherein R a is as defined above and cycloalkyl.

The term "arylsulfonyl group" -S (O) 2 is meant the group wherein R a is aryl as herein defined.

The term "heteroarylsulfonyl" refers to the group -S (O) 2 R a , wherein R a is a heteroaryl group as defined above.

The term "aminosulfonyl" refers to the group -S (O) 2 NH 2.

The term "cyano" means a -CN group.

The term "cyanoalkyl" is - intended to CN wherein

R a is alkyl as defined above.

The term "carboxyl" refers to the group -COOH.

The term "carbamoyl" refers to the group -C (O) NH 2.

The term "alkylcarbamoyl" refers to the group -C (O) N (R a ) 2, wherein one R a is alkyl as defined above and the other R a is independently hydrogen or alkyl as defined above.

The term "arylcarbamoyl" refers to the group -C (O) N (R a ) 2, wherein one of R a is aryl as defined above and the other R a is independently hydrogen or aryl as previously defined.

The term "heteroarylcarbamoyl" refers to the group -C (O) N (R a ) 2, wherein one R a is a heteroaryl as defined above and the other R a is independently hydrogen or a heteroaryl group as defined above.

The term "thiocarbamoyl" refers to the group -C (S) NH2.

The term "alkylthiocarbamoyl" refers to a group of the formula -C (S) N (R a ) 2, wherein one R a is an alkyl group as defined above and the other R a is independently hydrogen or an alkyl group as defined above.

The term "arylthiocarbamoyl" refers to the group -C (S) N (R a ) 2, wherein one of R a is aryl as defined above and the other R a is independently hydrogen or aryl as defined above.

The term "heteroarylthiocarbamoyl" refers to the group -C (S) N (R a ) 2, wherein one R a is heteroaryl as defined above and the other R a is independently hydrogen or heteroaryl as defined above.

The term "amino" refers to -NH2.

The term "alkylamino" refers to the group -N (R a ) 2, wherein one R a is an alkyl group as defined above and the other R a is independently hydrogen or an alkyl group as defined above.

The term "cycloalkylamino" refers to the group -N (R a ) 2, wherein one R a is cycloalkyl as defined above and the other R a is independently hydrogen or a cycloalkyl group as defined above.

The term "arylamino" refers to the group -N (R a ) 2, wherein one R a is aryl as defined above and the other R a is independently hydrogen or aryl as defined above.

The term "heteroarylamino" refers to the group -N (R a ) 2, wherein one R a is heteroaryl as defined above and the other R a is independently hydrogen or heteroaryl as defined above.

The term "acyl" refers to the group -C (O) R a wherein R a is an alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic group as defined above.

The term "thioacyl" refers to the group -C (S) R a wherein R a is alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic as defined above.

The term "hydroxy" refers to the -OH group.

The term "hydroxyalkyl" as used herein means R is OH, wherein. R a is an alkylene group as defined above.

As used herein, the term "optionally substituted" refers to a single or multiple but optionally existing substitution, i.e., as substituents, the following substituents: acyl; alkyl; alkenyl; alkynyl; alkylsulfonyl; alkoxy; CN; halogen; haloalkyl; hydroxy;

nitro; aryl which may be further substituted by halogen or acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, haloalkyl, hydroxyl or nitro; heteroaryl, which may be further substituted by halogen or acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, haloalkyl, hydroxyl or nitro; arylsulfonyl, which may be further substituted by halogen or acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, haloalkyl, hydroxyl or nitro; heteroarylsulfonyl, which may be further substituted by halogen or acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, haloalkyl, hydroxy or nitro; aryloxy optionally substituted with halo or acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, haloalkyl, hydroxyl30 or nitro; heteroaryloxy optionally substituted with halo or acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, haloalkyl, hydroxyl or nitro; -R'OR'R 4 radical; or -NR 4 R 5 ; which latter two groups R 'are independently alkylene, alkenylene or alkynylene each occurrence, represent and R 4 and R 5

- independently selected from 18 to 6 hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylsulfonyl, arylsulfonyl or heteroarylsulfonyl, wherein said aryl or heteroaryl groups may be optionally further substituted in each case; one or more halogen atoms or acyl, alkoxy, alkyl, alkenyl, alkylsulfonyl, cyano, haloalkyl, hydroxyl or nitro, or R 4 and R 5 together may form a ring optionally containing additional heteroatoms; or several times optionally unsaturated and optionally further substituted by halogen or acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, haloalkyl, hydroxyl or nitro.

The compounds of the present invention tend to crystallize in more than one form, known as polymorphism. All polymorphic forms (briefly referred to as polymorphs) are contemplated by the invention. Polymorphism generally appears as a phenomenon associated with changes in temperature or pressure, or both, but may result in different changes in the crystallization process. Polymorphs can be distinguished by their different physical characteristics as is well known in the art, such as their solubility, melting point, and X-ray diffraction parameters.

Some of the compounds described herein may contain one or more chiral centers or may otherwise exist in the form of multiple stereoisomers. The present invention encompasses pure stereoisomers as well as mixtures of stereoisomers such as purified enantiomers / diastereomers or enantiomerically-diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds of the invention themselves, as well as mixtures thereof, which are fully or partially balanced. Thus, certain isomers of the compounds represented by the above formulas as well as mixtures of isomers in which one or more chiral centers have been inverted are within the scope of the invention.

As mentioned above, salts, solvates and pharmaceutically acceptable functional derivatives of the compounds of the invention are contemplated as being within the scope of the invention. Salts include addition salts, metal salts, or optionally alkylated ammonium salts. Examples of such salts include salts with hydrogen chloride, hydrobromic acid, hydrogen iodide, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, maleic acid, pyrolic acid, malonic acid, succinic acid, citric acid, mandelic acid, benzoic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid or picric acid. Examples of other salts include lithium, sodium, potassium, and the like

- 19 * magnesium salts. Other salts include, for example, acetates, benzenesulfonates, benzoates, hydrogen carbonates, hydrogen sulfates, hydrogen tartrates, borates, bromides, calcium ethers, campylates, carbonates, chlorides, clavulanates, citrates, dihydrochlorides, edetates, edizilates, esfolates, esylates, fumarate, glyceptates, gluconates, glucates, gluconates, glutamates, glycollilaranilates, hexylresorcinates, hydrabamates, hydroxynaphthalates, isethionates, yakfates, lactobionates, laurates, malates, mandelates, mesylates, methylbromides, methylnitrates, methylsulfates, monocalcium maleate, mycates, napsilates, nitrates, N-methylglucaminates, pamoates (embonates), palmitates , pantothenates, phosphate / diphosphates, polygal 10 turonates, potassium salicylates, sodium stearates, subacetates, tannates, tartrates, theocytes, tosylates, triet iodides, trimethylammonium salts and valerates. In the case of salts, reference is made to Patent of Pharmaceutical Science, 66, 2 (1997).

By "solvate" is meant stoichiometric complexes formed by a solute or a salt or a pharmaceutically acceptable functional derivative and a solvent. For the purposes of the present invention, such solvents may not interfere with the biological activity of the solute. Examples of such solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably, the solvent is a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol and acetic acid.

The term "pharmaceutically acceptable functional derivative" means any pharmaceutically acceptable derivative of the compounds of the present invention, such as an ester or amide, which is capable of (directly or indirectly) administering a compound of the invention or an active metabolite thereof to a mammal. Such derivatives are well known to those skilled in the art and can be prepared without unacceptable experimentation. However, in this regard, reference is made to Burger's Medicinal Chemistry and Drug Discovery (5th ed.), Vol. 1, "Principals and Practice", to the teachings herein, for such pharmaceutically acceptable derivatives.

Although the compounds of the invention may be administered as crude chemical products, the compounds of the invention are preferably used as active ingredients of pharmaceutical compositions well known in the art. Thus, the present invention encompasses pharmaceutical compositions comprising as active ingredient a compound of the invention or a salt, solvate or pharmaceutically acceptable derivative thereof.

- 20 * together with one or more carriers and / or other excipients commonly used in the pharmaceutical industry.

The compositions of the present invention may optionally contain other therapeutic and / or prophylactic (active) agents. For example, the compounds of the present invention may be combined with another known antidiabetic agent such as one or more of the following agents: insulin, α-glucosidase inhibitors, biguanides, insulin secretagogue, or insulin sensitizers, as described in the Anglo-Saxon literature. Examples of α-glucosidase inhibitors include, but are not limited to, acarbose, emiglitate, miglitol, and voglibose. Non-limiting examples of biguanides include metformin, buformin and phenformin. As a non-limiting example of the compounds mentioned in the term insulin secretagogues, sulfonylureas are mentioned. Non-limiting examples of insulin sensitizers include peroxisome proliferator activated receptor (PPAR) ligands, such as PPAR-γ agonists, such as the following two-branded substance: Actos and Avandia.

The pharmaceutical compositions of the present invention may be in a form suitable for oral, buccal, parenteral, transdermal, inhalation, intranasal, transmucosal or rectal administration, or in the form of an implant. Of the various routes of administration, oral administration is typically preferred. For oral administration, for example, tablets and capsules suitable for this purpose may contain carriers / excipients commonly used in the pharmaceutical industry, such as binders, fillers, lubricants, disintegrants and / or wetting agents. Non-limiting examples of binders include sugar syrup, agar agar, gelatin, sorbitol, tragacanth resin, starch adhesive, or polyvinylpyrrolidone (PVP). Non-limiting examples of fillers include lactose, sugar, microcrystalline cellulose, potato starch, calcium phosphate or sorbitol. Non-limiting examples of lubricants include magnesium stearate, stearic acid, talc, polyethylene glycol, or silica. Non-limiting examples of disintegrating agents include potato starch or sodium starch glycolate.

Non-limiting examples of wetting agents include sodium lauryl sulfate. Tablets may be additionally incorporated by methods well known in the art.

Alternatively, the compounds of the present invention can be used in liquid form preparations for oral administration, such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. However, such compounds • ·· · · ·

Formulations containing -21 can also be prepared in the form of dry compositions, which can be formulated with a liquid formulation, for example, with water or other suitable diluent immediately before use. Liquid form preparations may also contain excipients and / or other excipients described in the literature for such compositions. Examples of such materials include, but are not limited to, suspending agents such as sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated digestible fats. Emulsifying agents such as lecithin, sorbitan monooleate or agar may also be used; non-aqueous diluents (including digestible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol. Such compositions may further comprise preservatives, such as methyl 4-hydroxybenzoate or propyl ester or sorbic acid. Such compositions may also be presented in the form of suppositories which may contain conventional suppository bases such as cocoa butter or other glycerides.

The pharmaceutical compositions of the present invention may be formulated for parenteral administration by injection or continuous infusion. Formulations suitable for injection may be, for example, suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain excipients such as suspending agents, stabilizers and / or dispersants. Alternatively, the active ingredient may be in the form of a powder which can be reconstituted with a suitable carrier, such as sterile, water-free water, immediately before use.

The pharmaceutical compositions of the present invention may be in the form of a so-called depot, i.e., sustained release formulations. Such long acting formulations may be administered as implants, for example, subcutaneously or intramuscularly, or by intramuscular injection. Thus, the compounds of the invention may be formulated into pharmaceutical compositions with suitable polymeric or hydrophobic materials, such as an emulsifiable oil emulsion, in combination with ion exchange resins, or as a poorly soluble derivative such as a poorly soluble salt.

The pharmaceutical compositions of the present invention may be formulated in dosage units containing a predetermined amount of the active ingredient. Such a dosage unit may comprise an amount of the active compound depending on the disease being treated, the route of administration, and the age, weight and general condition of the patient. In such dosage units, the amount of active ingredient may be from about 0.1% to about 99.9%. Dosage units containing, for example, a predetermined dose, such as a daily dose or an appropriate portion thereof, are preferred. Such dosage units can be prepared by methods well known in the pharmaceutical art.

As used herein, the term "effective amount" refers to an amount of the active ingredient or a therapeutically active agent that will provide the desired biological or medical response in a tissue, system, animal, or human, such as determined by the investigator or healer. Furthermore, the term "therapeutically effective amount" refers to any amount which, in comparison with a suitable case not treated with such an amount, provides for improved treatment, cure or prevention of a disease, disorder or side effect, or to accelerate the cure of a disease or disorder. As used herein, the term also refers to quantities capable of enhancing normal physiological function.

The amount of a therapeutically effective amount of a compound of the invention will depend on a number of factors, such as the age and weight of the animal or human being to be treated, the exact nature of the disease to be treated and its severity, the nature of the composition, and the route of administration. Therapeutic efficacy is ultimately determined by the treating physician or veterinarian. An effective amount of a salt or solvate or pharmaceutically effective derivative may be determined in proportion to the effective amount of the compound of the present invention. In addition, dosages may vary depending on the appropriate inhibition of DPP-IV for the treatment or prevention of various metabolic, gastrointestinal, viral and inflammatory diseases. Such diseases include, but are not limited to, metabolic disorders, gastrointestinal disorders, viral diseases, inflammatory diseases, diabetes, obesity, hyperlipidemia, dermatological or mucosal membrane disorders, psoriasis, intestinal distress, constipation, autoimmune disorders such as cerebrovascular inflammation; complement mediated diseases, such as glomerulonephritis, fatty tissue disorders and tissue damage, as well as psychosomatic, depressive and neuropsychiatric diseases such as anxiety, depression, insomnia, schizophrenia, epilepsy, spasms and chronic pain, HIV infection, allergic diseases, inflammation diseases, arthritis, graft rejection, hypertension, congestive heart failure, tumors and stress l induced abortions.

If a compound of the invention is used within the above-mentioned dosage range, no toxic effects are expected.

-23 • The invention will be illustrated by the following examples without limiting the scope of the invention to these examples. The symbols and rules used in the following procedures, schemes and examples are consistent with current scientific literature, such as the Journal of the American Chemical.

Society or Symbols and Rules Used in Journal of Biological Chemistry. Unless otherwise noted, all starting materials were purchased commercially and used without further purification.

ΙΗ-NMR spectra were recorded on a Varian VXR-300, Varian Unity-300, Varian Unity 400 or General Electric QE-300. The chemical shifts10 are given in many ppm δ units. The switching constants are given in hertz (Hz). The cleavage characteristics describe apparent multiplicities, denoted by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.

The low resolution mass spectrum (MS) was recorded on a JOEL JMS-AX505HA, JOEL SX-102 or SCIEX-APIiii spectrometer; and high resolution mass15 spectra with a JOEL SX-1Q2A spectrometer. All mass spectra were recorded by electrospray ionization (Si), chemical ionization (Cl), electron impact (El) or fast atom bombardment (FAB). Infrared (IR) spectra were recorded on a Nicolet 510 FTIR spectrometer using a 1 mm sodium chloride cell. All reactions were followed by thin layer chromatography using 0.25 mm silica gel plates 60F20254, supplied by E. Merck, followed by ultraviolet light, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. done. Flash column chromatography was performed on Merck 230-400 mesh silica gel. Optical rotation was tested using a Perkin Elmer Model 241 polarimeter. The melting points were determined by means of a Mel-Temp II apparatus, the values given being non-corrected values.

To further identify certain compounds of the invention, IUPAC names are given. The IUPAC names herein do not limit the scope of the invention in any way.

According to one aspect of the present invention and the process for preparing the compounds of the present invention, a compound of formula (II) is reacted with an α- or β-aminocarboxylate or an activated α- or β-aminocarboxylate - these compounds are generally referred to as aminocarboxylates. mentioned in conditions commonly used for coupling reactions such as: · · · · · ·

-24 * using HATU, DMF and Hunigs. The reaction is shown in Scheme 1.

Specifically, the compound of formula (II) is reacted with an amino-carboxylate suitably protected on its amino group, such as an amino-carboxylate having an appropriate protecting group such as a t-butoxycarbonyl group.

In an alternative embodiment of the process of the present invention, a compound of formula (II) is reacted with an amino group-activated carboxylate, such as an N-hydroxysuccinimide ester or acid chloride derivative, wherein the amino-activated carboxylate is suitably protected, e.g. protected on a nitrogen atom with a suitable protecting group such as tert-butyl carboxy. After deprotection under suitable conditions, for example by treatment with trifluoroacetic acid for tert-butyl carboxyl, a desired compound of formula (Ia) is obtained.

For the production of amino carboxylates for use in the preparation of the compounds of the present invention, reference is made to WO 95/15309 and WO 98/19998.

Example of Intermediates: Compound XII, i.e. (2S, 4S) -4-Fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate

A. Methyl- (2S, 4R) -4-hydroxy-2-pyrrolidinecarboxylate hydrochloride

Thionyl chloride (58.6 g, 492.3 mmol) was added dropwise to a stirred solution of L-hydroxyproline (62.67 g, 478 mmol) in methanol (420 mL), and the resulting suspension was stirred at room temperature for two hours. . The reaction mixture was then refluxed for 6 hours, cooled to room temperature and the solvent removed in vacuo. The resulting solid was filtered off under high vacuum to afford Compound A as a white solid (86.03 g, 474 mmol, 99%).

1 H-NMR (d 4 -MeOH) 400 MHz δ 4.62-4.57 (m, 2H), 3.85 (s, 3H), 3.43 (dd, 1H, J = 12.2, 3, 7 Hz), 3.30 (m, 1H), 2.41 (dd, 1H, J = 13.6, 7.6 Hz), 2.19 (m, 1H) ppm.

B. 1-tert-Butyl-2-methyl- (2S, 4R) -4-hydroxy-1,2-pyrrolidinedicarboxylate

88.67 g (0.49 mole) of Compound A and 109.8 g (0.50 mole) of di-tert-butyldicarbonate in 1.4 l of dichloromethane are added dropwise at 0 ° C over 1.5 h, 6 g (1.22 mol) of trimethylamine and then the resulting solution slowly added to a solution of i

• · * • · 0 · 0 ·

Allow to warm to room temperature over the night of -25. The solvent was then removed in vacuo and diethyl ether was added to the residual solid. The solid was then collected by vacuum filtration and washed thoroughly with diethyl ether. The solvent from the filtrate was removed in vacuo and the residue was dissolved in dichloromethane. The organic layer was then washed with saturated aqueous sodium chloride solution and saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The resulting light yellow oil was filtered off under high vacuum for about 15 minutes when solidified. To the resulting solid was added about 500 mL of hexane and then stirred overnight. The solid was collected by vacuum filtration and then filtered off under high vacuum. 104.5 g (0.43 mole, 87%) of compound B were obtained as a white solid.

1 H-NMR (d 4 -MeOH) 400 MHz δ 4.37-4.32 (m, 2H), 3.72-3.71 (m, 3H), 3.51 (m, 1H), 3.43 (m, 1H), 2.23 (m, 1H), 2.02 (m, 1H), 1.42 (m, 9H) ppm.

C. 1-tert-Butyl-2-methyl- (2S, 4S) -4-fluoro-1,2-pyrrolidinedicarboxylate

A solution of 1.25 L of 1,3-dichloroethane (124.25 g, 0.51 mol) in 1,3-dichloroethane was cooled to -30 ° C in 2 L and 125 g (0.78 mol) of DAST were added alone. . The reaction mixture was then allowed to warm slowly to -10 ° C over a period of one hour, and the cooler was removed. Stirring was continued for 24 hours and the resulting dark solution was poured into two 2L vessels containing crushed ice and solid sodium bicarbonate. The flasks were shaken periodically and mixed until carbon dioxide evolution was observed (note: occasionally an additional amount of solid sodium bicarbonate was added). The organic layer was then separated until the aqueous phase was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate and the solvent removed in vacuo. The residual dark oil was dissolved in ethyl acetate (200 mL) and hexane (800 mL) was added. Silica dioxide (100 g) was added and the mixture was stirred for 30 minutes. The solution was then filtered through silica gel washed with hexane-ethyl acetate (4: 1), and the solvent was removed in vacuo. The residue is filtered off under high vacuum. Thus, 121.81 g (0.40 mole, 97%) of Compound C is obtained as a dark oil30.

1 H-NMR (CDCl 3 ) 400 MHz δ 5.18 (broad d, 1H, J = 53 Hz), 4.53 (d, 1 / 2H, J = 9.7 Hz),

4.40 (d, 1 / 2H, J = 9.4 Hz), 3.87-3.59 (m, 2H), 3.73 (s, 3H), 2.51-2.28 (m, 2H), 1.46 (s, 3H, rotomer), 1.41 (s, 6H, rotomer) ppm.

· «« «« »· · ·» »» »» · ··· * * · · · λ

-26- D. (2S, 4S) -1- (tert-Butoxycarbonyl) -4-fluoro-2-pyrrolidinecarboxylic acid

To a solution of 121.8 g (0.49 mole) of Compound C in 1.11 dioxane was added 380 ml of water in 2 L of flask and then lithium hydroxide hydrate (103.6 g, 2.46 mole) at room temperature. The resulting solution was stirred for 23 hours (note: TLC showed complete reaction after 5 hours) during which time most of the dioxane was removed in vacuo. The residue was dissolved in additional water and activated carbon was added to the aqueous solution. After stirring for 15 minutes, the solution was filtered through a pad of Celite filter aid and solid sodium chloride was added to the filtrate until it was dissolved. At this time, the filtrate was cooled in an ice-water bath and acidified to pH 3 with concentrated aqueous hydrochloric acid, maintaining the temperature of the solution between 5 ° C and 10 ° C during acidification. The product starts to precipitate at pH 4, and when the pH is 3, the tan solid is collected by vacuum filtration. The solid was then filtered off under high vacuum overnight and then dissolved in 1.5 L of acetonitrile. The resulting solution was dried over magnesium sulfate and the solvent was removed in vacuo and the residue dried under high vacuum. 92.7 g (0.40 mol, 81%) of the title compound are obtained as a tan solid.

1 H-NMR (dg-MeOH) 400 MHz δ 12.5 (br s, 1H), 5.22 (broad d, 1H, J = 54 Hz), 4.25 (m, 1H), 3.60- 3.43 (m, 2H), 2.45 (m, 1H), 2.20 (m, 1H), 1.33 (m, 9H) ppm.

E. Tert-Butyl (2S, 4S) -2- (aminocarbonyl) -4-fluoro-1-pyrrolidinecarboxylate

In a 2-necked flask equipped with 2 1 air-driven mixers, 92.7 g (0.40 mole) of Compound D, 1.1 L of acetonitrile, 130 g (0.60 mole) of di-tert-butyldicarbonate and 32.4 g were charged. (0.41 mol) pyridine at room temperature. After 20 minutes, ammonium bicarbonate (47.2 g, 0.60 mole) was added to the reaction mixture, followed by stirring for 23 hours during which time most of the acetonitrile was removed in vacuo. The residue was dissolved in dichloromethane, and the resulting solution was washed with a 1: 1 mixture of 1M aqueous hydrochloric acid and saturated aqueous sodium chloride solution. The aqueous phase was then extracted twice with dichloromethane and the combined organic layer was dried over magnesium sulfate and the solvent removed in vacuo. The residual tan solid was triturated with 0.5 L of hexane and then collected by vacuum filtration. The isolated material was filtered off under high vacuum to give 68.75 g (0.30 mol, 74%) of Compound E as a pale tan solid. After removal of the solvent in vacuo, the filtrate gave a dark oil which contained an additional amount of product as determined by 1 H-NMR.

-27'H-NMR (dg-MeOH) 400 MHz δ 7.21 (broad s, 1/2H), 7.14 (broad s, 1/2H), 6.94 (br s, 1H), 5, 19 (broad d, 1H, J = 54 Hz), 4.11 (m, 1H), 3.63-3.47 (m, 2H), 2.38 (m, 1H), 2.11 (m, 1H), 1.39 (s, 3H, rotomer), 1.34 (s, 6H, rotomer) ppm.

F. Tert-butyl (2S, 4S) -2-cyano-4-fluoro-1-pyrrolidylcarboxylate

Imidazole (2.93 g, 43.1 mmol) was treated with pyridine (75 g, 0.9 mol, 15 times the amide weight) in a flask and cooled to 0 ° C, stirred for 10 minutes and then cooled to room temperature. BOC-4-fluoropropoline carboxamide (5.0 g, 21.6 mmol) was added in one portion. The solution was then cooled to -30 ° C (note: temperatures below this temperature may lead to a heterogeneous solution) and phosphorus oxide trichloride (13.2 g, 86.4 mmol) was added dropwise over 5 minutes. After the addition was complete, the dry ice bath was replaced with an ice bath and stirring was continued at 0 ° C for one hour. The reaction mixture is then poured into a mixture of fractions of ice, solid sodium chloride and ethyl acetate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The solvent was then removed under vacuum (note: the rotary vacuum evaporator was kept at a temperature of less than 35 ° C) and the residue was dissolved in ethyl acetate. The organic solution thus obtained was washed with a saturated aqueous solution of sodium chloride and then twice with 1 M aqueous hydrochloric acid. After drying over magnesium sulfate, the solvent was removed in vacuo to give 4.0 g (18.6 mmol, 86%) of Compound F as a pale tan solid.

1 H-NMR (δ-MeOH) 400 MHz δ 5.32 (broad d, 1H, J = 52 Hz), 4.78 (m, 1 H), 3,743.48 (m, 2H), 2.55-2, 40 (m, 2H), 1.52-1.43 (m, 9H) ppm.

G. (2S, 4S) -4-Fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate

75.4 g (0.40 mole) of p-toluenesulfonic acid hydrate were added to a 1 L acetonitrile solution containing 56.62 g (0.26 mole) of Compound F at room temperature and after 24 hours the acetonitrile was removed under vacuum and the residue was evaporated. brown oil was dissolved in 500 mL of ethyl acetate. After 1 minute, a solid is formed. The solid solution was cooled in an ice-water bath, stirred for one hour and then the solid was collected by vacuum filtration. The separated solid was rinsed with ethyl acetate (500 mL, -20 ° C) and filtered off under high vacuum overnight. 60.94 g (0.21 mol, 82%) of compound G are obtained as a pale tan solid.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.69 (d, 2H, J = 8, 1 Hz), 7.23 (d, 2H, J = 8.0 Hz), 5.52 (dd, 1H, J = 51, 3.4 Hz), 4.96 (dd, 1H, J = 9.8, 3.6 Hz), 3.78 (m, 1H), 3.55 (m, 1H), 2.84-2.63 (m, 2H), 2.36 (s, 3H) ppm.

»·« * · *

-28- Alternative Method for Preparation of Intermediate 1 (2S, 4S) -4-Fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate, i.e. Compound (VII)

A. Tert-butyl (2S, 4R) -2- (aminocarbonyl) -4-hydroxypyrrolidine-1-carboxylate

A solution of 420 ml, 30.0 g (129 ml) of BOC-L-hydroxyproline and 14.4 g (141.9 mmol) of triethylamine in tetrahydrofuran was cooled to -15 ° C and 15.4 g (141.9 mmol) was added dropwise. ) chloroacetic acid ethyl ester. The resulting solution was then stirred for 10 minutes and then 80 ml of 28% aqueous ammonium hydroxide solution was added. The reaction mixture was then allowed to warm slowly to 5 ° C over two hours, during which time a saturated aqueous solution of ammonium chloride was added until the total amount of white solid dissolved. The tetrahydrofuran was then isolated and the aqueous phase extracted with tetrahydrofuran. The combined organic layers were dried over magnesium sulfate and the solvent removed in vacuo. The residual oil was treated with diethyl ether and then with a small amount of dichloromethane and methanol. After 1 hour of storage in a refrigerator, the resulting white solid was collected by vacuum filtration to give Compound A (22.0 g, 95.6 mmol, 74%).

1 H-NMR (dg-DMSO) 400 MHz δ 7.33-7.29 (broad d, 1H, rotomers), 6.88-6.80 (broad d, 1H, rotomers), 4.94 (broad s) , 1H), 4.18 (broad s, 1H), 4.04 (m, 1H), 3.35 (m, 1H), 3.21 (m, 1H), 1.99 (m, 1H), 1.77 (m, 1H), 1.36-1.31 (d, 9H, rotomers) ppm.

B. Tert-butyl (2S, 4R) -2-cyano-4-hydroxypyrrolidine-1-carboxylate

Trifluoroacetic anhydride (40.8 g, 194.4 mmol) was added dropwise to a solution of pyridine (180 mL, 17.89 g, 77.8 mmol), cooled to -20 ° C, and the reaction mixture was brought to room temperature after complete addition. let it warm up. After 6 hours, the reaction mixture was quenched with water and poured into ethyl acetate (500 mL). The organic phases are washed with saturated aqueous sodium chloride solution, 1.0 M hydrochloric acid and 2.0 M sodium hydroxide solution, dried over magnesium sulfate, activated carbon is added to the filtrate, stirred for 10 minutes and the mixture is then added to Celite. It is filtered through a filter bed made of a filter aid of the brand name. The solvent was removed from the filtrate in vacuo (rotary evaporator temperature set at 34 ° C) to give 13.21 g (62.3 mmol, 80%) of Compound B as an orange oil.

T 1 NMR (d 4 -MeOH) 400 MHz δ 4.60 (m, 1H), 4.40 (br s, 1H), 3.49 - 3.41 (m, 2H), 2.36 - 2.34 (m, 2H), 1.51-1.48 (m, 9H, rotomers).

-29 "C. Tert-Butyl (2S, 4S) -2-cyano-4-fluoro-1-pyrrolidinecarboxylate

DAST (15.1 g, 93.4 mmol) was added to 300 ml of a 1.2-dichloroethane solution containing 13.21 g (62.3 mmol) of Compound B at -30 ° C and the cooling bath was removed after 30 minutes. and stirring is continued for 24 hours and then the reaction is carefully quenched by the addition of saturated sodium bicarbonate solution. The reaction mixture was poured onto crushed ice and the organic layer was extracted twice with dichloromethane. After final washing with saturated sodium hydrogen sulfate, the organic phase was dried over magnesium sulfate and the solvent removed in vacuo. Thus, 10.86 g (50.7 mmol, 81%) of Compound C was obtained as a brown semi-solid.

1 H-NMR (d 4 -MeOH) 400 MHz δ 5.32 (broad d, 1H, J = 52 Hz), 4.78 (m, 1 H), 3,743.48 (m, 2H), 2.55- 2.40 (m, 2H), 1.52-1.43 (m, 9H) ppm.

D. (2S, 4S) -4-Fluoro-2-pyrrolidinecarbanitrile-4-methylbenzenesulfonate

P-toluenesulfonic acid (14.8 g, 78 mmol) was added to 200 ml of acetonitrile solution containing 10.86 g (50.7 mmol) of Compound C at room temperature, and the resulting reaction mixture was stirred for 24 hours and the acetonitrile was removed in vacuo. The residual brown oil was dissolved in 300 ml of ethyl acetate to give a solid within 1 minute. The solution was cooled in an ice bath for two hours and the precipitated solid was collected by vacuum filtration. The solid was then washed with 300 ml of -20 ° C ethyl acetate to give 10.07 g (35.2 mmol, 69%) of Compound D.

{1 H-NMR (d 4 -MeOH) 400 MHz δ 7.69 (d, 2H, J = 8, 1 Hz), 7.23 (d, 2H, J8.0 Hz), 5.52 (dd, 1H, J = 51, 3.4 Hz), 4.96 (dd, 1H, J = 9.8, 3.6 Hz), 3.78 (m, 1H), 3.55 (m, 1H), 2, 84-2.63 (m, 2H), 2.36 (s, 3H) ppm.

Example 2: Intermediate XIII: (2S) -4,4-Difluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate

A. Tert-butyl (2S, 4S) -2- (aminocarbortyl) -4-hydroxy-1-pyrrolidinecarboxylate

A solution of 420 ml of BOC-L-hydroxyproline in 30.0 g (129 mmol) and triethylamine (14.4 g, 141.9 mmol) was cooled to -15 ° C and 15.4 g (140.9 mmol) was added dropwise. ) ethyl chloroformate. The white solution thus obtained was stirred at -15 ° C for 30 minutes and then 80 ml of 28% aqueous ammonium hydroxide solution was added using a syringe. After complete addition, the cooling bath was removed and stirring continued for 19 hours. The resulting homogeneous solution was poured into saturated aqueous ammonium chloride solution and the organic layer was separated. The aqueous phase was extracted with tetrahydrofuran and the combined organic layers were dried over magnesium sulfate and the solvent removed in vacuo. The resulting semi-solid was suctioned off under high vacuum at two «4 ♦

-30 hours. The white solid thus obtained is isolated by vacuum filtration using diethyl ether. 15.86 g (68.9 mmol, 53%) of Compound A are obtained.

1 H NMR (dg-DMSO) 400 MHz δ 7.34 (broad s, 1H, rotomer), 7.31 (broad s, 1H, rotomer), 6.90 (broad s, 1H, rotomer), 6.82 (broad s, 1H, rotomer), 4.95 (d, 1H, J = 3.1 Hz), 4.05 (m, 1H), 3.36 (m, 1H), 3.22 (m, 1H) , 2.03 (m, 1H), 1.78 (m, 1H), 1.37 (s, 3H, rotomer), 1.32 (s, 6H, rotomer) ppm.

B. Tert-butyl (2S) -2- (aminocarbonyl) -4-oxo-l-pyrrolidinecarboxylate ml, was added 3 ml of dichloromethane solution containing dimethyl sulfoxide at a temperature of dichloromethane solution containing 607 mg (4.78 mmol) oxaliíkloridot -78 Q C and, after 5 minutes, 1.0 g (4.35 mmol) of tert-butyl (2S, 4S) -2- (aminocarbonyl) -4-hydroxy-1-pyrrolidinecarboxylate, prepared as described in step E above, are added dropwise in 20 ml. a solution of dichloromethane in 15 ml of tetrahydrofuran. After complete addition, the reaction mixture was stirred for 20 minutes and then triethylamine (2.20 g, 21.7 mmol) was added. After 10 minutes, the cooling bath was removed and stirring continued for one hour. The solution was then poured into a saturated aqueous solution of sodium hydrogencarbonate and the organic materials were extracted with dichloromethane. After drying over magnesium sulfate, the solvent was removed under vacuum and the residual yellow oil was purified by column chromatography using dichloromethane / methanol (15: 1) as eluent. This gave 560 mg (2.45 mmol, 56%) of Compound B as a white solid.

1 H NMR (dg-DMSO) 400 MHz δ 7.58 (broad s, 1H), 7.15 (broad s, 1H, rotomer), 7.09 (broad s, 1H, rotomer), 4.51 (d , 1H, J = 9.7 Hz, rotomer), 4.46 (d, 1H, J = 8.8 Hz, rotomer), 3.76-3.64 (m, 2H), 3.02 (m, 1H), 2.28 (m, 1H), 1.39 (s, 3H, rotomer), 1.37 (s, 6H, rotomer) ppm.

C. Tert-Butyl (2S) -2- (aminocarbonyl) -4,4-difluoro-1-pyrrolidinecarboxylate

10.0 ml of dichloromethane solution containing 423 mg (1.85 mmol) of Compound B were cooled to -70 ° C, and 889 mg (5.50 mmol) of DAST was added and the resulting solution was stirred at -70 ° C. Stir for 30 minutes and then at room temperature for two hours. The reaction was quenched by the addition of saturated aqueous sodium hydrogencarbonate solution and the organic materials were extracted with dichloromethane. After drying over magnesium sulfate, the residual yellow solid was purified by column chromatography using dichloromethane / methanol (15: 1) as eluent. 211 mg (0.84 mmol, 46%) of compound C are obtained.

-31 H NMR (d 4 -MeOH) 400 MHz δ 4.38 (m, 1H), 3.84-3.75 (m, 2H), 2.76 (m, 1H), 2.41 (m , 1H), 1.44 (broad s, 9H) ppm.

D. Tert-butyl (2S) -2-cyano-4,4-difluoro-1-pyrrolidinecarboxylate, containing 658 mg (2.63 mmol) of Compound C and 358 mg (5.26 mmol) of imidazole. Phosphorus oxide trichloride (1.61 g, 10.5 mmol) was added to the pyridine solution cooled to <RTI ID = 0.0> C, </RTI> and the resulting suspension was stirred for 1.5 hours during which time it was heated to 10 ° C. The solution was then diluted with ethyl acetate and washed three times with 1 M aqueous hydrochloric acid. After drying over magnesium sulfate, the solvent was removed in vacuo to give 610 mg (2.63 mmol, 100%) of the solvent.

Compound D, which corresponds to Compound E below.

1 H NMR (d 4 -MeOH) 400 MHz δ 4.88 (broad s, 1H), 3.79-3.72 (m, 2H), 2.87 (m, 1H), 2.69 (m, 1H), 1.50 (s, 9H) ppm.

E. p-Toluenesulfonic acid hydrate (839 mg, 4.42 mmol) was added to a solution of (D) (2S) -4,4-Difluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (512 mg, 2.21 mmol) at room temperature. and the resulting solution was stirred at room temperature for two hours and then acetonitrile was removed in vacuo. Approximately 10 mL of ethyl acetate was added to the residual oil and then removed in vacuo. The resulting solid was triturated with diethyl ether and ethyl acetate was added. The solid was then isolated by vacuum filtration to give 375 mg (1.23 mmol, 56%) of Compound E as a white solid.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.70 (d, 2H, J = 8.2 Hz), 7.23 (d, 2H, J = 7.9 Hz), 5.12 (t, 1H, J = 7.9 Hz), 3.91-3.78 (m, 2H), 3.08-2.89 (m, 2H), 2.89 (s, 3H), 2.36 (s , 9H) ppm.

EXAMPLES

Example 1 (2S, 4S) -1 - [(2S) -2-amino-3,3-diphenylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XIV

A. (2S, 4S) -l - [(2S) -2-Amino-3-one 3 difenilpropanoil] in dry dimethylformamide was added 4-fluoropyrrolidine-2-carbonitrile hydrochloride mL (1.96 g, 6.0 mmol) ( 2S) -2 - [(tert-butoxycarbonyl) amino] -3,3-diphenylpropionic acid, 2.28 g (6.0 mmol) of HATU and 1.05 ml (6.0 mmol) of,-diisopropylethylamine, and stirring at room temperature for 30 minutes. (2S, 4S) -4-Fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (1.31 g, 4.5 mmol) and Ν, diisopropylethylamine (0.783 mL, 4.5 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours and then treated with 10 mL of saturated sodium bicarbonate.

-32 10 solutions are added. The resulting mixture was extracted twice with 100 ml of ethyl acetate, and the combined extract was washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The crude solid thus obtained was subjected to chromatography on silica gel eluting with hexane to give 4: 1 by volume. The resulting solid was then stirred in 20 ml of 4.0M HCl in dioxane for 2 hours and then 100 ml of diethyl ether were added. The resulting precipitate was collected by filtration and dried under high vacuum. Thus, 1.36 g (3.64 mmol, 81%) of Compound A are obtained as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 8.45-8.41 (broad s, 3H), 7.70 (m, 2H), 7.38-7.36 (m, 2H), 7.29 -7.26 (m, 3H), 7.24-7.18 (m, 3H), 5.39 (d, 1H, J = 51Hz), 4.89-4.85 (m, 2H), 4 , 38 (d, 1H, J = 11.3 Hz), 3.98 (ddd, 1H, J = 38.8, 12.4 and 3.1 Hz), 3.39-3.33 (m, 1H ), 2.30-2.18 (m, 2H) ppm.

Example 2 (2S, 4S) -1 - [(2S) -2-amino-3 ) 3-bis (4-fluorophenyl) propanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XV

A. To a solution of 3,3-Bis (4-fluorophenyl) -3-hydroxypropionic acid in a solution of 46 ml of 2.5 M n-butyllithium (115 mmol) in anhydrous tetrahydrofuran (80 ml) was added dropwise diisopropylamine (11.13 g, 115 mmol). then the resulting solution was stirred for 10 minutes. After maintaining the temperature of the solution at 0 ° C, acetic acid (2.64 g, 44 mmol) was added dropwise and the resulting mixture was stirred for 10 minutes and then warmed to 50 ° C. After 30 minutes, a precipitate is precipitated and the reaction mixture is allowed to cool. Then a solution of 4,4'-difluorobenzophenone (9.6 g, 0.044 mol) in 50 ml of dry tetrahydrofuran was added to the reaction mixture at 0 ° C and the resulting mixture was stirred at room temperature overnight. Water (100 mL) and diethyl ether (100 mL) were added and the aqueous layer was separated and acidified to pH 3 with 1M aqueous hydrochloric acid. The organic materials are then extracted three times with 200 ml of ethyl acetate, and the extract is dried over magnesium sulfate, and the solvent is removed in vacuo. The crude white solid thus obtained was washed with cold chloroform to remove traces of benzophenone. The resulting solid was dried under high vacuum to give Compound A (5.63 g, 20.2 mmol, 46%) as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 12.4 (br s, 1H), 7.48-7.39 (m, 4H), 7.19-7.02 (m, 4H), 5.91 (broad s, 1H), 3.25 (s, 2H) ppm.

- 33. B. To a solution of 3,3-Bis (4-fluorophenyl) acrylic acid in ml, 20% (v / v) sulfuric acid in acetic acid, compound A (5.6 g, 20.2 mmol) was added and the resulting mixture was stirred at room temperature for 30 minutes. stirred. Water (500 mL) was added to the resulting solution, and the organic materials were extracted three times with 150 mL of ethyl acetate (150 mL). The combined extract was dried over magnesium sulfate, filtered and the solvent removed in vacuo to give a white solid. The solid was then dried under high vacuum to give 4.97 g (19.1 mmol, 95%) of Compound B as a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.27-7.21 (m, 2H), 7.19-7.13 (m, 2H), 7.10-6.95 (m, 10 4H) , 6.26 (s, 1H) ppm.

C. 3,3-Bis (4-fluorophenyl) propionic acid

To a solution of compound B (2.5 g, 9.61 mmol) in ethyl acetate (250 mL) was added 50 wt% of a palladium on carbon catalyst (10 wt%) and hydrogenated under 1 atmosphere of hydrogen for 12 h. The heterogeneous solution is then added

It is filtered using a Celite filter aid and the filtrate is concentrated in vacuo. The resulting yellow oil was dried under high vacuum to give 2.40 g (9.16 mmol, 95%) of Compound C as a yellow oil.

1 H-NMR (d 6 -DMSO) 400 MHz δ 12.08 (br s, 1H), 7.40-7.30 (m, 4H), 7.15-7.05 (m, 4H), 4 , 45 (t, 1H, J = 8.1 Hz), 3.05 (d, 2H,> 8, 1 Hz) ppm.

D. (4S, 5R) -3- [3,3-Bis (4-fluorophenyl) propanoyl] -4-methyl-5-phenyl-1,3-oxazolidin-2-one, 2.0 g (7, To a solution of Compound C in anhydrous tetrahydrofuran (63 mmol) was added 18, diisopropylethylamine (1.18 g, 9.16 mmol), and the resulting solution was cooled to -78 ° C. To this solution was added trimethylacetyl chloride (0.97 g, 8.01 mmol) and allowed to warm to 0 ° C over an hour. The turbid reaction mixture was filtered and the filtrate was slowly added over 10 min at -78 ° C to a solution of lithium (4S, 5R) - (-) - 4-methyl-5-phenyl-2-oxazolidinone, which was prepared by To a solution of (4S, 5R) - (-) - 4-methyl-5-phenyl-2-oxazolidinone (1.35 g, 7.63 mmol) in tetrahydrofuran (50 mL) at -78 ° C was added dropwise 3.0 mL of 2, N-Butyllithium solution (7.63 mmol). After stirring for 10 minutes, lithium (4S, 5R) - (-) - 4-methyl-5-phenyl-2-oxazolidinone is obtained. The yellow reaction mixture was then warmed to 0 ° C and quenched with water (50 mL).

The aqueous mixture was extracted three times with 250 ml of diethyl ether, and the extract was dried over magnesium sulfate, and the solvent was evaporated in vacuo. The resulting solid was purified by flash chromatography on silica gel, eluting with 20% v / v.

Using -34-ethyl acetate hexane. Thus, compound D is obtained. The resulting white solid was dried under high vacuum to give 2.31 g (5.49 mmol, 72%) of a white solid.

¹H-NMR (dg-DMSO) 400 MHz δ 7.40-7.25 (m, 9H), 7.18-7.02 (m, 4H), 5.76 (d, 1H, > 7.6 Hz) ), 4.65 (m, 1H), 4.58 (t, 1H, > 7.6 Hz), 3.72 (dd, 1H, > 16.8, 7.0 Hz) 3.57 (dd, 1H,> 16.8, 7.0 Hz), 0.58 (d, 3H, J = 6.7 Hz) ppm.

E. (4S, 5R) -3 - [(2S) -2-Azido-3,3-bis (4-fluorophenyl) propanoyl] -4-methyl-5 - [(1E, 3Z) -1-methylhexa-1, To a solution of 3,5-triemyl-1,3-oxazolidin-2-one in anhydrous tetrahydrofuran containing compound D (2.0 g, 4.75 mmol) at -78 DEG C. is added dropwise 10.0 ml of 0.5 mol / l. After the addition of 1 concentration of potassium bis (trimethylsilyl) amide solution in toluene (4.98 mmol), followed by stirring for 10 minutes, 2,4,6-triisopropylbenzenesulfonyl azide (trisyl) (1.84 g, 5.94 mmol) was added in one portion. -azide) in 10 ml of anhydrous tetrahydrofuran. After 3 minutes, 1.31 g (21.8 mmol) of acetic acid was added at -78 ° C, and the reaction mixture was heated rapidly to 30 ° C and stirred at this temperature for one hour. Water (100 ml) was added to the resulting pale yellow solution, and the organic materials were extracted with 500 ml of ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate (100 mL), dried over magnesium sulfate and concentrated in vacuo. The resulting yellow oil was purified by column chromatography using a 1: 9 by volume mixture of ethyl acetate and hexane as eluent. Thus, compound E is obtained as a white solid. HPLC showed a single diastereomer. The white solid was dried under high vacuum to give 1.71 g (3.70 mmol, 78%) of Compound E as a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.42-7.35 (m, H), 7.25-7.18, (m, II), 7.10-7.06 (m, 2H) , 7.05-6.92 (m, 2H), 5.95 (d, 1H, > 10.8 Hz), 5.05 (d, 1H, J = 7.1 Hz), 4.60 (d, 1H, J = 10.8 Hz), 4.38 (m, 1H), 0.95 (d, 3H, J = 6.8 Hz) ppm.

F. (2S) -2-Azido-3,3-bis (4-fluorophenyl) propionic acid at 1.5 ° C Compound E (1.5 g, 3.25 mmol) in tetrahydrofuran / water (4: 1) was prepared by 50 ml. to a solution of lithium hydroxide (0.272 g, 6.49 mmol) in 30% aqueous hydrogen peroxide solution (48.75 mmol) (1.50 mL) and stirred at 0 ° C for one hour. and the reaction is stopped by the addition of 50 ml of 1.0 M aqueous sodium sulfate solution (6.3 g). The tetrahydrofuran was then removed in vacuo and the pH of the resulting solution was adjusted to 0 with 1N hydrochloric acid at 0 ° C. THE

35. The organic materials are then isolated by extraction with 200 ml of ethyl acetate twice and then dried over magnesium sulfate and concentrated in vacuo. The resulting clear oil was purified by column chromatography using ethyl acetate: hexane / acetic acid (50: 50: 1) as the eluent. The title compound was obtained as a white solid. The solid was dried under high vacuum to give 0.78 g (2.60 mmol, 80%) of a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 9.60 (bs, 1H), 7.25-7.10 (m, 4H), 7.10-6.95 (m, 4H), 4.50 ( d, 2H, J = 8.6Hz) ppm.

G. (2S) -2-Amino-3,3-bis (4-fluorophenyl) propionic acid

To 250 ml of ethyl acetate containing 1.5 g (4.95 mmol) of Compound F was added 10% by weight palladium on charcoal, and the reaction mixture was hydrogenated under 1 atmosphere of hydrogen for 12 hours. The resulting heterogeneous mixture was filtered through a pad of Celite (1 g) and the filtrate was concentrated in vacuo. The resulting clear oil was dried under high vacuum to give 1.30 g (4.70 mmol, 95%) of Compound G as a white solid.

1 H-NMR (dg-DMSO) 400 MHz δ 10.2 (broad s, 1H), 7.38-7.27 (m, 4H), 7.08-6.98 (m, 4H), 4, 25 (d, 1H, J = 8.3 Hz), 3.95 (d, 1H, J = 8.3 Hz) ppm.

H. (2S) -2 - [(tert-Butoxycarbonyl) amino] -3,3-bis (4-fluorophenyl) propionic acid

To 150 ml of dichloromethane solution containing 1.30 g (4.69 mmol) of dichloromethane was added triethylamine (2.37 g, 23.4 mmol) and dichloromethane (1.23 g, 5.63 mmol) followed by dichloromethane (12). After stirring for 1 hour, 50 ml of water and 300 ml of dichloromethane are added. The pH of the resulting mixture was adjusted to pH 3 with 1.0 M HCl. After separation of the ethyl acetate phase, drying over magnesium sulfate and evaporation in vacuo was carried out. The resulting clear oil was dried under high vacuum to give 1.68 g (4.4 mmol, 95%) of Compound H as a white solid.

! 1 H-NMR (d 6 -DMSO) 400 MHz δ 12.4 (br s, 1H), 7.35-7.22 (m, 4H), 7.15-6.95 (m, 4H), 10 4 , 78 (t, 1H, J = 8.9 Hz), 4.25 (d, 1H, J = 8.9 Hz), 3.05 (m, 1H), 1.20 (s, 3H), 1 , 15 (s, 6H) ppm.

I. (2S, 4S) -1 - [(2S) -2- (tert-Butoxycarbonyl) amino-3,3-bis (4-fluorophenyl) propanoyl] -4-fluoropyrrolidine-2-carbonitrile ml, 1.0 g To a solution of Compound H in anhydrous dimethylformamide (2.65 mmol) was added HATU (1.0 g, 2.65 mmol) followed by 2, diisopropylethylamine (0.462 mL, 2.65 mmol) followed by 30 min. 0.619 g (2.12 mmol) of (2S, 4S) -4-fluoro-2-36. Pyrrolidinecarbonitrile-4-methylbenzenesulfonate and further 0.37 mL (2.12 mmol) of N, N-diisopropylethylamine. The reaction mixture was stirred at room temperature for 12 hours and then saturated aqueous sodium bicarbonate (100 mL) was added. The resulting resinous mixture was extracted three times with 100 ml of ethyl acetate, and the combined extract was washed with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was removed in vacuo. The resulting clear oil was subjected to silica gel chromatography, eluting with a 4: 1 mixture of hexane and ethyl acetate. The resulting white solid was dried under high vacuum to give Compound I as a white solid (815 mg, 1.72 mmol, 65%).

1 H-NMR (CDCl 3 ) 400 MHz δ 7.38-7.32 (m, 2H), 7.21-7.15 (m, 2H), 7.12-6.98 (m, 4H), 5 , 15 (d, 1H, > 51Hz), 5.03 (d, 1H, > 8.9 Hz, 4.89 (d, 1H, > 11.2 Hz), 4.86 (d, 1H, > 8) , 9 Hz), 4.40 (d, 1H, > 11.2 Hz), 3.83 (ddd, 1H, > 36.8, 12.1, 3.7 Hz), 3.05 (d, 1H ,> 12.2 Hz), 2.62 (t, 1H,> 15.3 Hz), 2.25 (m, 1H), 1.38 (s, 9H) ppm.

J. (2S, 4S) -1 - [(2S) -2-Amino-3,3-bis (4-fluorophenyl) propanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride

To 0.5 g (1.05 mmol) of Compound I was added 10 mL of 1,4-dioxane (4.0 mmol) hydrochloric acid (40 mmol) and after 3 hours 100 mL of diethyl ether. The resulting precipitate was collected by filtration and then dried under high vacuum. Yield: 0.41 g (95%) of compound J as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 8.42 (broad s, 3H), 7.72-7.66 (m, 2H), 7.38-7.32 (m, 2H), 7 , 25-7.19 (m, 2H), 7.06-7.0 (m, 2H), 5.38 (d, 1H, > 51Hz), 4.91 (d, 2H, > 8.8 Hz) ), 4.82 (d, 1H, > 11.3 Hz), 4.41 (d, 1H, > 11.3 Hz), 3.86 (ddd, 1H, > 39.2, 12.4, 3) , 1Hz), 3.45 (q, 1H, > 12.4 Hz), 2.38-2.20 (m, 2H) ppm.

Example 3 (2S, 4S) -1- (2S) -2-amino-5- [4-fluorophenyl] -3,3-dimethylpentanoyl] -4-fluoro-2-pyrrolidinecarbonitrile hydrochloride of formula XVI

A. 4- (4-Fluorophenyl) -2,2-dimethyl-butyl

13.4 g (70.2 mmol), by Knochel, P., et al. Lett., 2, 3285 (2000) to a solution of 4- (4-fluorophenyl) -2,2-dimethylbutanitrile in toluene (300 mL) cooled to -78 ° C was treated with 70.2 mL of 1.5M toluene. DIBAL solution (105.3 mmol) was prepared and, after 2.5 h, a solution of 17.9 g of sodium acetate and 17.9 ml of acetic acid was gradually added from 250 ml of water and 50 ml of tetrahydrofuran. After the addition was complete, Celite branded filter aid and diethyl ether were added to the reaction mixture, and the contents of the vessel were then filled.

-37. Allow to warm to temperature. After stirring for one hour, the heterogeneous reaction mixture was filtered through a pad of Celite filter aid and the filter bed rinsed with diethyl ether and the filtrate washed with water. After drying over magnesium sulfate, the solvent was removed in vacuo and the residual oil was purified by column chromatography eluting with 5% ethyl acetate in hexane. 11.3 g (58.2 mmol, 83%) of Compound A are obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 9.47 (s, 1H), 7.12-7.10 (m, 2H), 7.09-6.93 (m, 2H), 2.51-2 , 47 (m, 2H), 1.77-1.72 (m, 2H), 1.12 (s, 6H) ppm.

B. 5 - (4-Fluorophenyl) -3,3-dimethyl-2 - [(1R) -1-phenyl-2 - [(trimethylsilyl) oxy] ethyl} amino] pentanenitrile 10 250 ml, 9.07 g ( (R) -phenylglycine (6.41 g, 46.8 mmol) was added to a solution of compound A in dichloromethane (46.8 mmol) at room temperature and stirred for 1.5 h at which time it was cooled to 0 ° C. Trimethylsilylcyanide (9.28 g, 93.5 mmol) was added. The resulting yellow solution was then allowed to warm slowly to room temperature overnight, then quenched by the addition of saturated aqueous sodium hydrogen sulfate solution and the organic layer was separated. The organic layer was then washed with water, dried over magnesium sulfate, decolorized with activated carbon and filtered through a Celite filter aid. The resulting yellow oil was purified by column chromatography using hexane / ethyl acetate 9: 1 as eluent. 11.9 g (28.9 mmol, 62% of compound B were obtained as diastereomers)

As a 6: 1 mixture.

Larger diastereomer: Tl-NMR (CDCl3) 400MHz δ 7.38-7.29 (m, 5H), 7.11-7.07 (m, 2H), 6.98-6.93 (m, 2H ), 4.03 (dd, 1H, J = 9.95, 3.8 Hz), 3.68 (m, 1H), 3.52 (t, 1H, J = 10.2 Hz), 3.06 (d, 1H), J = 13.4 Hz), 2.44-2.34 (m, 3H), 1.73-1.65 (m, 2H), 1.11 (s, 3H), 1 , 09 (s, 3H), 0.14 (s, 9H) ppm.

C. 5- (4-Fluorophenyl) -2 - {[(1R) -2-hydroxy-1-phenylethyl] amino} -3,3-dimethylpentanenitrile

Potassium fluoride (16.7 g, 287.6 mmol) was added to a methanol solution of 300 mL (11.85 g, 28.8 mmol) of compound B at room temperature and the mixture was stirred for one and a half hours during which time most of the methanol was added. was removed in vacuo. Dichloromethane and water were added to the residue, and the organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The resulting oil was purified by column chromatography using hexane / ethyl acetate (4: 1) as eluant to give Compound C (8.86 g, 26.1 mmol, 90%) as a 6: 1 mixture of diastereomers.

• ·· * · · ·

-38Nagyobb diastereomer: ¹H-NMR (CDC1 3) 400MHz δ 7.38-7.30 (m, 5H), 7.10-7.06 (m, 2H), 6.97-6.92 (m , 2H), 4.06 (dd, 1H,> 9.5, 4.0 Hz), 3.79 (m, 1H), 3.58 (m, 1H), 3.07 (d, 1H, > 12.5 Hz), 2.43-2.30 (m, 3H), 1.95 (dd, 1H, > 7.8, 4.1 Hz), 1.74-1.64 (m, 2H), 1.11 (s, 3H), 1.09 (s, 3H) ppm.

D. A mixture of 5- (4-fluorophenyl) -3,3-dimethyl-2 - [((E) -phenylmethylidene] amino} pentanenitrile in 1 ml of dichloromethane and 4 ml of methanol C was 494 mg (1.45 mmol). Anhydrous acetic acid (838 mg, 1.89 mmol) was added to the solution containing the compound (0) and cooled to 0 ° C, and the resulting mixture was stirred at room temperature overnight, during which time it warmed to ambient temperature. To this reaction mixture was then added 20 ml of phosphate buffer pH 7.2, and after 30 minutes, the cloudy reaction mixture was filtered through a pad of Celite filter aid and the filter layer rinsed thoroughly with dichloromethane. Water was added to the filtrate and the organic phase was separated. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The resulting oil was purified by column chromatography using hexane / ethyl acetate 9: 1 as the eluent to give 270 mg (0.88 mmol, 60%) of Compound D.

1 H-NMR (CDCl 3 ) 400 MHz δ 8.50 (d, 1H, > 1.4 Hz), 7.81-7.80 (d, 2H, > 6.6 Hz), 7.54-7 , 43 (m, 3H), 7.17-7.13 (m, 3H), 6.99-6.94 (m, 2H), 4.48 (s, 1H), 2.68-2.64 (m, 2H), 1.81-1.74 (m, 2H), 1.19 (s, 3H), 1.15 (s, 3H) ppm.

E. 5- (4-Fluorophenyl) -3,3-dimethylorvaline hydrochloride

7 ml of concentrated hydrochloric acid was added to a reaction vessel containing 268 mg (0.87 mmol) of Compound D, and the resulting solution was refluxed for 18 hours. The reaction mixture was then cooled and extracted with diethyl ether. The solvent was removed from the aqueous phase in vacuo and the residual oily solid was dissolved in a mixture of diethyl ether and methanol. The resulting solution was decolorized with charcoal and then filtered and concentrated in vacuo. The resulting residue was triturated with diethyl ether and the solvent removed in vacuo. Thus, 180 mg (0.65 mmol, 75%) of Compound E is obtained as an oily solid which is used in crude form.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.25-7.20 (m, 2H), 7.01-6.95 (m, 2H), 4.45 (br s, 1H), 2, 67-2.63 (m, 2H), 1.76-1.72 (m, 2H), 1.22-1.13 (m, 6H).

F. N- (Tert-Butoxycarbonyl) -5- (4-fluorophenyl) -3,3-dimethylnorvaline ml of dioxane solution containing 180 mg (0.65 mmol) of Compound E was added at room temperature to 2.5 mL of 2 M sodium hydroxide solution followed by «·

*

To this reaction mixture was added di-tert-butyldicarbonate (284 mg, 1.34 mmol). After stirring overnight, the reaction mixture was acidified with 1.0 M aqueous hydrochloric acid, and the organic components were extracted twice with ethyl acetate. The combined extract was dried over magnesium sulfate and concentrated in vacuo. The resulting oil was purified by column chromatography eluting with 5% methanol in dichloromethane. 76 mg (0.22 mmol, 34%) of compound F are obtained. 1 H-NMR (d 4 -MeOH) 400 MHz δ 7.18-7.15 (m, 2H), 6.96-6.92 (m, 2H), 6.62 (d, 1H,

J = 9.3 Hz), 4.18 (d, 1H, J = 9.5 Hz), 2.65-2.58 (m, 2H), 1.62-1.53 (m, 2H), 1.44 (s, 9H), 1.05 (s, 3H), 1.01 (s, 3H) ppm.

G. Tert-Butyl (1S) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidinyl] carbonyl} -4- (4-fluorophenyl) -2,2-dimethylbutylcarbamate ml, 172 mg (0 , 51 mmol of diisopropylethylamine (98 mg, 0.76 mmol) and HATU (213 mg, 0.56 mmol) were added to a dimethylformamide solution containing Compound F at room temperature. After 15 minutes, (2S, 4S) -4-fluoro-2-trifluoromethyl-4-methylbenzenesulfonate (153 mg, 0.53 mmol) was added and diisopropylethylamine (68 mg, 0.53 mmol) was added in 2 mL of dimethylformamide. The reaction mixture was stirred overnight and then poured into ethyl acetate. The organic components were washed twice with water followed by saturated aqueous sodium bicarbonate and saturated aqueous sodium hydrogen sulfate. After drying over magnesium sulfate, the solvent was removed in vacuo and the residual yellow oil was purified by column chromatography using 2% methanol in methylene chloride as eluant. Thus, 147 mg of Compound G is obtained which is further purified by semi-preparative HPLC. 80 mg of compound G are obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.15-7.12 (m, 2H), 6.96-6.92 (m, 2H), 5.40 (broad d,

1H, J = 52.0 Hz), 5.18 (d, 1H, J = 9.7 Hz), 5.04 (d, 1H, J = 9.3 Hz), 4.31 (d, 1H, > 9.9 Hz), 4.11 (s, 1H), 4.03 (m, 1H), 2.70-2.52 (m, 3H), 2.33 (m, 1H), 1.64 1.60 (m, 2H), 1.41 (s, 9H), 1.11 (s, 3H), 1.09 (s, 3H) ppm.

H. (2S, 4S) -1 - [(2S) -2-Ammo-5- (4-fluorophenyl) -3,3-dimethylpentanoyl] -4-fluoro-2-pyrrolidinecarbonitrile hydrochloride

To 4 ml of dichloromethane solution containing 80 mg (0.18 mmol) of Compound G are added 71 µl of trifluoroacetic acid (5 equivalents). After 30 minutes, an additional 5 equivalents of trifluoroacetic acid was added followed by an additional 10 equivalents after one hour. After stirring for 3.5 hours, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate. THE *· · "

The organic components were washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and the solvent removed in vacuo. To the residual oil was first added 1.5 ml of dioxane and then 2.0 ml of 4M hydrochloric acid in dioxane. The solvent was removed and diethyl ether was added to the residue. The precipitate was collected by vacuum filtration at 40 mg (0.11 mmol, 60%) of

Compound H is obtained.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.25-7.22 (m, 2H), 7.00-6.95 (m, 2H), 5.46 (broad d, 1H, J = 51 , 1 Hz), 5.09 (d, 1H, J = 9.4 Hz), 4.12 (m, 1H), 4.03 (s, 1H), 3.90 (ddd, 1H, J = 37, 6, 12.7, 3.0 Hz), 2.68-2.44 (m, 4H), 1.78-1.73 (m, 2H), 1.21 (s, 6H) ppm.

Example 4 (2S, 4R) -1 - [(2S) -2-amino-4- [4-fluorophenyl] -3,3-dimethylbutanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XVII

A. To a toluene solution cooled to 0 DEG C., containing 5.0 g (72.3 mmol) of isobutyronitrile in toluene at 0 DEG C., was added with toluene (0.5 M) in toluene (3- (4-fluorophenyl) -2,2-dimethylpropylmethyl). KHMDS solution (76.0 mmol) followed by 4-fluorobenzylbromide (14.4 g, 76.0 mmol) over 15 min. The reaction mixture was then slowly warmed to ambient temperature overnight and then quenched by the addition of water. The organic components were extracted with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogen sulfate solution, dried over magnesium sulfate and concentrated in vacuo. The resulting yellow oil was purified by column chromatography using 5% ethyl acetate / hexane as eluant to give Compound A (10.5 g, 56.8 mmol, 79%).

! 1 H-NMR (CDCl 3 ) 400 MHz δ 7.25-7.22 (m, 2H), 7.05-7.00 (m, 2H), 2.78 (s, 2H),

I, 34 (s, 6H) ppm.

B. 3- (4-Fluorophenyl) -2,2-dimethylpropanol

To 100 ml of toluene solution cooled to -78 ° C containing 10.0 g (56.5 mmol) of Compound A was added 56.5 ml of a 1.5 mol / L DIBAL solution (84.7 mmol). and after 2.5 hours, a solution of 14.3 g of sodium acetate and 14.3 ml of acetic acid in 160 ml of water and 40 ml of tetrahydrofuran. Thereafter, a Celite filter aid was added and the mixture was stirred for one hour and diethyl ether was added. The reaction mixture was then filtered through a Celite filter aid and rinsed thoroughly with diethyl ether. The filtrate was washed twice with water and then with a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified by column chromatography, eluting with 5 vol.

Using -41% ethyl acetate in hexane. Thus, 9.23 g (51.3 mmol, 91%) of Compound B are obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 9.56 (s, 1H), 7.06-7.03 (m, 2H), 6.97-6.93 (m, 2H), 2.75 (s , 2H), 1.04 (s, 6H) ppm.

C. To a methanol solution of 2-Ammo-4- (4-fluorophenyl) -3,3-dimethylbutanitrile (ml) containing 5.0 g (27.8 mmol) of Compound B was added 3.8 ml of a 30% ammonium hydroxide solution. Potassium cyanide (1.9 g, 29.2 mmol) and water (15 mL) were added to the reaction mixture, followed by ammonium chloride (1.64 g, 30.6 mmol) at room temperature, which was then stirred overnight and then at 70 ° C. After 5 hours, the reaction mixture was cooled, diluted with ethyl acetate and washed twice with water and then with a saturated aqueous solution of sodium bicarbonate, after drying over magnesium sulfate, the solvent was removed in vacuo and the residual yellow oil was purified by column chromatography eluting with hexane and \ t ethyl acetate (1: 1) to give Compound C (3.69 g, 17.9 mmol, 64%).

1 H-NMR (CDCl 3) 400 MHz δ 7.17-7.13 (m, 2H), 7.00-6.95 (m, 2H), 3.33 (t, 1H, J = 8.5 Hz) ), 2.80 (d, 1H, J = 13.4 Hz), 2.61 (d, 1H, J = 13.4 Hz), 1.58-1.57 (m, 2H), 1.03 (s, 3H), 1.02 (s, 3H) ppm.

D. 2-Amino-4- (4-fluorophenyl) -3,3-dimethylbutyric acid

Concentrated hydrochloric acid (80 mL) was added to a reaction vessel containing 3.00 g (17.9 mmol) of Compound C, and the resulting mixture was refluxed for 24 hours. The heterogeneous reaction mixture was then cooled in an ice bath and the precipitated white solid was collected by vacuum filtration. After drying under high vacuum, 4.06 g of a white powder are obtained. This material is used in crude form in the next reaction step.

Ε. To 2 - [(tert-butoxycarbonylamino) -4- (4-fluorophenyl) -3,3-dimethylbutyric acid, 5 ml of water and 9.6 ml of water are added to a dioxane solution of compound D (2.0 g, 7.6 mmol). To this reaction mixture was added di-tert-butyldicarbonate (2.34 g, 10.7 mmol) and stirred overnight to give a heterogeneous reaction mixture with saturated aqueous sodium bicarbonate. The diethyl ether layer was then washed with a saturated aqueous solution of sodium hydrogencarbonate and then the combined aqueous phases were acidified with 1.0 M aqueous hydrochloric acid and extracted twice with ethyl acetate. · »« ·

-42. the solvent was removed in vacuo. 928 mg (2.86 mmol, 37%) of compound E are obtained.

1 H-NMR (δ-MeOH) 400 MHz δ 7.21-7.18 (m, 2H), 7.00-6.95 (m, 2H) 6.74 (d, 1H, > 9.0 Hz) , 3.98 (d, 1H, J = 9.0 Hz), 2.68 (d, 1H, > 13.4 Hz), 2.62 (d, 1H, > 13.3 Hz), 1.45 (broad s, 9H), 0.93 (s, 3H), 0.92 (s, 3H) ppm.

F. Tert-Butyl (1S) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -3- (4-fluorophenyl) -2,2-dimethylpropylcarbamate, m.p. Diisopropylethylamine (406 mg, 3.14 mmol) and HATU (1.14 g, 3.00 mmol) were added to a dimethylformamide solution containing E (mg, 2.86 mmol) at room temperature. After 30 minutes, (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (857 mg, 3.00 mmol) was added and diisopropylethylamine (388 mg, 3.00 mmol) was added in 13 mL of dimethylformamide. After stirring overnight, the reaction mixture was poured into ethyl acetate, and the resulting mixture was washed twice with water, then with saturated aqueous sodium hydrogen carbonate solution and finally with 1.0 M aqueous hydrochloric acid. After drying over magnesium sulfate, the solvent was removed in vacuo and the residual oil was purified by column chromatography using hexane, ethyl acetate and dichloromethane (5: 4: 1) as eluent. Thus, 273 mg (0.65 mmol, low Rf) of (S) -diastereomer can be obtained as determined by vibrational circular dichroism and 226 mg of a mixture of (R) -diastereomer and an unknown contamination. In the following, the (S) -diastereomer is utilized.

Ή NMR (CDC1 3) 400MHz δ 7.15-7.11 (m, 2H), 7.01-6.96 (m, 2H), 5.32 (dt, 1H,> 51.3, 3 , 3 Hz), 5.20 (d, 1H, > 9.7 Hz), 5.01 (d, 1H, > 9.3 Hz), 4.16 (d, 1H, > 10.1 Hz), 3 91 (m, 1H), 3.68 (dd, 1H,> 23.6, 12.1 Hz), 2.72-2.56 (m, 2H), 2.30 (m, 1H), 1 , 43 (s, 9H), 1.08 (s, 3H), 0.95 (s, 3H) ppm.

G. (2S, 4R) -1 - [(2S) -2-Amino-4- (4-fluorophenyl) -3,3-dimethylbutanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride ml, 242 mg (0, Trifluoroacetic acid (443 µl, 10 equivalents) was added to a solution of compound F containing dichloromethane (58 mmol) at room temperature, followed by addition of an additional 10 equivalents of trifluoroacetic acid. After stirring for a total of three hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and the organic components were extracted with ethyl acetate, the extract was dried over magnesium sulfate and the solvent removed in vacuo. The residual oil was dissolved in dioxane (4 ml), and 4 ml of 4M hydrochloric acid in dioxane was added to the resulting solution. The * ··· · ** r «

The solvent was then removed in vacuo and triturated with the appropriate diethyl ether. The solid thus obtained was isolated by vacuum filtration. 175 mg (0.46 mmol, 79%) of compound G are obtained.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.22-7.19 (m, 2H), 7.08-7.04 (m, 2H), 5.43 (broad 5 d, 1H,> 51.1 Hz), 5.09 (d, 1H,> 9.5 Hz), 4.05 (s, 1H), 3.97-3.74 (m, 2H), 2.82 (d, 1H, > 13.4

Hz), 2.72 (d, 1H, 3 = 13.2 Hz), 2.64-2.39 (m, 2H), 1.07 (s, 3H), 1.00 (s, 3H) ppm .

Example 5 (2S, 4S) -1 - {(2RJ-2-amino-3 - [(4-methoxybenzyl) thio] -3-methylbutanoyl) -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XVIII

A. Tert-Butyl (1R) - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2 - [(4-methoxybenzyl) thio] -2-methylpropylcarbamate ml To a solution of (2R) -2 - [(tert-butoxycarbonyl) amino] -3 - [(4-methoxybenzyl) thio] -3-methylbutyric acid in dimethylformamide (2.0 g, 5.41 mmol, 1.2 eq) 1.06 ml (6.09 mmol, 1.35 eq.) of Ν-diisopropylethylamine was added followed by 2.9 g (7.67 mmol, 1.7 eq. The amber solution thus obtained was stirred at room temperature for 20 minutes, and then with stirring (1.29 g, 4.51 mmol, 1.0 eq.) Of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and 864 μ4. (4.96 mmol, 1.0 equiv) of a solution of N, N-diisopropylethylamine in 12 mL of dimethylformamide. The reaction mixture was then stirred at room temperature for 18 hours and then quenched by the addition of about 50 mL of saturated aqueous sodium bicarbonate solution. The resulting cloudy mixture was then poured into water (about 100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed twice with water and once with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting amber oil was purified by flash chromatography eluting with hexane and ethyl acetate.

Using a 1: 1 mixture. 1.96 g (4.23 mmol, 78%) of compound A are obtained as a white foam.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.29 (d, 2H, J = 8.8 Hz), 6.83 (d, 2H,> 8.6 Hz), 5.48 (d, 1H,> 51.4 Hz), 5.43 (d, 1H, > 9.2 Hz), 5.04 (d, 1H, > 9.3 Hz), 4.38 (d, 1H, > 8.9 Hz) 4.27 (m, 1H), 4.04 (m, 1H), 3.80 (s, 2H), 3.77 (s, 3H), 2.72 (t, 1H, 15.5 Hz) , 2.37 (m, 1H), 1.4730, 1.41 (m, 14H) ppm.

x

-44. B. (2S, 4S) -1- {(2R) -2-Amino-3 - [(4-methoxybenzyl) thio] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride ml, containing 8 ml of trifluoroacetic acid Compound A (1.2 g, 2.58 mmol, 1.0 eq.) was added to the dichloromethane solution and the resulting pale yellow solution was stirred at room temperature for 2 hours. The solvent was then removed in vacuo and the resulting trifluoroacetate was converted to the corresponding free base by the addition of saturated aqueous sodium bicarbonate solution. The resulting aqueous phase was then extracted twice with ethyl acetate, and the combined organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting off-white foam was purified by flash chromatography eluting with dichloromethane containing 5% methanol (0.1% ammonia). White foam was obtained (897 mg, 2.45 mmol, 95%). To prepare the corresponding hydrochloride salt, this free base is taken up in diethyl ether and acetone is added until the total amount of solids is dissolved. Then, a 2.0 mol / L salt acid solution in diethyl ether was added dropwise until no more precipitate formed. The precipitate was filtered off and washed several times with diethyl ether. The salt thus obtained is dried under high vacuum.

1 H-NMR (D 2 O) 400 MHz δ 7.31 (d, 2H, J = 8.6 Hz), 6.88 (d, 2H, J = 8.5 Hz), 5.49 (d, 1H, J = 50.5 Hz), 5.00 (d, 1H, J = 9.8 Hz), 4.02-3.52 (m, 8H), 2.65 (t, 1H, J = 15 , 7 Hz), 2.40 (m, 1H), 1.44 (s, 3H), 1.31 (s, 3H) ppm.

Example 6 (2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(3-phenylpropyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XIX

A. Methyl (2R) -2-amino-3-mercapto-3-methylbutanoate was added to a methanol solution of L-penicillamine (1.14 M), 3.0 g (20.11 mmol, 1.0 eq.) Of L-penicillamine. Thionyl chloride (1.5 mL, 20.7 mmol, 1.03 eq.) Was added and the reaction mixture was refluxed for 18 hours and then the solvent was removed in vacuo. The resulting pure semi-solid was used without further purification in the next step. Volume 3.28 g (20.1 mmol, 100%).

B. Methyl- (2R) -2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylbutanoate

To a solution of 60 ml of 3.28 g (20.1 mmol, 1.0 eq.) Of dichloromethane in a solution of dichloromethane was added 4.48 g (20.5 mmol, 1.02 equivalents) of di-tert-butyldicarbonate and 7.0 ml of dichloromethane. (50.3 mmol, 2.5 equivalents) of triethylamine, followed by stirring at room temperature for 18 hours. The solvent was removed in vacuo and the residue was taken up in diethyl ether. The insoluble white solid was filtered off, and the filtrate was filtered off.

- washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The resulting white solid was used in the next step without further purification. An amount of product (5.01 g, 19.02 mmol, 95%) was isolated.

1 H-NMR (d 4 -MeOH) 400 MHz δ 4.26 (m, 1H), 3.72 (s, 3H), 1.44-1.42 (m, 15H) ppm.

C. Methyl- (2R) -2 - [(tert-butoxycarbonyl) amino] -3-methyl-3 - [(3-phenylpropyl) thio] butanoate ml, 346 mg (1.31 mmol, 1.0 eq) B Sodium tert-butylate (138 mg, 1.44 mmol, 1.1 eq.) was added to the acetonitrile solution containing Compound # 1 and the resulting pale yellow mixture was stirred at room temperature for 10 minutes. Then, 1-bromo-3-phenylpropane (219 μΐ, 1.44 mmol, 1.1 eq.) Was added to the reaction mixture and the resulting solution was stirred at room temperature for 18 hours. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and poured into water. The aqueous mixture was extracted twice with ethyl acetate, and the combined extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using a 2: 1 mixture of hexane and ethyl acetate as the mobile phase. 376 mg (0.988 mmol, 76%) of the title compound are obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.30-7.16 (m, 5H), 5.38 (d, 1H, J = 8.8 Hz), 4.29 (d, 1H, J = 9 , 0 Hz), 3.71 (s, 3H), 2.72 (t, 2H, J = 7.4 Hz), 2.58-2.51 (m, 2H), 1.89-1.82 (m, 2H), 1.44 (s, 9H), 1.36 (d, 6H, J = 8.8Hz) ppm.

D. (2R) -2 - [(tert-Butoxycarbonyl) amino] -3-methyl-3 - [(3-phenylpropyl) thio] butyric acid

To a solution of compound C (376 mg, 0.988 mmol, 1.0 eq.) In dioxane (7.5 mL, 2.5 mL) was added lithium hydroxide monohydrate (207 mg, 4.94 mmol, 5.0 eq. The resulting heterogeneous reaction mixture was stirred at room temperature for 18 hours. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and then poured into water. The aqueous mixture was extracted twice with ethyl acetate, and the combined extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using a 1: 1 by volume mixture of hexane and ethyl acetate containing 0.1% acetic acid as the mobile phase. 230 mg (0.626 mmol, 64%) of the title compound are obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.31-7.16 (m, 5H), 5.51 (d, 1H, J-9.5 Hz), 4.33 (d, 1H, J = 9 , 5 15 Hz), 3.41 (t, 2H, J = 6.8 Hz), 2.79 (t, 2H, J-7.3 Hz), 2.20-2.13 (m, 2H) , 1.47-1.44 (m,

15H) ppm.

'Ri *

-46 »E. Tert-Butyl- (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - [(3-phenylpropyl) Thio] propylcarbamate (DMF) containing 230 mg (0.626 mmol, 1.2 equiv.) of Compound D was treated with 123 µΐ (0.705 mmol, 1.35 equivalents) of N, N-diisopropylethylamine and then 337 mg (0.887 mmol, 1.7 mmol). equivalent) HATU. The amber solution thus obtained was stirred at room temperature for 20 minutes, and then, with stirring, 149 mg (0.522 mmol, 1.0 eq.) Of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and 100 μΐ (0.574 mmol) were added. , 1.1 equivalents) of a solution of N, N-diisopropylethylamine in 2 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours and then quenched by the addition of about 5 mL of saturated aqueous sodium bicarbonate solution. The resulting turbid reaction mixture was poured into water (about 20 mL) and extracted three times with ethyl acetate (10 mL). The combined organic extracts were washed twice with water and once with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting amber oil was purified by flash chromatography using a 1: 1 mixture of hexane and ethyl acetate as the mobile phase. 190 mg (0.411 mmol, 79%) of compound E are obtained as a white foam.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.28-7.17 (m, 5H), 5.46 (d, 1H, J = 51.4 Hz), 5.37 (d, 1H, J = 9 , 0 Hz), 5.00 (d, 1H,> 9.3 Hz), 4.38-4.29 (m, 2H), 4.01 (m, 1H), 2.77-2.58 ( m, 5H), 2.35 (m, 1H), 1.92-1.80 (m, 2H), 1.44-1.34 (m, 15H) ppm.

F. (2S, 4S) -1 - {(2R) -2-Amino-3-methyl-3 - [(3-phenylpropyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile, dichloromethane containing 1 ml of trifluoroacetic acid Compound E (190 mg, 0.411 mmol, 1.0 eq.) was added to the solution, and the resulting pale yellow solution was stirred at room temperature for two hours. The solvent was then removed in vacuo and the resulting trifluoroacetate salt was converted to the corresponding free base by addition of saturated aqueous sodium bicarbonate solution and then extracted twice with ethyl acetate. The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting off-white foam was purified by flash chromatography using dichloromethane containing 5% by volume of methanol (containing 0.1% ammonia) as the mobile phase. 134 mg (0.389 mmol, 94%) of a white foam were obtained. To obtain the corresponding hydrochloride salt, the free base obtained is taken up in diethyl ether and acetone is added until the total amount of solids is dissolved in solution. Addition of 2 M hydrochloric acid in diethyl ether dropwise until · · *

-47 * no more precipitation is formed. The precipitate was then filtered off and washed several times with diethyl ether. The salt thus obtained is dried under high vacuum.

1 H-NMR (D 2 O) 400 MHz δ 7.23-7.11 (m, 5H), 5.46 (d, 1H,> 50.4 Hz), 4.98 (d, 1H,> 9 1 Hz), 4.04-3.96 (m, 2H), 3.68 (m, 1H), 2.62-2.30 (m, 6H), 1.78-1.71 (m, 2H ), 1.29 (d,

6H, J = 5.7 Hz) ppm.

Example 7 (2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(2-phenylethyl) thio] butanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride (XX)

A. Methyl- (2R) -2 - [(tert-butoxycarbonyl) amino] -3-methyl-3 - [(2-phenylethyl) thio] butanoate

Methyl (2R) -2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylbutanoate, prepared as described above, 50 ml, 1.26 g (4.78 mmol, 1.0 eq) To the solution was added sodium tert-butylate (597 mg, 6.21 mmol, 1.3 eq.), and the resulting pale yellow reaction mixture was stirred at room temperature for 10 minutes. Then, 718 µl (5.26 mmol, 1.1 eq.) Of (2-bromomethyl) benzene was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 18 hours. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and the reaction mixture was poured into water and the aqueous mixture was extracted twice with ethyl acetate. The combined extract was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography using a 5: 1 mixture of hexane and ethyl acetate as the mobile phase. Yield 761 mg (2.07 mmol, 45%) of Compound A.

1 H-NMR (CDCl 3) 400 MHz δ 7.31-7.19 (m, 5H), 5.36 (d, 1H,> 9.0 Hz), 4.33 (d, 1H,> 9.1 Hz) , 3.71 (s, 3H), 2.83-2.78 (m, 4H), 1.44 (s, 9H), 1.36 (d, 6H, > 7.5 Hz) ppm.

B. (2R) -2 - [(Tert-Butoxycarbonyl) amino] -3-methyl-3 - [(2-phenylethyl) thio] butyric acid in a mixture of ml of dioxane and 7 ml of water, 761 mg (2.07 mmol, 1 , 0 equivalent) A.

lithium hydroxide monohydrate (434 mg, 10.35 mmol, 5.0 eq.) was added to the solution containing the compound, and the resulting heterogeneous reaction mixture was stirred at room temperature for 18 hours. The reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and then poured into water. The aqueous mixture was extracted twice with ethyl acetate, and the combined extract was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography using a 1: 1 by volume mixture of hexane and ethyl acetate containing 0.1% acetic acid as the mobile phase. This gave 502 mg (1.42 mmol, 69%) of Compound B.

• ·· · ·

-48'H NMR (CDC1 3) 400MHz δ 7.31-7.18 (m, 5H), 5.42 (1H, d,> 8.3 Hz), 4.32 (br s, 1H) , 2.87-2.81 (m, 4H), 1.44 (s, 9H), 1.40 (s, 3H), 1.36 (s, 3H) ppm.

C. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - [(2-phenylethyl) thio] propylcarbamate

To 10 ml of dimethylformamide solution containing 502 mg (1.42 mmol, 1.2 equivalents) of Compound B was added 278 µΐ (1.59 mmol, 1.35 equivalents) of Ν-diisopropylethylamine and 764 mg (2.01 mmol). , 1.7 equivalent) HATU. The amber solution thus obtained was stirred at room temperature for 20 minutes and then, with stirring, 338 mg (1.18 mmol, 1.0 eq.) Of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and 226 μΐ were added. 1.3 mmol, 1.1 equivalents) of a solution of N, N-diisopropylethylam in 5 mL of dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours and quenched by the addition of about 5 mL of saturated aqueous sodium bicarbonate solution. The resulting turbid reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed twice with water and once with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The amber oil thus obtained was subjected to flash chromatography using a 1: 1 mixture of hexane and ethyl acetate as mobile phase. Thus, 371 mg (0.803 mmol, 80%) of Compound C is obtained as a white foam.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.30-7.20 (m, 5H), 5.46 (d, 1H,> 51.0 Hz), 5.38 (d,

1H, > 9.2 Hz), 5.01 (d, 1H, > 9.4 Hz), 4.36-4.25 (m, 2H), 4.06 (m, 1H), 2.87- 2.84 (m, 4H),

2.70 (t, 1H, J = 15.0 Hz), 2.35 (m, 1H), 1.41-1.37 (m, 15H) ppm.

D. (2S, 4S) -1 - {(2R) -2-Amino-3-methyl-3 - [(2-phenylethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile, dichloromethane containing 2 ml of trifluoroacetic acid Compound C (361 mg, 0.803 mmol, 1.0 eq) was added to the solution, and the resulting pale yellow solution was stirred at room temperature for 2 hours. The solvent was then removed in vacuo and the resulting trifluoroacetate was converted to the corresponding free base by the addition of saturated aqueous sodium bicarbonate solution and then the aqueous phase extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The resulting off-white foam foam was purified by flash chromatography using dichloromethane containing 5% methanol (containing 0.1% ammonia) as the mobile phase. This gave 223 mg (0.638 mmol, 80%) of a white foam. To prepare the corresponding hydrochloride salt, the free base is taken up in diethyl ether and then added

Acetone is added to the solution until all solids are dissolved. 2N HCl in diethyl ether was then added dropwise until no more precipitate had formed. The precipitate was then filtered off and washed several times with diethyl ether. Finally, the salt thus obtained is dried under high vacuum.

1 H-NMR (D 2 O) 400 MHz δ 7.20-7.09 (m, 5H), 5.43 (d, 1H, J = 50.5 Hz), 4.94 (d, 1H,

J = 9.5 Hz), 4.13 (m, 1H), 3.89 (s, 1H), 3.71 (m, 1H), 2.84-2.70 (m, 4H), 2, 59 (t, 1H, J = 15.7 Hz), 2.37 (m, 1H), 1.28 (s, 3H), 1.22 (s, 3H) ppm.

Example 8 (2S, 4S) -1 - ((2R) -2-amino-3 - {([3- (4-fluorophenyl) propylthio] -3-methylbutanoyl) -4-fluoropyrrolidin-2-yl (XXI) -karbonitriI hydrochloride

A. 3- (4-Fluorophenyl) propam-1-ol

200 ml of a 1M solution of lithium aluminum hydride (0.2 mol) in diethyl ether (200 ml) were added over a period of half an hour to a solution of 200 ml of tetrahydrofuran in 33.6 g (0.2 mole) of propionic acid. the reaction mixture was stirred at room temperature for 18 h. The reaction is then quenched by slow addition of water and the aqueous phase is extracted with diethyl ether. The combined organic extract was dried over magnesium sulfate and concentrated in vacuo. The resulting oil was used without further purification in the next step to give 31.4 g (0.2 mol, 100%) of Compound A.

B. 1- (3-Chloropropyl) -4-fluorobenzene

300 ml of dichloromethane solution containing 31.4 g (0.2 mol) of Compound A are added

Dichlorotriphenylphosphorane (110 g, 0.33 mol) was added and the reaction mixture was stirred at room temperature for 20 minutes and then concentrated in vacuo. To the residue was added about 200 ml of hexane and the resulting heterogeneous mixture was stirred at room temperature for 30 minutes. The insoluble solid was then filtered off and washed with hexane. The filtrate was concentrated in vacuo and the resulting oil was used in the next step without further purification. 33.3 g (0.193 mol, 96%) of Compound B are obtained.

C. Methyl (2R) -2 - [(tert-butoxycarbonyl) amino] -3 - {[3- (4-fluorophenyl) propyl] thio} -3-methylbutanoate, 1.51 g (5.73 mmol, To a solution of (2R) -2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylbutanoate (1.0 eq.) Was added 716 mg (7.45 mmol,

1.3 equivalents) of sodium tert-butylate and the resulting pale yellow mixture was stirred at room temperature for 10 minutes. 1.09 g (6.3 mmol, 1.1 eq.) Of 1- (3-chloropropyl) -4-fluorobenzene as described in Step B above were then added to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hours and then quenched by the addition of saturated aqueous ammonium chloride solution. The reaction mixture was poured into water

And then the aqueous mixture was extracted twice with ethyl acetate. The combined extract was dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography using a 5: 1 by volume mixture of hexane and ethyl acetate as the mobile phase. This gave 700 mg (1.75 mmol, 31%) of Compound C.

Iff H NMR (CDC1 3) 400MHz δ 7.14-7.10 (m, 2H), 6.98-6.93 (m, 2H), 5.36 (d, 1H,

J = 9.1 Hz), 4.29 (d, 1H, J = 9.2 Hz), 3.71 (s, 3H), 2.68 (t, 2H, J = 7.4 Hz), 2, 56-2.49 (m, 2H), 1.86-1.79 (m, 2H), 1.43 (s, 9H), 1.35 (d, 6H, J = 6.8 Hz) ppm.

D. (2R) -2 - [(Tert-Butoxycarbonyl) amino] -3 - {[3- (4-fluorophenyl) propyl] thio} -3-methylbutyric acid in dioxane and 7 ml of water, 700 mg (1, To a solution of Compound C (75 mmol, 1.0 eq.) Was added lithium hydroxide monohydrate (367 mg, 8.75 mmol, 5.0 eq.) And the resulting heterogeneous reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and the reaction mixture was poured into water and the aqueous mixture extracted twice with ethyl acetate. The combined extract was dried over magnesium sulfate and concentrated in vacuo. The ma15 radicals were purified by flash chromatography using a 1: 1 by volume mixture of hexane and ethyl acetate containing 0.1% acetic acid as the mobile phase. 512 mg (1.33 mmol, 76%) of compound D are obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.13-7.10 (m, 2H), 6.99-6.93 (m, 2H), 5.41 (d, 1H, J = 8, 1 Hz) 4.29 (broad s, 1H), 2.68-2.55 (m, 4H), 1.88-1.80 (m, 2H), 1.43 (s, 9H), 1.39 ( and,

3H), 1.36 (s, 3H) 5ppm.

E. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2 - {[3- (4-fluorophenyl) propyl] thio} To a dimethylformamide solution containing -2-methylpropylcarbamate (512 mg, 1.33 mmol, 1.2 equiv.), 261 µΐ (1.5 mmol, 1.35 equivalents) of Ν, diisopropylethylamine was added, followed by

717 mg (1.89 mmol, 1.7 equivalents) of HATU. The amber solution thus obtained was stirred at room temperature for 20 minutes and then, with stirring, 317 mg (1.11 mmol, 1.0 eq.) Of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and 213 μΐ were added. 1.22 mmol, 1.1 equivalents) of a solution of N, N-diisopropylethylamine in 10 mL of dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours and then quenched by the addition of about 5 mL of saturated aqueous sodium bicarbonate solution. The resulting turbid reaction mixture was then poured into water (about 20 mL) and the aqueous mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic extract was washed twice with water and then with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.

-51 is evaporated. The resulting amber oil was purified by flash chromatography using a 1: 1 mixture of hexane and ethyl acetate as the mobile phase. Thus, 420 mg (0.872 mmol, 79%) of Compound E is obtained as a white foam.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.14-7.11 (m, 2H), 6.97-6.92 (m, 2H), 5.47 (d, 1H, 5 J = 50.9) Hz), 5.36 (d, 1H, J = 8.4 Hz), 5.00 (d, 1H, > 9.3 Hz), 4.42-4.32 (m, 2H), 4.01 (m, 1H)

2.74-2.57 (m, 5H), 2.36 (m, 1H), 1.89-1.76 (m, 2H), 1.41-1.37 (m, 15H) ppm.

F. (2S, 4S) -1 - ((2R) -2-Amino-3 - {[3- (4-fluorophenyl) propyl] yl} -3-methylhutanoyl) -4-fluoropyrrolidine-2-carbonitrile ml To a solution of dichloromethane containing 3 ml of trifluoroacetic acid was added 420 mg of 10 (0.872 mmol, 1.0 eq.) Of E, and the resulting pale yellow solution was stirred at room temperature for 2 hours. The solvent was then removed in vacuo and the resulting trifluoroacetate salt was converted to the corresponding free base by addition of saturated aqueous sodium bicarbonate solution and then extracted twice with ethyl acetate. The combined organic extract was dried over sodium sulfate and evaporated in vacuo. The resulting off-white foam was purified by flash chromatography using 5% methanol in dichloromethane (0.1% ammonia) as mobile phase. White foam was obtained (275 mg, 0.721 mmol, 83%). To prepare the hydrochloride salt, this white foam is taken up with diethyl ether and acetone is added until the total amount of solids is dissolved. At this time, 2M hydrochloric acid solution in diethyl ether was added until further precipitate formed. The precipitate was filtered off and washed several times with diethyl ether. The salt thus obtained is dried under high vacuum.

1 H NMR (D 2 O) 400 MHz δ 7.15-7.10 (m, 2H), 6.96-6.90 (m, 2H), 5.48 (d, 1H,> 50.9 Hz) ), 4.99 (d, 1H,> 9.6 Hz), 4.07-3.98 (m, 2H), 3.74 (m, 1H), 2.64-2.32 (m, 6H ), 1.8025 1.68 (m, 2H), 1.30 (d, 6H, J = 6.6Hz) ppm.

Example 9 (2S, 4S) -1 - {(2R) -2-amino-3 - [(4-methoxybenzyl) sulfonyl] -3-methylbutanoyl) -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XXII

A. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2 - [(4-methoxybenzyl) sulfonyl] -2-methylpropylcarbamate ml, 473 mg (1.017 mmol, 1.0 eq.) of tert-butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-ylcarbonyl) as previously described To a chloroform solution of 2 - [(4-methoxybenzyl) thio] -2-methylpropylcarbamate was added 3-chloroperoxybenzoic acid (1.76 g, 10.18 mmol, 1.0 eq), and the resulting mixture was stirred at room temperature for 18 hours. The reaction was then quenched by the addition of nearly 5 ml of a 1M aqueous sodium hydroxide solution and the phases were separated and the organic layer was dried over magnesium sulfate and concentrated in vacuo to give a white, fluffy precipitate which was used in the next step without further purification. This gave 400 mg (0.805 mmol, 80%) of the title compound, i.e., compound A uk.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.35 (d, 2H, J = 8.8 Hz), 6.92 (d, 2H, J-8.8 Hz), 5.48 (d,

1H, J = 51.0 Hz), 5.04 (d, 1H, J = 9.1 Hz), 4.99 (d, 1H, J = 9.4 Hz), 4.34-3.98 (m , 4H), 3.81 (s, 3H), 2.73 (t, 1H, J = 15.0 Hz), 2.39 (m, 1H), 1.58 (s, 3H), 1.53 (s, 3H), 1.42 (s, 9H) ppm.

B. (2S, 4S) - {(2R) -2-Amino-3 - [(4-methoxybenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-10-2-carbonitrile, dichloromethane solution containing 4 ml of trifluoroacetic acid Compound A (400 mg, 0.805 mmol, 1.0 eq) was added and the resulting pale yellow solution was stirred at room temperature for two hours. The solvent was then removed in vacuo and the resulting trifluoroacetate salt was converted to the free base by the addition of saturated aqueous sodium bicarbonate solution 15 and then extracted twice with ethyl acetate. The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting off-white foam was purified by flash chromatography using 5% methanol in dichloromethane (0.1% ammonia) as mobile phase. White foam was obtained (296 mg, 0.745 mmol, 93%). To prepare the corresponding hydrochloride salt, the free base is taken up in diethyl ether and acetone is added until the total amount of solids is dissolved in solution. To this solution was then added dropwise a solution of 2M hydrochloric acid in diethyl ether until no more precipitate had formed. The precipitate was filtered off and washed several times with diethyl ether. Finally, the resulting salt is dried under high vacuum.

1 H-NMR (D 2 O) 400 MHz δ 7.28 (d, 2H, J = 8.8 Hz), 6.92 (d, 2H, J = 8.8 Hz), 5.47 (d,

1H, J = 50.6 Hz), 5.00 (d, 1H, J = 10.0 Hz), 4.66 (s, 1H), 4.51 (s, 2H), 4.05 (m, 1H), 3.81 (m, 1H), 3.69 (s, 3H), 2.64 (t, 1H, J = 15.7 Hz), 2.42 (m, 1H), 1.62 ( s, 3H), 1.48 (s, 3H) ppm.

Example 10 (2S, 4S) -1 - {(2R) -2-amino-3 - [(4-methoxybenzyl) sulfinyl] -3-methylbutanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XXIII

A. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2 - [(4-methoxybenzyl) sulfmyl] -2-methylpropylcarbamate ml , 660 mg (1.42 mmol, 1.0 eq.), Tert-butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidine-1-ylcarbonyl, prepared as previously described To a solution of -2 - [(4-methoxybenzyl) -53-thio] -2-methylpropylcarbamate in methanol was added a solution of 334 mg (1.56 mmol, 1.1 equivalents) of sodium periodate in 10 ml of water, and the reaction mixture thus obtained was stirred at room temperature for 18 hours. stir over. The resulting heterogeneous reaction mixture was then partitioned between dichloromethane and water, and the organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting white, fluffy precipitate was used in the next step without further purification. Thus, 600 mg (1.25 mmol, 87%) of Compound A is obtained as a mixture of diastereomers.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.27-7.25 (m, 2H), 6.90-6.88 (m, 2H), 5.87 (br s, 1H), 5.40 ( m, 1H), 5.03-4.95 (m, 2H), 4.19-3.66 (m, 7H), 2.65 (m, 1H), 2.36 (m, 1H), 1 , 4910, 1.38 (m, 15H) ppm.

B. (2S, 4S) -1 - {(2R) -2-Amino-3 - [(4-methoxybenzyl) sulfinyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile, dichloromethane solution containing 5 ml of trifluoroacetic acid Compound A (600 mg, 1.25 mmol, 1.0 eq.) was added and the resulting pale yellow solution was stirred at room temperature for 2 hours and the solvent was removed in vacuo to give the trifluoroacetate thus obtained as a free base. The combined organic extract was dried over sodium sulfate and evaporated in vacuo to give an off-white foam foam which was purified by flash chromatography using 5% methanol (0.1%) as a mobile phase. containing 368 mg (0.965 mmol, 77%) of a white foam foam. To obtain the corresponding hydrochloride salt, this material was taken up in diethyl ether and acetone was added until the total amount of solids had gone into solution. To this solution was then added dropwise a solution of 2M hydrochloric acid in diethyl ether until no more precipitate had formed. The precipitate was filtered off and washed several times with diethyl ether. Finally, the resulting salt is dried under high vacuum.

1 H-NMR (D 2 O) 400 MHz δ 7.25-7.21 (m, 2H), 6.93-6.90 m, 2H), 5.42 (m, 1H), 5.02 (m , 1H), 4.48 (m, 1Η), 4.24-3.70 (m, 7H), 2.68-2.31 (m, 2H), 1.52-1.32 (m, 6H ) ppm.

Example 11 (2S, 4S) -1 - ((2R) -2-amino-3-methyl-3 - {[4- (trifluoromethyl) benzyl] thio} butanoyl) -4-fluoropyrrolidin-2-one of formula (XXIV) carbonitrile hydrochloride

-54A. (2R) -2 - [(Τerc-butoxycarbonyl) amino] -3-mercapto-3-methylbutyric acid

Potassium hydroxide (1.88 g, 33.51 mmol, 1.0 eq.) Was added to a solution of 300 ml (5.0 g, 33.51 mmol, 1.0 eq.) Of tetrahydrofuran containing L-penicillinamine and the reaction mixture was stirred at 0 ° C. After cooling to room temperature, di-tert-butyldicarbonate (7.31 g, 33.51 mmol, 1.0 eq) was added. The resulting reaction mixture was then allowed to warm to room temperature with stirring overnight. The reaction mixture was poured into water (300 mL) and the aqueous mixture was extracted twice with ethyl acetate. The combined organic extract was dried over magnesium sulfate and concentrated in vacuo. The resulting white solid was used in the next step without further purification.

Thus, 7.68 g (30.80 mmol, 92%) of Compound A are obtained.

1 H NMR (CDCl 3 ) 400 MHz δ 5.51 (d, 1H, J = 9.6 Hz), 4.33 (d, 1H, J = 9.6 Hz), 1.55 (s,

3H), 1.45 (s, 9H), 1.41 (s, 3H) ppm.

B. (2R) -2 - [(Tert-Butoxycarbonyl) amino] -3-methyl-3 - {[4- (trifluoromethyl) benzyl] thio} butyric acid, 1.0 g (4.011 mmol, 1.0 equivalents) Sodium tert-butylate (810 mg, 8.42 mmol, 2.1 equiv.) Was added to acetonitrile solution containing Compound A and the resulting pale yellow solution was stirred for 10 minutes. 4- (Trifluoromethyl) benzyl bromide (1.05 g, 4.41 mmol, 1.1 eq.) Was then added to the reaction mixture, and the reaction mixture was then heated to 50 ° C and stirred for 18 hours. The reaction mixture was poured into water (about 50 mL) and the aqueous mixture was extracted twice with ethyl acetate. The combined extract was dried over magnesium sulfate and concentrated in vacuo. The resulting solid was used in the next step without further purification. 1.45 g (3.55 mmol, 89%) of compound B are obtained.

1 H NMR (CDCl 3 ) 400 MHz δ 7.55 (d, 2H, J = 8, 1 Hz), 7.44 (d, 2H, J = 8, 1 Hz), 5.39 (br s, 1H), 4.44 (broad s, 1H), 3.85 (s, 2H), 1.45-1.43 (m, 15H) ppm.

C. Tert-Butyl- (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - {[4- (trifluoromethyl) benzyl] thio} propylcarbamate ml, 1.45 mg (3.55 mmol, 1.2 equiv.) of Compound B containing dimethylformamide was added 698 μΐ (4.01 mmol, 1.35 equivalents) of Ν, diisopropylethylamine and then 1.92 g (5.05 mmol, 1.7 equivalents) of HATU. The amber solution thus obtained was stirred at room temperature for 20 minutes and then, with stirring, 849 mg (2.97 mmol, 1.0 eq.) Of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and 569 μΐ were added. (3.27 mmol, 1.1 equivalents) of a solution of N, N-diisopropylethylamine in 25 mL of dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours and then reacted with water.

-5510 was quenched by the addition of about 5 mL of saturated aqueous sodium bicarbonate solution. The resulting turbid reaction mixture was then poured into water (about 20 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed twice with water and once with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting amber oil was purified by flash chromatography using a 1: 1 mixture of hexane and ethyl acetate as the mobile phase. White Compound C (682 mg, 1.35 mmol, 45%) was obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.55 (d, 2H, > 8.1 Hz), 7.50 (d, 2H, > 8.8 Hz), 5.49 (d, 1H, > 50) , 8 Hz), 5.42 (d, 1H, > 9.9 Hz), 5.03 (d, 1H, > 10.0 Hz), 4.40 (d, 1H, > 9.5 Hz), 4.32 (m, 1H), 4.04 (m, 1H), 3.88 (s, 2H), 2.74 (t, 1H, > 15 Hz), 2.38 (m, 1H), 1.47 (s, 3H), 1.42 (s, 9H), 1.41 (s, 3H) ppm.

D. (2S, 4S) -1 - ((2R) -2-Amino-3-methyl-3 - {[4- (trifluoromethyl) benzyl] thio} butanoyl) -4-fluoropyrrolidine-2-carbonitrile ml, 7 ml To a solution of trifluoroacetic acid in dichloromethane was added compound A (682 mg, 1.35 mmol, 1.0 eq.), and the resulting pale yellow solution was stirred at room temperature for 2 hours and then the solvent was removed in vacuo. The resulting trifluoroacetate salt was converted to the free base by the addition of saturated aqueous sodium bicarbonate solution and then extracted twice with ethyl acetate. The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting off-white foam was purified by flash chromatography using 5% methanol in dichloromethane (0.1% ammonia) as mobile phase. White foam was obtained (390 mg, 0.967 mmol, 72%). To prepare the corresponding hydrochloride salt, the free base is taken up in diethyl ether and acetone is added until the total amount of solids is dissolved in solution. To this solution was then added 2N hydrochloric acid solution dropwise with diethyl ether until no more precipitate had formed. The precipitate was filtered off and washed several times with diethyl ether. Finally, the resulting salt is dried under high vacuum.

1 H-NMR (D 2 O) 400 MHz δ 7.57 (d, 2H,> 8, 1 Hz), 7.49 (d, 2H,> 8.5 Hz), 5.46 (d, 1H,> 51 , 4 Hz), 4.98 (d, 1H,> 9.5 Hz), 4.05-3.53 (m, 5H), 2.62-2.28 (m, 2H), 1.40 ( s, 3H)

1.31 (s, 3H) ppm.

Example 12 (2S, 4S) -1 - [(2S) -2-amino-2- (1-vinylcyclopentyl) ethanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XXV

-56A. Tert-Butyl (1S) -2 - [(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] -2-oxo-1- (1-vinylcyclopentyl) ethylcarbamate, 1.07 g (3 , 97 mmol) racemic [(tert-butoxycarbonyl) amino] (1-vinylcyclopentyl) acetic acid (can be prepared by Robi, Jefffey A., Sulsky, Richard B., Augeri, David David, Magnin, David

To a solution of dimethylformamide containing DM35 (Preparation of Fused Cyclopropylpyrrolidine-Based Inhibitor of Dipeptidyl Peptidase IV), R., Hamann, Lawrence G., and Betebenner, David A., is added 0.835 mL (4.37). mmol) and HATU (1.66 g, 4.37 mmol), followed by stirring at room temperature for 15 minutes, followed by dropwise addition of HATU.

(2S, 4S) -4-Fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (1.14 g, 3.97 mmol) and Hünig base (0.835 mL, 4.37 mmol) were added over a period of 2-3 min. solution. The reaction mixture was stirred at room temperature for 18 hours and then quenched by the addition of water. The reaction mixture was poured into water and the organic components were extracted twice with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and then with 1 M aqueous hydrochloric acid, dried over magnesium sulfate and concentrated in vacuo. The resulting dark oil was purified on silica using a Biotage FlashElute system, i.e. gradient elution with 3: 1 to 1: 1 hexane / ethyl acetate. Thus, two types of products are obtained, i.e., at the α-amino position (Cl) diastereomers in a weight ratio of about 1: 1 (582 mg diastereomer 1 and 628 mg diastereomer 2, total yield 83%). The slower eluting diastereomer, based on the so-called vibrational circular dichroism analysis of the final product, proves (S) absolute stereochemistry.

1 H-NMR (CDCl 3 ) 400 MHz δ 5.92 (dd III,> 10.8, 17.3 Hz), 5.38 (m, 1H), 5.22 (dd,

H, 10.8, 27.4 Hz), 5.02 (d, 1H, > 10.3 Hz), 4.23 (d, 1H, > 9.2 Hz), 4.06 (m, 2H) ), 2.63 (t,

1H,> 15.5 Hz), 2.40-2.23 (m, 2H) 1.85 (m, 1H), 1.75-1.52 (m, 6H), 1.43 (m, 1H) , 1.37 (s, 9H) ppm.

B. (2S, 4S) -1 - [(2S) -2-Amino-2- (1-vinylcyclopentyl) ethanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride mg (0.19 mmol) 1 ml A solution of 1,4-dioxane (4 ml) in hydrochloric acid (1.4 ml) was added to a reaction vessel containing 1,4-dioxane, followed by 1 ml of 2N hydrochloric acid in diethyl ether. The reaction mixture was stirred at room temperature for 3 hours. By this time, the starting compound was consumed as detected by TLC. Diethyl ether (3 ml) was added followed by hexane (1 ml). The resulting pale tan precipitate was filtered off and filtered with diethyl ether.

-57a, separated by vacuum filtration and dried under vacuum. Thus, 35 mg (70%) of Compound B is obtained as a cream solid.

1 H-NMR (d 4 -MeOH) 400 MHz δ 5.83 (dd, 1H, J = 10.7, 17.6 Hz), 5.36 (dd, 2H, J = 10.7.27.7 Hz), 5.07 (d, 1H, J = 9.7 Hz), 4.16 (m, 2H), 3.79 (m, 1H), 2.63 (t, 1H, J = 16.2) Hz);

2.45 (m, 1H), 1.86-1.58 (m, 7H), 1.36 (Μ, 3H) ppm.

Example 13 (2S, 4S) -1 - [(2S) -2-amino-5- (4-methoxyphenyl) -3,3-dimethylpentanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XXVI

A. 4- (4-Methoxyphenyl) -2,2-dimethylbutanol

80 ml, 3.65 g (18.0 mmol), by Knochel, P., et al. Became. To a solution of 4- (4-methoxyphenyl) -2,2-dimethylbutanitrile, which is prepared as described in 2, 3285 (2000), 18.0 ml of DIBAL with toluene is added to a toluene solution cooled to -78 ° C. solution (27.0 mmol) was added and the resulting reaction mixture was allowed to stand at -78 ° C for 3 hours. The reaction was then quenched with water (75 mL)

A solution of 15 ml of tetrahydrofuran in 4.6 g of sodium acetate and 4.6 ml of acetic acid was added at -78 ° C, followed by the addition of a Celite filter aid followed by diethyl ether. The reaction mixture was then allowed to warm to room temperature and then filtered through a pad of Celite filtration aid. The filter layer was thoroughly washed with diethyl ether and the filtrate was washed with water, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography using hexane / ethyl acetate (9: 1) as eluent. This gave 3.55 g (17.2 mmol, 96%) of Compound A.

1 H-NMR (CDCl 3 ) 400 MHz δ 9.47 (s, 1H), 7.07 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.4 Hz) ), 3.78 (s, 3H), 2.48-2.44 (m, 2H), 1.77-1.73 (m, 2H), 1.11 (s, 6H) ppm.

B. 1,1,1-Trichloro-5- (4-methoxyphenyl) -3,3-dimethylpentan-2-ol, 511 mg 82.48 mmol) of Compound A and 311 mg (2.60 mmol) of anhydrous chloroform To a solution of tetrahydrofuran cooled to -78 DEG C. was added dropwise over a period of 5 minutes 2.6 ml of a 1.0 M solution of LiHMDS in THF, and the resulting mixture was stirred at -78 ° C for 30 minutes. The reaction was then quenched by the addition of water and then extracted with ethyl acetate. The extract was dried over magnesium sulfate and the solvent removed in vacuo. The residual yellow oil was purified by column chromatography eluting with 10% ethyl acetate in hexane. This gave 588 mg (1.81 mmol, 73%) of Compound B as a white solid.

«» ·

-58 1 H-NMR (CDCl 3) 400 MHz δ 7.10 (d, 2H, J = 8.7 Hz), 6.82 (d, 2H, J = 8.4 Hz), 4.05 (d, 1H, J = 5.7 Hz), 3.78 (s, 3H), 2.95 (d, 1H, J = 5.7 Hz), 2.64-2.59 (m, 2H), 1, 95 (m, 1H), 1.73 (m, 1H), 1.32 (s, 3H), 1.25 (s, 3H) ppm.

C. 2-Azido-5- (4-methoxyphenyl) -3,3-dimethylpentanecarboxylic acid

To 4 ml of DME solution containing 581 mg (1.79 mmol) of Compound B was added 7 ml of DME solution.

Sodium azide (232 mg, 3.58 mmol) and aqueous sodium hydroxide (286 mg, 7.15 mmol) were added at room temperature and the resulting mixture was stirred overnight. The reaction mixture was poured into 2M aqueous sodium hydroxide solution and then extracted with diethyl ether. The aqueous layer was acidified with saturated aqueous sodium hydrogencarbonate solution and then extracted twice with ethyl acetate. The combined extract was dried over magnesium sulfate and the solvent removed in vacuo. The residual oil was purified by column chromatography eluting with 5% methanol in dichloromethane. 186 mg (0.67 mmol, 37%) of Compound C are obtained.

1 H-NMR (CDCl 3) 400 MHz δ 7.09 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H, J = 8.6 Hz), 3.91 (s,

1H), 3.78 (s, 3H), 2.58-2.52 (m, 2H), 1.71-1.61 (m, 2H), 1.10 (s, 6H) ppm.

D. (2S, 4S) -1- [2-Azido-5- (4-methoxyphenyl) -313-dimethylpentanoyl) -4-fluoropyrrolidine-2-carbonitrile ml, 696 mg (2.52 mmol) of Compound C and 358 To a solution of N, N-diisopropylethylamine in mg (2.77 mmol) of dimethylformamide was added HATU (1.05 g, 2.77 mmol) at room temperature and after 8 minutes, 8 mL, 755 mg (2.64 mmol) (2S) was added. 4S) -4-Fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and dimethylformamide solution containing 341 mg (2.64 mmol) of N, N-diisopropylethylamine. The reaction mixture was stirred overnight, then diluted with ethyl acetate and washed three times with water, once with saturated aqueous sodium bicarbonate and once with 2M aqueous hydrochloric acid. After drying over magnesium sulfate, the solvent was removed in vacuo and the residual yellow oil was purified by column chromatography, eluting with hexane, ethyl acetate and dichloromethane (6: 3: 1, then 3: 1: 1). Thus, 605 mg (1.62 mmol, 64%) of Compound D is obtained as a white solid, which, according to H-NMR, shows a diastereomeric mixture of 3: 2. The mixture of diastereomers is utilized in the next step.

E. (2S, 4S) -1 - [(2S) -2-Amino-5- (4-methoxyphenyl) -3,3-dimethylpentanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride, 200 mg, 10% by weight to a ethanolic solution containing a metal-containing palladium catalyst containing 10 ml of tetrahydrofuran and ethanol (1: 1).

-59, 593 mg (1.59 mmol) of Compound D, then the reaction mixture was degassed four times and then placed under hydrogen pressure. After 6.5 hours, the reaction mixture was filtered through a pad of Celite, and the filter layer was washed thoroughly with dichloromethane. The solvent was removed in vacuo and the residual solid was purified by column chromatography using dichloromethane (5% v / v methanolic ammonium hydroxide) as eluent. Thus, 251 mg (0.72 mmol) of Compound E is obtained as the free base. This material was then dissolved in dichloromethane (2 mL), and 3.0 mL of 4M in dioxane was added to the resulting solution. The solvent was then removed under vacuum and the residual oil was triturated with diethyl ether. The resulting solid was collected by vacuum filtration. Thus, 231 mg (0.60 mmol) of Compound E is obtained as the hydrochloride salt.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.13 (d, 2H, > 8.6 Hz), 6.81 (d, 2H, > 8.7 Hz), 5.31 (edge d, 1H ,> 51.1 Hz), 5.09 (d, 1H,> 9.5 Hz), 4.10 (m, 1H), 4.01 (s, 1H), 3.86 (m, 1H), 3 74 (s, 3H), 2.65-2.42 (m, 4H), 1.76-1.72 (m, 2H), 1.20 (s, 6H) ppm.

Example 14 (2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(3-phenylpropyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile of formula (XXVII)

A. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - [(3-phenylpropyl) sulfonyl] propylcarbamate, ml 830 mg (1.79 mmol, 1.0 eq.) Of tert-butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-ylcarbonyl] prepared as described above To a chloroform solution containing -2-methyl-2 - [(3-phenylpropyl) thiopropylcarbamate, 3.09 g (17.9 mmol, 10 equivalents) of 3-chloroperoxybenzoic acid were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction was then quenched by the addition of about 10 mL of a 1 M aqueous sodium hydroxide solution and the phases were separated. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The resulting white, fluffy precipitate was used in the next step without further purification. 800 mg (1.62 mmol, 91%) of Compound A are thus isolated.

B. (2S, 4S) -1 - {(2R] -2-Amino-3-methyl-3 - [(3-phenylpropyl) sulfonyl] butanoyl} 4-fluoropyrrolidine-2-carbonitrile, dichloromethane containing 5 ml of trifluoroacetic acid Compound A (800 mg, 1.62 mmol, 1.0 eq.) was added to the solution, and the resulting pale yellow solution was stirred at room temperature for two hours and then the solvent was removed in vacuo.

The resulting trifluoroacetate salt was then converted to the free base by the addition of saturated aqueous sodium bicarbonate solution and then extracted twice with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting off-white foam was purified by flash chromatography using 5% methanol in dichloromethane (0.1% ammonia) as mobile phase. Thus, 532 mg (1.35 mmol, 83%) of Compound B is obtained as the free base. To prepare the hydrochloride salt, the free base is taken up in diethyl ether and acetone is added until the total amount of solids is dissolved in solution. To this solution was added 2M hydrochloric acid solution dropwise with diethyl ether, until no more precipitate had formed. The precipitate was filtered off and washed several times with diethyl ether. Finally, the resulting salt was dried under high vacuum.

1 H-NMR (D 2 O) 400 MHz δ 7.26-7.13 (m, 5H), 5.48 (d, 1H, J = 50.7 Hz), 5.00 (d, 1H, J = 9.7 Hz), 4.63 (s, 1H), 4.02 (m, 1H), 3.81 (m, 1H), 3.20-3.15 (m, 2H), 2.71 (t, 2H, 1 = 7.5 Hz), 2.65-2.33 (m, 2H), 2.09-2.01 (m, 2H), 1.50 (s, 3H), 1, 35 (s, 3H) ppm.

Example 15 (2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(4-methylbenzyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile (XXVIII)

A. (2R) -2 - [(Tert-Butoxycarbonyl) amino] -3-methyl-3 - [(4-methylbenzyl) thio] butyric acid, 1.0 g (4.01 mmol, 1.0 equivalents), To a sodium hydroxide solution containing 20 (2R) -2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylacid, prepared as described above, was added 584 µl (4.41 mmol, 1, 1) of an aqueous solution. 1 equivalent) 4-methylbenzyl chloride and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into a separatory funnel and washed once with diethyl ether to remove any unreacted chloride. Concentrated aqueous hydrochloric acid is then added to the aqueous phase until the pH is between 2 and 3. The aqueous phase was then extracted twice with diethyl ether and the combined organic extract was dried over magnesium sulfate and concentrated in vacuo. The resulting white, fluffy precipitate was used in the next step without further purification. Thus, 1.29 g (3.65 mmol, 91%) of Compound A is isolated.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.21 (d, 2H, J = 7.9 Hz), 7.11 (d, 2H, J = 8.3 Hz), 5.46 (broad d, 1H, J = 8.5 Hz), 4.40 (broad s, 1H), 3.83 (q, 2H, J = 11.7 Hz), 2.31 (s, 3H), 1.48-1 , 42 (m, 15H) ppm.

• * • ·

-61 B. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - [(4-methylbenzyl) thiopropylcarbamate To a dimethylformamide solution containing 1.29 g (3.65 mmol, 1.2 equiv.) of Compound A, 715 µΐ (4.1 mmol, 1.35 equivalents) of?

1.96 g (5.17 mmol, 1.7 eq.) Of HATU. The amber solution thus obtained was stirred at room temperature for 20 minutes and then, with stirring, 869 mg (3.04 mmol, 1.0 eq.) Of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and 582 μΐ were added. 3.34 mmol, 1.0 equivalent) of a solution of N, N-diisopropylethylamine in 15 mL of dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours and then quenched by the addition of about 5 mL of saturated aqueous sodium bicarbonate solution. The resulting turbid reaction mixture was poured into water (about 20 mL) and extracted three times with ethyl acetate (10 mL). The combined organic extracts were washed twice with water and once with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting amber oil was purified by flash chromatography using a 1: 1 mixture of hexane and ethyl acetate as the mobile phase. Thus, 1.14 g (2.54 mmol, 84%) of Compound D is obtained as a white foam.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.26 (d, 2H, J = 8.4 Hz), 7.10 (d, 2H, > 7.8 Hz), 5.48 (d, 1H, > 51.9 Hz), 5.44 (d, 1H,> 9.5 Hz), 5.04 (d, 1H,> 9.2 Hz), 4.37 (d, 1H, > 9.0 Hz) ), 4.25 (m, 1H), 4.04 (m, 1H), 3.81 (s, 2H), 2.72 (t, 1H,> 15.2 Hz), 2.45-2, 28 [m, 4H], 1.47-1.41 (m,

15H) ppm.

C. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - [(4-methylbenzyl) sulfonyl] propylcarbamate, m.p. To a chloroform solution containing 1.14 g (2.54 mmol, 1.0 eq.) Of Compound B was added 3.09 g (17.9 mmol, 10 eq.) Of 3-chloroperoxybenzoic acid and the resulting mixture was stirred at room temperature for 18 h. . The reaction was then quenched by the addition of about 15 mL of a 1 M aqueous sodium hydroxide solution and the phases were separated. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The resulting white, fluffy precipitate was used in the next step without further purification. 1.03 g (2.14 mmol, 84%) of Compound C can be isolated.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.32 (d, 2H, > 8.0 Hz), 7.19 (d, 2H, > 7.9 Hz), 5.51 (m, 1H), 5 , 48 (d, 1H,> 50.7 Hz), 5.04 (d, 1H,> 9.2 Hz), 4.99 (d, 1H, > 9.7 Hz), 4.32-3, 97 (m, 4H), 2.72 (t, 1H,> 15.7 Hz), 2.46-2.29 (m, 4H), 1.58 (s, 3H), 1.52 (s, 3H), 1.41 (s, 9H) ppm.

• ·· «« • * · · · · ♦ ·· * * · ♦ ·· *

-62D. (2S, 4S) -l - {(2R) -2-amino-3-methyl-3 - [(4-methylbenzyl) sulfonyl] butanoyl} -4-fluorpirrolidm-2-carbonitrile

To a solution of 100 ml of dichloromethane in 10 ml of trifluoroacetic acid was added compound C (1.03 g, 2.14 mmol, 1.0 eq.), And the resulting pale yellow solution was stirred at room temperature for 2 hours and the solvent was removed in vacuo. The resulting trifluoroacetate salt is converted to the corresponding free base by adding saturated aqueous sodium bicarbonate solution and then extracting the aqueous phase twice with ethyl acetate. The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting off-white foam was purified by flash chromatography using 5% methanol in dichloromethane (0.1% ammonia) as mobile phase. This gave 577 mg (1.51 mmol, 71%) of the title compound as a free base as a white foam. To prepare the hydrochloride salt, the free base is taken up in diethyl ether and acetone is added until the total amount of solids is dissolved. To this solution was then added 2N hydrochloric acid solution dropwise with diethyl ether until no more precipitate had formed. The precipitate was filtered off and washed several times with diethyl ether. Finally, the resulting salt is dried under high vacuum.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.38 (d, 2H, J = 8, 1 Hz), 7.24 (d, 2H, J = 7.7 Hz), 5.56 (d, 1H, J = 50.7 Hz), 5.12 (d, 1H, J = 9.7 Hz), 4.74 (s, 1H), 4.64 (ABq, 2H, J = 19.7, 13) , 3 Hz), 4.12 (m, 1H), 3.94 (m, 1H), 2.70-2.43 (m, 2H), 2.36 (s, 3H), 1.76 (s , 3H), 1.58 (s, 3H) ppm.

EXAMPLE 16 (2S, 4S) -1 - [(2R) -2-amino-3 - {[4- (benzoyl) benzyl] phenyl] -3-ethybutanoyl) (XXIX) fluoropyrrolidine-2-carbonitrile

A. (2R) -3 - {[4- (Benzyloxy) benzyl] thio} -2 - [(tert-butoxycarbonyl) amino] -3-methylbutyrr, ml, 500 mg (2.01 mmol, 1.0 equivalent), 515 mg (2.21 mmol, 1%) of an aqueous solution of 25 (2R) -2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylacetic acid prepared as described above was added to a 1 M aqueous solution. 1 equivalent of 4-benzyloxybenzyl chloride and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into a separatory funnel and washed once with diethyl ether to remove any unreacted chloride present. The pH of the aqueous phase was then adjusted to between 2 and 3 with concentrated aqueous hydrochloric acid and the aqueous phase was extracted twice with diethyl ether. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting white, fluffy precipitate was used in the next step without further purification. Thus, 700 mg (1.57 mmol, 78%) of Compound A can be isolated.

• · V

-63 1 H-NMR (CDCl 3 ) 400 MHz δ 7.42-7.31 (m, 5H), 7.24 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H, > 8.6 Hz), 5.46 (broad s, 1H), 5.03 (s, 2H), 4.39 (broad s, 1H), 3.81 (q, 2H, > 11.5 Hz) , 1.471.41 (m, 15H) ppm.

B. Tert-Butyl- (1R) -2 - {[4- (benzyloxy) benzyl] thio} -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} - To a dimethylformamide solution containing 2-methylpropylcarbamate (700 mg, 1.57 mmol, 1.2 equiv.), 308 µl (1.77 mmol, 1.35 equivalents) of Ν-diisopropylethylamine was added followed by 847 mg (2, 1 mmol). 23 mmol, 1.7 equivalents) of HATU. The amber solution thus obtained was stirred at room temperature for 20 minutes and then, with stirring, 375 mg (1.31 mmol, 1.0 eq.) Of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and 251 μΐ were added. 1.44 mmol, 1.1 equivalents) of a solution of N, N-diisopropylethylamine in 10 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours and then quenched by the addition of about 5 mL of saturated aqueous sodium bicarbonate solution. The resulting turbid reaction mixture was poured into water (about 20 mL) and extracted three times with ethyl acetate (10 mL). The combined organic extracts were washed twice with water and once with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting amber oil was purified by flash chromatography using a 1: 1 mixture of hexane and ethyl acetate as the mobile phase. Thus, 340 mg (0.628 mmol, 48%) of a white foamy substance can be isolated as Compound B.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.42-7.27 (m, 7H), 6.91 (d, 2H, > 8.8 Hz), 5.46 (d, 1H, > 50, 9 Hz), 5.43 (d, 1H, > 9.3 Hz), 5.05-5.01 (m, 3H), 4.37 (d, 1H, > 9.0 Hz), 4.26 (m, 1H), 4.03 (m, 1H), 3.80 (s, 2H), 2.71 (t, 1H,> 15.2 Hz), 2.36 (m, 1H), 1, 47-1.41 (m, 15H) ppm.

C. Tert-Butyl- (1R) -2 - {[4- (benzyloxy) benzyl] sulfonyl} -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2 -metilpropiIkarbamát

To 30 ml of 340 mg (0.628 mmol, 1.0 eq.) Of Compound B in chloroform was added 3-chloroperoxybenzoic acid (1.08 g, 6.28 mmol, 10 eq.), And the reaction mixture was stirred at room temperature for 18 hours. The reaction was then quenched by the addition of about 5 mL of 1 N aqueous sodium hydroxide solution and the phases were separated. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The resulting white, fluffy precipitate was used in the next step without further purification. Thus, 280 mg (0.488 mmol, 78%) of Compound C can be isolated.

V 9 »·>

** ·

1 »

-64ΪΗ NMR (CDC1 3) 400MHz δ 7.43-7.32 (m, 7H), 7.00 (2H, d,> 8.8 Hz), 5.51 (br s, 1H), 5 , 48 (d, 1H,> 50.7 Hz), 5.06-4.97 (m, 4H), 4.34-3.99 (m, 4H), 2.73 (t, 1H, > 15) , 2 Hz), 2.38 (m, 1H), 1.59 (s, 3H), 1.53 (s, 3H), 1.42 (s, 9H) ppm.

D. (2S, 4S) -1 - [(2R) -2-Amino-3 - {[4- (benzyloxy) benzyl] sulfonyl} -3-methylbutanoyl) -4-fluoro-pyrrolidine-2-carbonitrile ml, 3 ml To a solution of trifluoroacetic acid in dichloromethane was added compound C (280 mg, 0.488 mmol, 1.0 eq.), and the resulting pale yellow solution was stirred at room temperature for 2 hours and then the solvent was removed in vacuo. The resulting trifluoroacetate salt is converted to the corresponding free base by the addition of saturated aqueous sodium hydrogen carbonate solution and then extracted twice with ethyl acetate. The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting off-white foam was purified by flash chromatography using 5% methanol in dichloromethane (0.1% ammonia) as mobile phase. 182 mg (0.385 mmol, 79%) of the free base of Compound D were obtained as a white foam. To prepare the corresponding hydrochloride salt, the free base is taken up in diethyl ether and acetone is added until the total amount of solids is dissolved in solution. To this solution was then added 2N hydrochloric acid solution dropwise with diethyl ether until no more precipitate had formed. The precipitate was collected and washed several times with diethyl ether. Finally, the resulting salt is dried under high vacuum.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.44-7.29 (m, 7H), 7.05 (d, 2H,> 8.8 Hz), 5.56 (d, 1H,> 50.0 Hz), 5.11-5.09 (m, 3H), 4.72 (s, 1H), 4.61 (ABq, 2H,> 18.1, 13.5 Hz), 4.13 (m, 1H), 3.91 (m, 1H), 2.70-2.42 (m, 2H), 1.75 (s, 3H), 1.58 (s, 3H) ppm.

Example 17 (2S, 4S) -1 - {(2R) -2-amino-3 - [(4-cyanobenzyl) sulfonyl] -3-methylbutanoyl]} - 4-fluoropyrrolidine-2-carbonitrile (XXX)

A. (2R) -2 - [(Tert-Butoxycarbonyl) amino] -3 - [(4-cyanobenzyl) thio] -3-methylbutyric acid, 500 mg 82.01 mmol, 1.0 equivalents) as described above (2R) -2 - [(tert-Butoxycarbonyl) amino] -3-mercapto-3-methylbutyric acid, sodium hydroxide (1M) was added to a 1M solution of water (433 mg, 2.21 mmol, 1.1 equivalents). cyanobenzyl bromide and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured into a separatory funnel and then washed once with diethyl ether to remove any unreacted bromide which might be present. Concentrated aqueous hydrochloric acid was then added to adjust the pH to 2 to 3 to the aqueous phase.

Extraction with er »-65 and diethyl ether twice. The combined organic extract was dried over magnesium sulfate and concentrated in vacuo. The resulting white, fluffy precipitate was used in the next step without further purification. Thus, 792 mg (1.72 mmol, 86%) of Compound A can be isolated.

B. Tert-Butyl- (1R) -2 - [(4-cyanobenzyl) thio] -1 - {[(2S, 4S) -2-cyano-4-trifluoropyrrolidin-1-yl] carbonyl} -2-methylpropylcarbamate ml To a di-methyl formamide solution containing 792 mg (1.72 mmol, 1.2 equiv.) Of Compound A was added 337 µΐ (1.93 mmol, 1.35 equivalents) of Ν-diisopropylethylamine followed by 924 mg (2.43 mmol). , 1.7 equivalent) HATU. The amber solution thus obtained was stirred at room temperature for 20 minutes and then, with stirring, 409 mg (1.43 mmol, 1.0 eq.) Of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and 274 μΐ were added. (1.57 mmol, 1.1 equivalents) of a solution of N, N-diisopropylethylamine in 10 mL of dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours and then quenched by the addition of about 5 mL of saturated aqueous sodium bicarbonate solution. The cloudy reaction mixture was then poured into water (about 20 mL) and extracted three times with ethyl acetate (10 mL). The combined extract was washed twice with water and once with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting amber oil was purified by flash chromatography using hexane as the mobile phase and a 1: 1 by volume mixture. 572 mg (1.24 mmol, 87%)

Compound B can be isolated as a white foam in the amount of%).

1 H-NMR (CDCl 3 ) 400 MHz δ 7.59 (d, 2H, J = 8.4 Hz), 7.50 (d, 2H, J = 8.4 Hz), 5.50 (d,

1H, J = 50.5 Hz), 5.42 (d, 1H, J = 9.7 Hz), 5.03 (d, 1H, J = 9.5 Hz), 4.41-4.30 ( m, 2H), 4.04 (m, 5H), 3.88 (s, 2H), 2.75 (t, 1H, J-15.7 Hz), 2.39 (m, 1H), 1 , 46-1.41 (m, 15H) ppm.

C. Tert-Butyl- (1R) -2 - [(4-cyanobenzyl) sulfonyl] -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carboxyl} -2- To a chloroform solution containing 57 ml (1.24 mmol, 1.0 eq.) of methylpropyl-carbamide, 2.14 g (12.4 mmol, 10 eq.) of 3-chloroperoxybenzoic acid was added to the chloroform solution, and the resulting mixture was stirred at room temperature for 18 hours. stirred. The reaction was then quenched by the addition of about 5 mL of 1 N aqueous sodium hydroxide solution and the phases were separated. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The resulting white, fluffy precipitate was used in the next step without further purification. Thus, 487 mg (0.989 mmol, 80%) of Compound C can be isolated.

-66 1 H-NMR (CDCl 3) 400 MHz δ 7.70 (d, 2H, > 8.5 Hz), 7.57 (d, 2H, > 8.4 Hz), 5.53 (broad s, 1H), 5.51 (d, 1H, J = 50.7 Hz), 5.04 (d, 1H, > 9.9 Hz), 4.99 (d, 1H, > 9.8 Hz), 4.444.29 ( m, 3H), 4.04 (m, 1H), 2.77 (t, 1H,> 15.0 Hz), 2.42 (m, 1H), 1.61 (d, 6H, > 5.8) Hz), 1.44 (s, 9H) ppm.

D. (2S, 4S) -1 - {(2R) -2-Amino-3 - [(4-cyanobenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile in dichloromethane solution containing 6 ml of trifluoroacetic acid Compound C (487 mg, 0.989 mmol, 1.0 eq) was added and the resulting pale yellow solution was stirred at room temperature for two hours. The solvent was removed in vacuo and the resulting trifluoroacetate was converted to the free base by the addition of saturated aqueous sodium bicarbonate solution and then extracted twice with ethyl acetate. The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting off-white foam was purified by flash chromatography using 5% methanol in dichloromethane (0.1% ammonia) as mobile phase.

Thus, 285 mg (0.726 mmol, 73%) of Compound D is obtained as a free base as a white foam. To prepare the corresponding hydrochloride salt, the free base is taken up in diethyl ether and acetone is added until all solids are dissolved. To this solution was then added dropwise a solution of 2M hydrochloric acid in diethyl ether until no more precipitate had formed. the precipitated chicken pad is then filtered off, washed several times with diethyl ether and dried under high vacuum.

1 H-NMR (D 2 O) 400 MHz δ 7.72 (d, 2H,> 8.6 Hz), 7.51 (d, 2H,> 8.5 Hz), 5.49 (d, 1H,> 50.6 Hz), 5.02 (d, 1H, > 9.7 Hz), 4.72-4.67 (m, 3H), 4.08 (m, 1H), 3.85 (m, 1H ), 2,662.35 (m, 2H), 1.66 (s, 3H), 1.51 (s, 3H) ppm.

Example 18 (2S, 4S) -1 - [(2R) -2-amino-3-methyl-3 - {[4- (methylsulfonyl) benzyl] sulfonyl} butanoyl-4-fluoropyrrolidine-2-carbonitrile (XXXI)

A. (2R) -2 - [(tert-Butoxycarbonyl) amino] -3-methyl-3 - {[4- (methylsulfonyl) benzyl] thio} butyric acid, 500 mg (2.01 mmol, 1.0 equivalents) to a solution of (2R) -2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylacetic acid, prepared as described above, in a solution of 1 M sodium hydroxide solution (452 mg, 2.21 mmol). 1.1 equivalents) of 4-methylsulfonylbenzyl chloride, followed by stirring at room temperature for 18 hours. The reaction mixture is then poured into a separatory funnel and washed once with diethyl ether to remove any unreacted chloride that may be present. After this time, the pH of the aqueous phase was adjusted to between 2 and 3 with concentrated aqueous hydrochloric acid and the aqueous layer was extracted twice with diethyl ether. The combined organic extract was dried over magnesium sulfate and concentrated in vacuo. The resulting white fluffy solid was used in the next step without further purification. Thus, 768 mg (1.84 mmol, 92%) of Compound A can be isolated.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.87 (d, 2H, > 8.5 Hz), 7.54 (d, 2H, > 8.5 Hz), 5.39 (broad s, 1H) , 4.44 (bs, 1H), 3.88 (s, 2H), 3.03 (s, 3H), 1.46-1.43 (m, 15H) ppm.

B. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - {[4- (methylsulfonyl) benzyl] thio} propylcarbamate

To 25 ml of dimethylformamide solution containing 768 mg (1.84 mmol, 1.2 equivalents) of Compound A was added 361 μΐ (2.07 mmol, 1.35 equivalents) of Ν-diisopropylethylamine followed by 989 mg (2.60 mmol). , 1.7 equivalent) HATU. The amber solution thus obtained was stirred at room temperature for 20 minutes and then, with stirring, 438 mg (1.53 mmol, 1.0 eq.) Of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and 293 μΐ were added. 1.68 mmol, 1.1 equivalents) of a solution of N, N-diisopropylethylamine in 10 mL of dimethylformamide. The reaction mixture was stirred at room temperature for 18 hours and quenched by the addition of saturated aqueous sodium bicarbonate (5 mL). The resulting turbid reaction mixture was then poured into water (nearly 20 ml) and extracted with ethyl acetate (10 ml) three times. The combined organic extracts were washed twice with water and once with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The amber oil thus obtained was then purified by flash chromatography using a 1: 1 by volume mixture of hexane and ethyl acetate as the mobile phase. Thus, 683 mg (1.33 mmol, 87%) of Compound B is obtained as a white foam.

1 H-NMR (CDCl 3) 400 MHz δ 7.86 (d, 2H,> 8.5 Hz), 7.58 (d, 2H, > 8.3 Hz), 5.50 (d,

1 H, > 50.9 Hz), 5.43 (d, 1H, > 9.9 Hz), 4.43-4.30 (m, 2H), 4.03 (m, 1H), 3.90 ( s, 2H), 3.02 (s, 3H), 2.74 (t, 1H,> 15.6 Hz), 2.39 (m, 1H), 1.47-1.41 (m, 15H) ppm.

C. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidinyl] yl] carbonyl} -2-methyl-2 - {[4- (methylsulfonyl) benzyl] Thio} propylcarbamate, 683 mg (1.33 mmol, 1.0 eq.) of Compound B in chloroform was treated with 2.30 g (13.3 mmol, 10 equivalents) of 3-chloroperoxybenzoic acid and the reaction mixture was stirred at room temperature for 18 hours. stir for an hour. Then, to stop the reaction, add about 5 ml of 1.0 M sodium hydroxide solution and separate the phases. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The resulting white fluffy solid was used in the next step without further purification. Thus, 581 mg (1.06 mmol, 80%) of Compound C can be isolated.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.98 (d, 2H, > 8.6 Hz), 7.66 (d, 2H, > 8.5 Hz), 5.53 (s, 5 1H) , 5.51 (d, 1H,> 50.5 Hz), 5.08 (d, 1H, > 10.0 Hz), 4.99 (d, 1H, > 9.5 Hz), 4.44- 4.32 (m,

2H), 4.03 (m, 1H), 3.06 (s, 3H), 2.77 (t, 1H, > 16.0 Hz), 2.41 (m, 1H), 1.63 (s , 3H), 1.60 (s,

3H), 1.43 (s, 9H) ppm.

D. (2S, 4S) -1 - ((2R) -2-Ammo-3-methyl-3 - {[4- (methylsulfonyl) benzyl] sulfonyl} butmolyl) -4-fluoropyrene idin-2-carbonitrile

To 63 ml of dichloromethane solution containing 7 ml of trifluoroacetic acid was added compound C (581 mg, 1.06 mmol, 1.0 eq.) And the resulting pale yellow solution was stirred at room temperature for two hours. The solvent was then removed in vacuo and the resulting trifluoroacetate was converted to the corresponding free base by addition of saturated aqueous sodium bicarbonate solution and then extracted twice with ethyl acetate. The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting off-white foam was purified by flash chromatography using 5% methanol in dichloromethane (0.1% ammonia) as mobile phase. 296 mg (0.664 mmol, 63%) of Compound D are obtained as a free base as a white foam. To prepare the corresponding hydrochloride salt, the free base is taken up in diethyl ether and acetone is added until all solids are dissolved. To this solution was then added dropwise a solution of 2M hydrochloric acid in diethyl ether until no more precipitate had formed. the precipitate formed is then filtered off, washed several times with diethyl ether and dried under high vacuum.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.91 (d, 2H, δ, 8 Hz), 7.63 (d, 2H, ≥ 8.2 Hz), 5.49 (d, 1H,> 50.3 Hz), 5.02 (d, 1H, > 9.7 Hz), 4.77-4.68 (m, 3H), 4.09 (m, 1H), 3.85 (m, 1H ), 3.14 (s, 3H), 2.66-2.36 (m, 2H), 1.67 (s, 3H), 1.53 (s, 3H) ppm.

Example 19 (2S, 4S) -1 - {(2S) -2-amino-2- [1- (4-fluorobenzyl) cyclopentyl] ethanoyl} -4-fluoro-pyrrolidine-2-carbonitrile hydrochloride of formula XXXII

A. 1- (4-Fluorobenzyl) cyclopentanecarbonitrile

To a solution of 4-fluorobenzylbromide (10.0 g, 52.9 mmol) in toluene (100 mL) was added cyclopentanecarbonitrile (6.1 mL, 58.2 mmol) and the resulting mixture was stirred well and cooled to 0 ° C. Then on a feeding funnel • ·

69 ml of a 0.5 M solution of KHMDS (79.35 mmol) in toluene was slowly added to 69 ml, and the resulting mixture was warmed to room temperature and stirred for 14 hours. The reaction mixture was then adjusted to pH 7 with 1.0 M aqueous hydrochloric acid to stop the reaction. The phases are separated and the aqueous phase is reextracted with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium bicarbonate, water and finally with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10: 1 mixture of hexane and ethyl acetate. Thus, 8.61 g (80%) of Compound A are obtained as a yellow solid liquid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.28-7.24 (m, 2H), 7.01 (t, J = 8.7 Hz, 2H), 2.84 (s, 2H), 2, 07-2.01 (m, 2H), 1.89-1.66 (m, 6H) ppm.

B. 1- (4-Fluorobenzyl) cyclopentanecarbaldehyde

While stirring, a solution of Compound A (8.61 g, 42.36 mmol) in toluene (150 mL) was cooled to -78 ° C and diisobutylaluminum hydride (DIBAL) (11.3 mL, 63.54 mmol) was added dropwise via syringe. the reaction mixture was stirred at -78 ° C for two hours. Then, a solution of 100 ml of tetrahydrofuran, 30 ml of water, 8 ml of acetic acid and 7 g of sodium acetate was carefully added to the reaction mixture, and the reaction mixture was warmed to room temperature and stirred for an additional hour. After the addition of diethyl ether, the biphasic reaction mixture was subjected to vacuum filtration on a Celite filter aid filter, and the filtrate was poured into a separating funnel and the aqueous phase separated. The organic layer was washed with saturated aqueous sodium bicarbonate, water and finally with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography, eluting with a 10: 1 mixture of hexane and ethyl acetate. This gave 6.55 g (75%) of Compound B as a colorless liquid.

1 H-NMR (CDCl 3 ) 400 MHz δ 9.53 (s, 1H), 7.07 (dd, J = 8.4, 5.5 Hz, 2H), 6.93 (t, J = 8.7) Hz, 2H), 2.88 (s, 2H), 1.93-1.87 (m, 2H), 1.67-1.48 (m, 6H) ppm.

C. Amino [1- (4-fluorobenzyl) cyclopentyl] acetonitrile

To a stirred solution of Compound B (6.55 g, 31.76 mmol) in methanol (30 mL) and water (18 mL) was added an aqueous ammonium hydroxide solution (33.35 mmol) (4.4 mL, 30% ammonia), 2.17 g. Potassium cyanide (33.35 mmol) and ammonium chloride (1.87 g, 34.94 mmol). The resulting turbid reaction mixture was heated at 70 ° C for 14 hours and then cooled to room temperature, diluted with ethyl acetate. Dilution of each other • · · · «· •« ······

After washing with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate. Thus, 5.99 g (81%) of Compound C is obtained as a colorless viscous oil.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.23-7.19 (m, 2H), 6.98 (t, > 8.7 Hz, 2H), 3.54 (d, > 3.5 Hz) , 1H), 2.97 (d, 13.6 Hz, 1H), 2.63 (d, 13.7 Hz, 1H), 2.08 (br s, 2H), 1.751.57 (m, 8H) ppm.

D. Amino [1- (4-fluorobenzyl) cyclopentylacetic acid hydrochloride

While stirring, a solution of Compound C (5.99 g, 25.79 mmol) in glacial acetic acid (20 mL) was added to a concentrated aqueous hydrochloric acid solution (100 mL), and the resulting mixture was refluxed (130 ° C) and kept for 16 hours. . After cooling to room temperature, the reaction mixture was evaporated to dryness in vacuo, and the white solid obtained was washed on a glass filter with diethyl ether under high vacuum conditions and finally dried under high vacuum. Thus, 6.33 g (85%) of compound D were obtained as a white solid.

1 H-NMR (CD 3 OD) 400 MHz δ 7.30 (dd, δ 8.7, 5.4 Hz, 2H), 7.04 (t, > 8.8 Hz, 2H), 3.89 (s , 1H), 2.85-2.76 (m, 2H), 1.79-1.43 (m, 8H) ppm.

E. [(tert-Butoxycarbonyl) amino] [1- (4-fluorobenzyl) cyclopentyl] acetic acid

To a stirred solution of Compound D (6.33 g, 21.99 mmol) in 1,4-dioxane (100 mL) was added 76 mL of 1 M NaOH (75.57 mmol) in water followed by 24 mL of water. The resulting mixture was stirred at room temperature for several hours until the total amount of starting material was completely dissolved. Then, 8.25 g (37.78 mmol) of solid tert-butyldicarbonate (BOCgO) was added and the reaction mixture was stirred at room temperature for 14 hours. Concentrated aqueous hydrochloric acid was then slowly added until the pH of the reaction mixture was adjusted to less than 7 and then diluted with ethyl acetate. The aqueous layer was then separated and re-extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. This gave 7.95 g (90%) of compound E as a white foam.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.20 (dd, δ 8.6, 5.5 Hz, 2H), 6.96 (t, > 8.7 Hz, 2H), 5.00 (d, 9.1 Hz, 1H), 4.28 (d, 9.0 Hz, 1H), 2.72-2.64 (m, 2H), 1.63-1.35 (m, 8H), 1.45 (s, 9H) ppm.

- tert-Butyl- (1S) -2 - [(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] -1- [1- (4-fluorobenzyl) cyclopentyl] ~ -2 -oxoetilkarbamát

To a stirred solution of E (1.90 g, 5.41 mmol) in dimethylformamide (54 mL) was added (2S, 4S) -4-fluoropyrrolidine-2-carbonitrile-4-methyl-benzenesulfonate (1.55 g, 5.41 mmol). HATU (2.06 g, 5.41 mmol) and diisopropylethylamine (2.83 mL, 16.23 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. After the addition of 50 ml of water, the reaction mixture was extracted five times with ethyl acetate, and the combined extract was washed with water, saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and finally with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The two diastereomers obtained were separated by flash chromatography on silica gel using a 2: 1 by volume mixture of hexane and ethyl acetate. This gave 586 mg (25% of the desired diastereomer) of Compound F as a colorless oil. Compound F is the more polar (lower Rf) of the two diastereomers.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.20-7.16 (m, 2H), 7.00 (t, J = 8.7, 2H), 5.22 (broad d,

J = 51.1 Hz, 1H), 5.15 (d, J = 5.9 Hz, 1H), 4.93 (d, J = 9.3 Hz, 1H), 4.26 (d, J = 9.7 Hz, 1H), 3.77-5 3.63 (m, 1H), 3.28-3.19 (m, 1H), 2.78-2.52 (m, 4H), 2, 32-2.11 (m, 2H), 1.73-1.52 (m, 6H),

1.42 (s, 9H) ppm.

G. (2S, 4S) -1 - {(2S) -2-Amino-2- [1- (4-fluorobenzyl) cyclopentyl] ethanoyl} -4-fluoropyrrolidine-220-carbonitrile

To a stirred solution of Compound F (586 mg, 1.31 mmol) in dichloromethane (13 mL) was added trifluoroacetic acid (1.00 mL, 13.1 mmol), and the resulting mixture was stirred at room temperature for 14 h. After concentration in vacuo, the reaction mixture was redissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using dichloromethane containing 5% methanol (0.1% ammonia) as mobile phase gave 160 mg (35%) of compound G as a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.21-7.17 (m, 2H), 6.99 (t, J = 8.6 Hz, 2H), 5.24 (broad d, J = 51 , 1 Hz, 1H), 4.93 (d, J = 9.3 Hz, 1H), 3.53-3.40 (m, 1H), 3.34 (s, 1H), 3.29-3 , 20 (m, 1H), 2.92 (d, J = 13.6 Hz, 1H), 2.66 (d, J = 13.7 Hz, 1H), 2.63-2.49 (m, 2H), 2.31-1.32 (m, 8H) ppm.

-72H. (2S, 4S) -l - {(2S) -2-Amino-2- [l- (4-fluorobenzyl) cyclopentyl] ethanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride

With stirring, a solution of G. g (160 mg, 0.460 mmol) in diethyl ether (5 mL) was added with 1.0 mL of 2N hydrochloric acid in diethyl ether, and the resulting reaction mixture was stirred at room temperature for 5 minutes. A white precipitate was formed which was collected by vacuum filtration on a glass filter and dried overnight under high vacuum. 139 mg (79%) of compound H are obtained as a white solid.

1 H-NMR (CD 3 OD) 400 MHz δ 7.31-7.27 (m, 2H), 7.13 (t, J = 8.8 Hz, 2H), 5.30 (broad 10 d,, J = 51.1, 1H), 5.01 (d, 9.5 Hz, 1H), 4.04 (s, 1H), 3.56-3.43 (m, 1H), 3.20-3 , 11 (m, 1H),

2.90 (d, 13.9 Hz, 1H), 2.73 (d, 14.0 Hz, 1H), 2.60-2.30 (m, 2H), 2.14-1.37 (m, 8H) ppm. Example 20 (2S, 4S) -1 - ((2S) -2-amino-2- {1- [4- (trifluoromethyl) phenyl] cyclopentyl} ethanoyl) -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XXXIII

A. 1- [4- (Trifluoromethyl) phenyl] cyclopentanecarbonitrile

To a solution of 4-fluorobenzotrifluoride (5.0 g, 30.47 mmol) in toluene (40 mL) was added with stirring, cyclopentanecarbonitrile (10.5 mL, 100.55 mmol) was added followed by a solution of 0.5 M KHMDS in toluene (92 mL). 45.71 mmol). The reaction mixture was stirred at 70 ° C for 14 hours, then cooled to room temperature and quenched by adjusting the pH of the reaction mixture to 7 mol / L aqueous hydrochloric acid. The phases are separated and the organic phase is washed with saturated aqueous sodium bicarbonate, water and finally with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography, eluting with a 6: 1 mixture of hexane and ethyl acetate. This gives 7.53 g of a mixture of Compound A and residual cyclopentanecarbonitrile. Given that these two types of compounds are not readily separable by chromatography, the resulting mixture is directly used in the next reaction step.

B. 1- [4- (Trifluoromethyl) phenyl] cyclopentylcarbaldehyde

While stirring, 7.53 g of Compound A prepared as in the previous step

A solution of toluene (100 mL) was cooled to -78 ° C and 32.0 mL of DIBAL (47.21 mmol) in toluene (32.0 mL) was slowly added via syringe. The reaction mixture was then stirred at -78 ° C for two hours and then carefully added to a solution of 100 ml of tetrahydrofuran, 20 ml of water, 6 ml of acetic acid and 6.6 g of sodium acetate. The reaction mixture was then warmed to room temperature.

-73 followed by stirring for an additional hour. After the addition of diethyl ether, the biphasic reaction mixture was filtered through a pad of Celite, filtered through vacuum, and then poured into a separatory funnel and the aqueous phase removed. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography, eluting with a 10: 1 mixture of hexane and ethyl acetate. 3.91 g (53% yield based on the last two steps) of Compound D as a colorless liquid.

1 H-NMR (CDCl 3 ) 400 MHz δ 9.41 (s, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.2 Hz, 10 2H) , 2.58-2.52 (m, 2H), 1.93-1.65 (m, 6H) ppm.

C. Amino {1- [4- (trifluoromethyl) phenyl] cyclopentyl} acetonitrile

While stirring, a solution of 3.91 g (16.14 mmol) of Compound B in a mixture of 20 ml of methanol and 12 ml of water was added 2.20 ml of an aqueous ammonium hydroxide solution (16.95 mmol) containing about 30% ammonia (1.95 mmol). Potassium cyanide (16.95 mmol) and ammonium chloride (950 mg, 17.76 mmol) were added and the resulting turbid reaction mixture was heated at 70 ° C for 6 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a 2: 1 by volume mixture of hexane and ethyl acetate as mobile phase. 2.16 g (50%) of Compound C were obtained as a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.63 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 3.74 (s, 1H ), 2.43-2.36 (m, 1H), 2.32-2.25 (m, 1H), 2.15-2.08 (m, 1H), 2.01-1.93 (m , 1H), 1.85-1.72 (m, 4H), 1.54 (broad s, 2H) ppm.

D. Amino {1- [4- (trifluoromethyl) phenyl] cyclopentyl} acetic acid hydrochloride

While stirring, a solution of Compound C (2.16 g, 8.05 mmol) in glacial acetic acid (10 mL) was added to 50 mL of concentrated aqueous hydrochloric acid and the resulting mixture was heated at 130 ° C for 16 h under gentle reflux. After cooling to room temperature, the reaction mixture was evaporated to dryness in vacuo and the white solid obtained was dried under high vacuum. 2.61 g (100%) of compound D are obtained as a white solid.

-74 µM NMR (d 4 -MeOM) 400 MHz δ 7.69 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 4.20 (d, J = 2.4 Hz, 1H), 2.42-2.34 (m, 2H), 2.27-2.19 (m, 1H), 2.14-2.07 (m, 1H) ), 1.86-1.79 (m, 2H), 1.61-1.51 (m, 2H) ppm.

E. [(tert-Butoxycarbonyl) amino] {[4- (trifluoromethyl) phenyl] cyclopentyl} acetic acid

While stirring, a solution of D (2.61 g, 8.05 mmol) in a mixture of 20 ml of 1,4-dioxane and 20 ml of 20 ml of water was added to solid sodium hydroxide (1.08 g, 27.06 mmol) followed by a few minutes at room temperature. After stirring, solid di-tert-butyldicarbonate (BOC 2 O) (3.94 g, 18.04 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours, then concentrated to a pH of 7, concentrated hydrochloric acid was added and diluted with ethyl acetate. The aqueous phase was then separated, saturated with sodium chloride and re-extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. Thus, 3.01 g (86%) of Compound E is obtained as a colorless viscous oil.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.55 (d, J = 7.8 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 4.85 (d,

J = 8.5 Hz, 1H), 4.55 (d, J = 8.5 Hz, 1H), 2.43-1.59 (m, 8H), 1.42 (s, 9H) ppm.

Tert-Butyl- (1S) -2 - [(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] -2-oxo-1- {1- [4- (trifluoromethyl) phenyl] cyclopentyl } ethyl carbide brown

To a stirred solution of E (1.01 g, 2.61 mmol) in 26 mL of dimethylformamide was added (2S, 4S) -4-fluoropyrrolidine-2-carbonitrile-4-methylbenzenesulfonate (747 mg, 2.61 mmol). (2.61 mmol) HATU and 1.40 mL (7.83 mmol) diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 hours and then water (20 mL) was added. The reaction mixture was extracted five times with ethyl acetate, and the combined extract was washed successively with water, 1.0 M sodium hydrogen sulfate solution, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using hexane / ethyl acetate 1: 1 as the eluent. This gave 442 mg (35%) of the desired product as a mixture of diastereomers. Additional chromatography on silica gel to separate the diastereomers using a 2: 1 by volume mixture of hexane and ethyl acetate. 145 mg of compound F are obtained as a white foam. Compound F is the more polar (lower Rf) of the two diastereomers.

- 75 1 H-NMR (CDCl 3 ) 400 MHz δ 7.63 (d,> 8.4 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 5.27 (d, > 9.7 Hz, 1H), 5.08 (broad d, J = 50.9 Hz, 1H), 4.84 (d, J = 9.5 Hz, 1H), 4.49 (d,> 9 , 9 Hz, 1H), 3.63 - 3.50 (m, 1H), 2.77 (dd,> 23.6, 12.0 Hz, 1H), 2.48 (t,> 15.5 Hz) , 1H), 2.25-2.20 (m, 2H), 2.10-2.03 (m, 2H), 1.77-1.71 (m, 2H), 1.52-1.48 (m, 2H), 1.41 (s, 9H) ppm.

G. (2S, 4S) -1 - ((2S) -2-Amino-2- {1- [4- (trifluoromethyl) phenyl] cyclopentyl} ethanoyl) -4-fluoropyrrolidine-2-carbonitrile

To a stirred solution of Compound F (145 mg, 0.30 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.116 mL, 1.50 mmol) and the resulting mixture was stirred at room temperature for 14 h. After concentration in vacuo, the reaction mixture was redissolved in ethyl acetate, and the resulting solution was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using dichloromethane containing 5% methanol (2% ammonia) as mobile phase. 62 mg (54%) of compound G were obtained as a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.62 (d,> 8.2 Hz, 2H), 7.54 (d,> 8.6 Hz, 2H), 5.12 (broad d,> 51, 1, H, 4.86 (d,> 9.5 Hz, 1H), 3.57 (s, 1H), 3.55-3.42 (m, 1H), 2.97-2.88 ( m, 1H), 2.50 (t, 15.2 Hz, 1H), 2.24-2.10 (m, 5H), 1.99 (broad s, 2H), 1.76-1.71 (m, 2H), 1.54-1.41 (m, 2H) ppm.

H. (2S, 4S) -1 - ((2S) -2-Amino-2- {1- [4- (trifluoromethyl) phenyl] cyclopentyl} etanoyl) -4-fluoropyrrolidin-2-carbonitrile hydrochloride mg (0.133 mmol) 3 ml of diethyl ether was added to a reaction vessel containing Compound G and a few drops of acetone were added to make the solution homogeneous. 1.0 ml of 2N hydrochloric acid in diethyl ether was added and the reaction mixture was stirred at room temperature for 5 minutes. The solvent was removed in vacuo and the resulting solid was dried overnight under high vacuum. 55 mg (98%) of compound H were obtained as a white solid.

1 H-NMR (D 2 O) 400 MHz δ 7.62 (d, δ 8.8 Hz, 2H), 7.58 (d, 9.0 Hz, 2H), 5.13 (broad d, > 51.1 Hz, 1H), 4.86 (d, 9.5 Hz, 1H), 4.37 (s, 1H), 3.54-3.40 (m, 1H), 2.95-2 , 86 (m, 1H), 2.44-2.18 (m, 4H), 1.92-1.84 (m, 2H), 1.64-1.58 (m, 2H), 1.33 -1.25 (m, 2H) ppm.

Example 21 (2S, 4S) -1 - {(2S) -2-amino-2- [1- [4-fluorobenzyl] cyclopropyl] ethanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrate hydrate of formula XXXIV · · 4

-76A. l- (4-fluorobenzyl) ciklopropánkarbomtril

While stirring, a solution of cyclopropanecarbonitrile (4.3 mL, 58.2 mmol) in toluene (100 mL) was cooled to 0 ° C and 159 mL of a 0.5 M solution of KHMDS (79.35 mmol) in toluene was slowly added. ). After the addition was complete, the reaction mixture was stirred at 0 ° C for 30 minutes, and a solution of 4-fluorobenzylbromide (10.0 g, 52.9 mmol) in toluene (20 mL) was added dropwise at the same temperature. The reaction mixture was then warmed to room temperature and stirred for 3 hours. The reaction was stopped by lowering the pH to below 7 by adding 1.0 M aqueous hydrochloric acid. The phases are separated and the aqueous phase is reextracted with ethyl acetate. The combined organic layers were washed successively with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 5% ethyl acetate in hexane. This gave 7.76 g (84%) of Compound A as a yellow liquid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.25-7.22 (m, 2H), 7.03 (t, &gt; 8.7 Hz, 2H), 2.77 (s, 2H),

1.28 (dd, > 7.1, 5.1 Hz, 2H), 0.94 (dd, > 7.1, 5.1 Hz, 2H) ppm.

B. 1- (4-Fluorobenzyl) cyclopropanecarbaldehyde

While stirring, a solution of Compound A (7.76 g, 44.29 mmol) in toluene (150 mL) was cooled to -78 ° C and then DIBAL (11.8 mL, 66.43 mmol) was added dropwise via a syringe. stirring at two hours.

A solution of 100 ml of tetrahydrofuran, 40 ml of water, 8 ml of acetic acid and 7.5 g of sodium acetate was then carefully added, and the reaction mixture was warmed to room temperature and stirred for an additional hour. After addition of diethyl ether, the biphasic reaction mixture was filtered through a pad of celite filtration filtration and the filtrate was poured into a separatory funnel. The aqueous phase is discarded, and the organic phase is washed successively with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 5 volumes of ethyl acetate-hexane. This gave 7.20 g (91%) of the title compound B as a colorless liquid.

1 H-NMR (CDCl 3 ) 400 MHz δ 8.71 (s, 1H), 7.16-7.13 (m, 2H), 6.94 (t, > 8.8 Hz, 2H),

2.96 (s, 2H), 1.20-1.17 (m, 2H), 1.00-0.97 (m, 2H) ppm.

• · ··· · »9 ·>

-77C. Amino [l- (4-fluorobenzaldehyde) cyclopropyl] acetonitrile

To a stirred solution of Compound B (7.20 g, 40.40 mmol) in MeOH (40 mL) and H 2 O (25 mL) was added aqueous ammonium hydroxide solution (42.42 mmol, 5.41 mL, about 30%), 2.76. g (42.42 mmol) of potassium cyanide and 2.38 g (44.44 mmol) of ammonium chloride. The resulting turbid reaction mixture was heated at 70 ° C for 14 hours, then cooled to room temperature and diluted with ethyl acetate. The dilution was successively washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 20% ethyl acetate / hexane as mobile phase to give Compound C as a colorless viscous oil (2.21 g, 27%).

1 H-NMR (CDCl 3 ) 400 MHz δ 7.22-7.19 (m, 2H), 6.98 (t, > 8.6 Hz, 2H), 3.62 (d, > 3.3 Hz, 1H), 3.12 (d, 14.3 Hz, 1H), 2.56 (d, J = 14.3 Hz, 1H), 1.93 (br s, 1H), 1.82 (br, 1H) , 0.78-0.76 (m, 2H), 0.67-0.64 (m, 1H), 0.54-0.51 (m, 1H) ppm.

D. Amino [1- (4-fluorobenzyl) cyclopropyl] acetic acid hydrochloride

While stirring, a solution of Compound C (2.21 g, 10.82 mmol) in glacial acetic acid (10 mL) was added to 50 mL of concentrated aqueous hydrochloric acid and the resulting mixture was heated at reflux (130 ° C) for 16 h. After cooling to room temperature, the reaction mixture was evaporated to dryness in vacuo, and the resulting white solid was washed with diethyl ether on a glass filter under vacuum filtration and dried under high vacuum. 2.81 g (100%) of compound D are obtained as a white solid.

1 H-NMR (d 4 -MeOM) 400 MHz δ 7.18 (dd, > 8.8, 5.5 Hz, 2H), 7.01 (t, > 8.8 Hz, 2H), 3.54 ( s, 1H), 2.84 (d, 4.9 Hz, 2H), 0.89-0.84 (m, 1H), 0.70-0.59 (m, 2H), 0.51 - 0.47 (m, 1H) ppm.

E. [(tert-Butoxycarbonyl) amino] [1- (4-fluorobenzyl) cyclopropyl] acetic acid

While stirring, a solution of 2.80 g (10.85 mmol) of Compound D in 1,4-dioxane was added with 33 mL of water, 1.0 M aqueous sodium hydroxide solution (33.03 mmol) followed by 17 mL of water. . The resulting mixture was stirred at room temperature for a few minutes until the total amount of starting material was completely dissolved. Solid di-tert-butyldicarbonate (3.60 g, 16.52 mmol) was added and the mixture was stirred at room temperature for 14 h. To stop the reaction, the pH was lowered to pH 7 with concentrated hydrochloric acid and diluted with ethyl acetate. The aqueous phase was separated and re-extracted twice with ethyl acetate. This combines organic phases with magnesium sulfate * »« ·· ·

It is dried over -78, filtered and concentrated in vacuo. 4.06 g (112%) of this was then obtained

Compound E is obtained as a viscous, pale yellow oil.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.19-7.15 (m, 2H), 6.95 (t, &gt; 8.7 Hz, 2H), 4.98 (d, > 7.0 Hz) , 1H), 3.98 (d, 7.5 Hz, 1H), 2.85 (d, 14.5 Hz, 1H), 2.60 (d, 14.2 Hz, 1H), 1 -45 (s, 9H), 0.79-0.72 (m, 2H), 0.51-0.47 (m, 2H) ppm.

Tert-Butyl (1S) -2 - [(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] -1 - [1- (4-fluorobenzyl) cyclopropyl] -2-oxoethylcarbamate

While stirring, a solution of 4.06 g (12.56 mmol) of E in 125 mL of dimethylformamide was added 3.60 g (12.56 mmol) of (2S (45) -4-fluoropyrrolidine-2-carbonitrile-4-methyl-10-benzenesulfonate). 4.78 g (12.56 mmol) of HATU and 6.60 mL (37.68 mmol) of diisopropylethylamine are added and the reaction mixture is stirred at room temperature for 16 h. After the addition of 125 mL of water, the reaction mixture is extracted four times with ethyl acetate. the combined extract was washed successively with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a residue which was purified by flash chromatography on silica gel with hexane and ethyl acetate as the mobile phase. 1: 1, to give 1.29 g (25%) of the title compound as a mixture of diastereomers. Further flash chromatography on silica gel using a mobile phase mixture of hexane and ethyl acetate (2: 1) as the diastereomers was performed. Thus, 853 mg of Compound F is obtained as a white foam. Compound F is the more polar (lower Rf) of the two diastereomers.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.29 (dd, δ 8.6, 5.5 Hz, 2H), 7.03 (t,> 8.7 Hz, 2H), 5.15 (d , 9.3 Hz, 1H), 5.14 (broad d, 51.1, 1H), 4.76 (d, 9.3 Hz, 1H), 4.42 (d,> 9.3)

Hz, 1H), 3.29-3.16 (m, 1H), 3.15-3.11 (m, 1H), 3.07-2.98 (m, 1H), 2.52 (t, > 15.2 Hz, 1H), 2.24-2.17 (m, 1H), 2.14-2.07 (m, 1H), 1.44 (s, 9H), 0.86-0, 76 (m, 2H), 0.56-0.45 (m, 2H) ppm.

G. (2S, 4S) -1 - {(2S) -2-Amino-2- [1- (4-fluorobenzyl) cyclopropyl] ethanoyl} -4-fluoropyrrolidine-2-carbonitrile

To a stirred solution of Compound F (853 mg, 2.03 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (1.56 mL, 20.4 mmol) and the reaction mixture was stirred at room temperature for 18 h. After concentration in vacuo, the reaction mixture was redissolved in ethyl acetate, and the resulting solution was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The remainder • ·

Purification by flash chromatography on silica gel using mobile dichloromethane containing 5% methanol (0.1% ammonia) as mobile phase. 401 mg (62%) of compound G were obtained as a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.27-7.24 (m, 2H), 7.00 (t,> 8.6 Hz, 2H), 5.17 (broad 5 d,> 51, 3 Hz, 1H), 4.76 (d, 9.3 Hz, 1H), 3.48 (s, 1H), 3.32-3.01 (m, 3H), 2.54 (t, &gt;) 15.0 Hz

1 H), 2.22-2.05 (m, 2H), 1.74 (broad s, 2H), 0.79-0.71 (m, 2H), 0.53-0.39 (m, 2H) ) ppm.

H (2S, 4S) -1 - {(2S) -2-Amino-2- [1- (4-fluorobenzyl) cyclopropyl] ethanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride

8 ml of diethyl ether was added to a flask containing 401 mg (1.26 mmol) of Compound G, followed by addition of about 1 L of acetone to make the solution homogeneous. Hydrochloric acid (2.0 ml, 2 M in diethyl ether) was added and the reaction mixture was stirred for 5 minutes. The solvent was evaporated in vacuo and the resulting white solid was triturated with a mixture of hydrochloric acid and diethyl ether. The resulting solid was collected by vacuum filtration on a glass filter, washed several times with diethyl ether and dried overnight under high vacuum. 376 mg (84%) of the title compound are obtained as a white solid.

1 H-NMR (D 2 O) 400 MHz δ 7.29-7.23 (m, 2H), 7.07-7.01 (m, 2H), 5.22 (broad d,> 50.6 Hz, 1H ), 4.82 (d,> 9.1?, 1H), 4.10 (s, 1H), 3.25-2.92 (m, 3H), 2.28 (t, > 16.0 Hz, 1 H), 2.32-2.21 (m, 2H), 1.16-0.43 (m, 4H) ppm.

Example 22 (2S, 4S) -1 - [(2R) -2-amino-3- (benzylsulfonyl) -3-methylbutanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XXXV

A. (2R) -3- (Benzylthio) -2 - [(tert-butoxycarbonyl) amino] -3-methylbutyric acid, 1 g (0.00401 mol) of (2R) -2 - [(tert-butoxycarbonyl) amino] To a potassium hydroxide solution containing 3-mercapto-3-methyl-alpha-25 acid, 755 mg of benzyl bromide was added to a 1 M aqueous solution at room temperature, and after 17 hours, the reaction mixture was diluted with water and washed with diethyl ether. The organic layer was discarded while the aqueous phase was cooled to 0-5 ° C and acidified to pH 3.5 with concentrated hydrochloric acid. Extraction was repeated several times with ethyl acetate, and the combined extract was dried over magnesium sulfate and evaporated to dryness. Yield 1.1 g (81%) of Compound A as a clear oily substance.

1 H-NMR (CDCl 3) 400 MHz δ 7.32-7.20 (m, 5H), 5.44 (broad d, 1H, 7.2 Hz), 4.38 (broad d, 1H,> 8 , 0 Hz), 3.80 (m, 2H), 1.45-1.43 (m, 15H) ppm.

· * ♦ fc

-80B. Tert-Butyl- (1R) -2- (benzylthio) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methylpropylcarbamate, ml, 1.1 g , 1.32 g (0.0049 mol) of HATU was added to a solution of Compound A and dimethylformamide in a solution containing 1.4 g (0.0107 mol) of N, N-diisopropylethylamine at room temperature, followed by 1 g (0 min). (0035 mole) (2S, 4S) -4-Fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate. After stirring overnight, the reaction was quenched by the addition of sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with a 1: 1 mixture of hexane and ethyl acetate. This gave 445 mg (32%) of Compound B.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.36-7.18 (m, 5H), 5.37 (broad d, 1H), 5.45 (broad d, 1H, J = 51.6 Hz), 5.00 (d, 1H, J = 9.2 Hz), 4.35 (d, 1H, J = 8.8), 4.27-3.92 (m, 4H), 2.67-2, 59 (m, 1H), 2.40-2.23 (m, 1H), 1.46-1.36 (m, 15H) ppm.

C. Tert-Butyl (1R) -2- (benzylsulfonyl) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methylpropyl [brown bar, 445 mg] (0.00102 mole) of dichloromethane solution containing compound B was added 1.8 g of 57-86% 3-chloroperoxybenzoic acid (0.0102 mole), and the resulting mixture was stirred at room temperature for 16 h and then concentrated to 2 mol / l. neutralize with aqueous potassium hydroxide solution. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness. 421 mg (88%) of crude C are obtained. The resulting tan solid was used in the next step without further purification.

D. (2S, 4S) -1 - [(2R) -2-Amino-3- (benzylsulfonyl) -3-methylbutanoyl] -4-fluoropyrrolidine-2-carbo-nitrile hydrochloride ml, 421 mg (0.00102 mol) Trifluoroacetic acid (5 mL) was added to the dichloromethane solution containing Compound C, and the reaction mixture was stirred at room temperature for 16 hours and then neutralized with saturated sodium bicarbonate solution. The organic layer was then dried over magnesium sulfate and evaporated to dryness. The crude solid obtained was purified by chromatography on silica gel, eluting with 99% dichloromethane and 1% methanol in 2M ammonia. The pure tan solid obtained was dissolved in 1: 1 acetone / diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The formed • 4> «·« · «·

The solid was filtered off under vacuum and washed with diethyl ether and dried under high vacuum to give 96 mg of Compound D.

1 H-NMR (d 4 -MeOM) 400 MHz δ 7.49-7.35 (m, 5H), 5.47 (broad d, 1H, J = 50.8 Hz), 5.10 (d, 1H, > 8.8 Hz), 4.92-4.59 (m, 3H), 4.15-3.91 (m, 2H), 2.71-2.43 (m, 2H), 1.77 ( s, 3H), 1.60 (s, 3H) ppm.

Example 23 (2S, 4S) -1 - {(2R) -2-amino-3 - [(3-methoxybenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XXXVI

A. (2R) -2 - [(tert-Butoxycarbonyl) amino] -3 - [(3-methoxybenzyl) thio] -3-methylbutyric acid, 1 g (0.00401) (2R) -2 - [(tertiary) 3-methoxybenzyl chloride (691 mg, 0.00441 mol) was added to a solution of butoxycarbonylamino] -3-mercapto-3-methylbutyric acid in 1 M aqueous potassium hydroxide solution at room temperature and then diluted with water (50 ml) after 17 hours. . The organic layer was then discarded while the aqueous phase was cooled to 0-5 ° C. The aqueous layer was then acidified to pH 3.5 using concentrated aqueous hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to dryness. 1.35 g (91%) of the title compound are obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.19 (dd, 1H, J = 7.8 Hz), 6.90 (d, 1H, J = 7.2 Hz), 6.86 (s, 1H) , 6.76 (dd, 1H, > 8.4 Hz), 5.43 (broad d, 1H, > 6.4 Hz), 4.39 (broad d, 1H, > 6.8 Hz), 3, 82-3.74 (m, 5H), 1.45-1.35 (m, 15H) ppm.

B. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidinyl] carbonyl} -2 - [(3-methoxybenzyl) thio] -2-methylpropylcarbamate, ml, , 3 g (0.0035 mol) of Compound A and 1.36 g (0.0106 mol) of N, N-diisopropylethylamine in dimethylformamide are added at room temperature 2.0 g (0.0053 mol) of HATU and 30 min. after 1.1 g (0.0038 mol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile 4-methylbenzenesulfonate. After stirring overnight, the reaction was quenched by the addition of sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography using a 1: 1 mixture of hexane and ethyl acetate as eluent. This gave 617 mg (38%) of Compound B.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.18 (dd, 1H, > 7.8 Hz), 6.95 (s, 1H), 6.92 (broad d, 1H, > 2.8), 6 74 (dd, 1H, > 8.2 Hz), 5.41 (broad d, 1H, > 8.8 Hz), 5.39 (broad d, 1H,

-82-> 51.2), 5.00 (d, 1H, > 9.6 Hz), 4.35 (d, 1H, > 8.8 Hz), 4.28-3.78 (m, 7H ), 2.71-2.52 (m,

1H), 2.46-2.27 (m, 1H), 1.62-1.39 (m, 15H) ppm.

C. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2 - [(3-methoxybenzyl) sulfonyl] -2-methylpropylcarbamate

To 100 ml of dichloromethane solution containing 617 mg (0.0013 mol) of Compound B was added 57-86% 3-chloroperoxybenzoic acid (2.3 g, 0.013 mol), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then neutralized with 2M aqueous potassium hydroxide solution and the organic layer was dried over magnesium sulfate and evaporated to dryness. At this time, crude product (647 mg, 98%) was obtained as a solid (10 mL). The resulting off-white solid was used without further purification in the next step.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.30-7.25 (m, 1H), 7.01-6.98 (m, 2H), 6.92-6.88 (m, 1H), 5.49 (broad d, 1H, > 8.4 Hz), 5.39 (broad d, 1H, > 50.8 Hz), 5.03 (broad d, 1H, > 9.2), 4.96 (d, 1H, > 9.2 Hz), 4.32-3.80 (m, 4H), 3.79 (s, 3H), 2.71-2.54 (m, 1H), 2.46 -2.24 (m, 1H),

1.59-1.39 (m, 15H) ppm.

D. (2S, 4S) -1 - {(2R) -2-Amino-3 - [(3-methoxybenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride mg, 647 mg (0 Trifluoroacetic acid (5 mL) was added to a solution of Compound C in dichloromethane (0013 mole), and the resulting mixture was stirred at room temperature for 16 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness. The crude solid thus obtained was subjected to silica gel chromatography, eluting with 99% dichloromethane and 1% methanol in 2M ammonia. The resulting pure solid was dissolved in a 1: 1 mixture of acetone and diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The solid formed was filtered off under vacuum and then washed with diethyl ether and dried under high vacuum to give 221 mg of Compound D.

1 H-NMR (d 4 -MeOM) 400 MHz δ 7.31 (dd, 1H,> 8.0 Hz), 7.18-7.06 (m, 2H), 6.98 (d, 1H,> 8.0 Hz), 5.49 (broad d, 1H, > 50.8 Hz), 5.10 (d, 1H, > 9.2 Hz), 4.72-4.58 (m, 3H), 5

4.15-3.88 (m, 2H), 3.81 (s, 3H), 2.69-2.44 (m, 2H), 1.75 (s, 3H), 1.59 (s, 3H) ppm.

Example 24 (2S, 4S) -1 - {(2R) -2-amino-3 - [(1,1'-biphenyl-4-ylmethyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine of formula XXXVII 2-carbonitrile hydrochloride

-83 A. (2R) -3 - [(1,1'-Biphenyl-4-ylmethyl) thio] -2 - [(tert-butoxycarbonyl) amino] -3-methylbutyric acid, 10 ml of 1,4-dixoan and To a 1.0 M aqueous solution of potassium hydroxide (1R, 0.00401 mol) containing (2R) -2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylbutyric acid, 894 mg (0%) was added at room temperature. 00441 mol) 4-phenylbenzyl chloride, and after 17 hours, the reaction mixture was diluted with water and washed with diethyl ether. The organic phase was discarded and the aqueous phase was cooled to 0-5 ° C and then acidified to pH 3.5 with concentrated hydrochloric acid. The aqueous reaction mixture was then extracted with diethyl ether, and the extract was dried over magnesium sulfate and evaporated to dryness. 1.4 g (82%) of Compound A were obtained as a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.59-7.31 (m, 9H), 5.49 (m, 1H), 4.32 (broad d, 1H,

J = 9.6 Hz), 3.88-3.71 (m, 2H), 1.57-1.40 (m, 15H) ppm.

B. Tert-Butyl- (1R) -2 - [(1,1'-biphenyl-4-ylmethyl) thio] -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methylpropylcarbamate, 1.4 g (0.0034 mole) of Compound A and 1.3 g (0.0101 mole) of N, N-diisopropyl-ethylamine in dimethylformamide are added at 1.9 g (0 ° C). 0051 mole) and after 30 minutes, the reaction mixture was mixed with 1.1 g (0.0037 mol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate. After stirring overnight, the reaction was quenched by the addition of sodium bicarbonate and then extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography using a 1: 1 mixture of hexane and ethyl acetate as eluent. This gave 828 mg (48%) of an extremely pure product.

1 H-NMR (CDCl 3) 400 MHz δ 7.57-7.30 (m, 9H), 5.47-5.33 (m, 2H), 5.03 (broad d,

1H, J = 9.6), 4.39 (d, 1H, J = 8.8 Hz), 4.31-3.97 (m, 2H), 3.89 (s, 2H), 2.68 (dd, 1H, 1 = 15.6 Hz)

2.44-2.28 (m, 1H), 1.58-1.41 (m, 15H) ppm.

C. Tert-Butyl (1R) -2 - [(1,1'-biphenyl-4-ylmethyl) sulfonyl] -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-metilpropilkarbamát

To 100 ml of 828 mg (0.0016 mol) of dichloromethane solution containing compound B was added 2.8 g (0.0162 mol) of 57-86% 3-chloroperoxybenzoic acid, and the resulting mixture was stirred at room temperature for 16 hours. then neutralized with 2 M aqueous potassium hydroxide solution. The organic layer was then dried over magnesium sulfate and evaporated to dryness in vacuo. This gave 867 mg (99%) of Compound C 84. The resulting white solid was used in the next step without further purification.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.63-7.33 (m, 9H), 5.53 (broad d, 1H, J = 8.4 Hz), 5.42 (broad d, 1H, J = 50.8 Hz), 5.07 (broad d, 1H, J = 9.2), 4.99 (d, 1H, J = 9.2 Hz), 4.39-4.00 (m .

4H), 2.70 (dd, 5 1H,> 15.2 Hz), 2.47-2.34 (m, 1H), 1.62-1.40 (m, 15H) ppm.

D. (2S, 4S) -1 - {(2R) -2-Amino-3 - [(1,1'-biphenyl-4-ylmethyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloric acid, dichloromethane containing 867 mg (0.0016 mol) of Compound C, trifluoroacetic acid (5 ml) was added, and the resulting mixture was stirred at room temperature for 16 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness to give a crude solid. This solid was purified by chromatography on silica gel using a mixture of 99% dichloromethane and 1% methanol in 2M ammonia. The resulting clear solid was dissolved in a 1: 1 mixture of acetone and diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The solid formed was filtered off under vacuum and then washed with diethyl ether and dried under high vacuum to give 307 mg of Compound D.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.66-7.32 (m, 9H), 5.48 (broad d, 1H, J = 50.4 Hz), 5.10 (d, 1H, > 8.0), 4.86-4.64 (m, 3H), 4.19-3.86 (m, 2H), 2.70-2.41 (m, 2H), 1.78 (s , 3H)

1.63 (s, 3H) ppm.

Example 25 (2S, 4S) -1 - {(2R) -2-amino-3-f [2-methoxybenzyl] sulfonyl] -3-inethylbutanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XXXVHI

A. (2R) -2 - [(Tert-Butoxycarbonyl) amino] -3 - [(2-methoxybenzyl) thio] -3-methylbutyric acid

To 50 ml, 1 g (0.00401 mole) of (2R) -2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylbutyric acid was added to a 1M solution of potassium hydroxide at room temperature (691 mg). 00441 mol) 2-methoxybenzyl chloride and after 17 hours the reaction mixture was diluted with water and washed with diethyl ether. The organic layer was discarded while the aqueous phase was cooled to 0 ° C to 5 ° C and then acidified to pH 3.5 using concentrated hydrochloric acid. After extraction with ethyl acetate, the extract was dried over magnesium sulfate and evaporated to dryness. Yield: 1.1 g (74%) of Compound A.

! 1 H-NMR (CDCl 3 ) 400 MHz δ 7.25-7.21 (m, 2H), 6.90-6.85 (m, 2H), 5.63-5.55 (m, 1H), 4 , 31 (broad d, 1H, > 9.2 Hz), 3.88-3.79 (m, 5H), 1.58-1.33 (m, 15H) ppm.

-85 B. Tert-butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2 - [(2-methoxybenzyl) thio] -2- Methylpropylcarbamate ml, 1.0 g (0.0027 mole) of Compound A and 1.05 g (0.0081 mole) of N, N-diisopropylethylamine in dimethylformamide are added at room temperature to 1.5 g (0.00405 mol) of HATU. and after 30 minutes 851 mg (0.003 mol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate. After stirring overnight, the reaction was quenched by the addition of sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography using a 1: 1 mixture of hexane and ethyl acetate as eluent. This gave 668 mg (53%) of Compound B.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.31 (dd, 1H, &gt; 7.6 Hz), 7.19 (dd, 1H, J = 8.0 Hz), 6.926.83 (m, 2H), 5.47-5.31 (m, 2H), 5.03 (broad d, 1H, J = 9.2), 4.34 (d, 1H,> 8.4 Hz), 4.26-3, 66 (m, 7H), 2.68 (dd, 1H,> 15.2 Hz), 2.43-2.26 (m, 1H), 1.57-1.37 (m, 15H) ppm.

C. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2 - [(2-methoxybenzyl) sulfonyl] -2-methylpropylcarbamate ml To 668 mg (0.0014 mol) of dichloromethane solution containing compound B were added 2.5 g (0.0144 mol) of 57-86% 3-chloroperoxybenzoic acid, and the resulting mixture was stirred at room temperature for 16 h and then 2 mol. It is neutralized with a 1 L aqueous solution of potassium hydroxide. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness. Yield: 678 mg (95%). The resulting off-white solid was used in the next step without further purification.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.44 (dd, 1H, > 7.6 Hz), 7.34 (m, 1H), 6.99-6.91 (m,

2H), 5.61-5.57 (m, 1H), 5.40 (broad d, 1H, > 51.2 Hz), 5.00-4.95 (m, 2H), 4.49-3 , 85 (m, 7H),

2.65 (dd, 1H, > 15.6 Hz), 2.45-2.28 (m, 1H), 1.62-1.37 (m, 15H) ppm.

D. (2S, 4S) -1 - {(2R) -2-amino-3 - [(2-methoxybenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride ml, 678 mg (0 Trifluoroacetic acid (5 ml) was added to a solution of Compound C in dichloromethane (00136 mol), and the reaction mixture was stirred at room temperature for 16 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness. The resulting crude solid was chromatographed on silica gel using 99% dichloromethane / 1% methanol in 2M ammonia as eluent. so pure solid · ·

-86 was dissolved in a 1: 1 mixture of acetone and diethyl ether, followed by precipitation with 2N hydrochloric acid in diethyl ether. The solid formed was filtered off under vacuum and washed with diethyl ether and dried under high vacuum. Thus, 313 mg of compound D are obtained.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.45-7.38 (m, 2H), 7.06 (d, 1H,> 8.4 Hz), 6.996.99 (dd, 1H,> 7.2 Hz), 5.49 (broad d, 1H, > 50.8 Hz), 5.09 (m, 1H, > 9.2), 4.13-3.84 (m, 6H), 2 , 67-2.44 (m, 2H), 1.74 (s, 3H), 1.58 (s, 3H) ppm.

Example 26 (2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(pyridin-3-ylmethyl) thio] butanoyl} -410-fluoropyrrole-2-carbonitrile of formula XXXIX

A. (2R) -2 - [(Tert-Butoxycarbonyl) amino] -3-methyl-3 - [(pyridin-3-ylmethyl) thio] butyric acid, 1 g (0.00401) (2R) -2- [ To potassium hydroxide containing (tert-butoxycarbonyl) amino] -3-mercapto-3-methylbutyric acid, 1- (1-bromomethyl) pyridine hydrobromide (1.1 g, 0.00411 mol) was added to a 1 M aqueous solution at room temperature and then treated for 17 hours. the reaction mixture was diluted with water and washed with diethyl ether. The organic layer was then discarded while the aqueous phase was cooled to 0 ° C to 5 ° C and then acidified to pH 0.4 with concentrated aqueous hydrochloric acid. After extraction with ethyl acetate, the extract was dried over sodium sulfate and evaporated to dryness. 403 mg (30% of the title compound as a clear oily solid).

1 H-NMR (CDCl 3 ) 400 MHz δ 8.77 (s, 1H), 8.56 (d, 1H, > 5.6 Hz), 7.80 (d, 1H, > 8.0)

Hz), 7.37 (dd, 1H, > 8.0 Hz), 5.47 (broad d, 1H, J = 9.6 Hz), 4.53 (broad d, 1H, > 9.6 Hz) , 3.95 (dd, 2H,> 69.6 Hz), 1.60-1.35 (m, 15H) ppm.

B. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - [(pyridin-3-ylmethyl) thio] propylcarbamate

To 20 ml, 400 mg (0.0012 mol) of Compound A and 456 mg (0.0035 mol) of N, N-diisopropylethylamine in dimethylformamide are added HATU 670 mg (0.0018 mol) at room temperature and after 30 min 370 mg (0.0013 mol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate. After stirring overnight, the reaction was interrupted by the addition of sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting residue was subjected to silica gel chromatography, eluting with a 1: 1 mixture of hexane and ethyl acetate to give 314 mg (61%) of Compound B.

- 87 ] 1 H-NMR (CDCl 3 ) 400 MHz δ 8.58 (s, 1H), 8.46 (d, 1H, J = 4.8 Hz), 7.71 (d, 1H, J = 8, 0 Hz), 7.21 (dd, 1H, J = 8.0 Hz), 5.45 (broad d, 1H, J = 9.2 Hz), 5.43 (broad d, 1H, J = 51, 2 Hz), 5.02 (d, 1H, J = 9.2 Hz), 4.41 (d, 1H, J = 9.6 Hz), 4.37-3.79 (m, 4H), 2 , 70 (dd, 1H, J = 15.6 Hz), 2.46-2.29 (m, 1H), 1.55-1.39 (m, 15H) ppm.

C. (2S, 4S) -1 - {(2R) -2-Amino-3-methyl-3 - [(pyridin-3-ylmethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride ml, 314 Trifluoroacetic acid (3 ml) was added to a solution of Compound B containing mg (0.720 mmol) of Compound B, and the mixture was stirred at room temperature for 16 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The resulting crude solid was purified by silica gel chromatography using 99% (v / v) dichloromethane and 1% (v / v) methanol (2M ammonia) as eluent. The pure solid was then dissolved in a 1: 1 mixture of acetone and diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The solid formed was filtered off under vacuum and washed with diethyl ether and dried under high vacuum. 69 mg of compound C are obtained.

1 H-NMR (CDCl 3) 400 MHz δ 8.57 (s, 1H), 8.46 (d, 1H, J = 5.2 Hz), 7.71 (d, 1H, J = 6.4 Hz), 7.23 (dd, 1H, J = 8.0 Hz), 5.44 (broad d, 1H, J = 51.2 Hz), 4.97 (d, 1H, J = 9.6 Hz), 4.203 , 58 (m, 5H), 2.66 (dd, 1H, .1 = 15.2 Hz), 2.39-2.22 (m, 1H), 1.78 (broad s, 2H), 1, 48 (s, 3H)

1.39 (s, 3H) ppm.

Example 27 (2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(pyridin-2-ylmethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile (XL) hydrochloride

A. (2R) -2 - [(Tert-Butoxycarbonyl) amino] -3-methyl-3 - [(pyridin-2-ylmethyl) thio] butyric acid 25 50 ml, 1 g (0.00401 mol) (2R) - To potassium hydroxide containing 2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylbutyric acid, 1 g (0.00441 mol) of 2- (bromomethyl) pyridine hydrobromide was added to a 1 M aqueous solution at room temperature. and after 17 hours, the reaction mixture was diluted with water and washed with diethyl ether. The organic layer was discarded while the aqueous phase was cooled to 0 ° C to 5 ° C and then acidified to pH30 with concentrated hydrochloric acid. After extraction with ethyl acetate, the extract was dried over sodium sulfate and evaporated to dryness. This gave 557 mg (41%) of Compound A as a white solid.

- 88 1 H-NMR (CDCl 3) 400 MHz δ 8.53 (d, 1H, > 4.8 Hz), 7.75 (dd, 1H, > 7.6 Hz), 7.377.30 (m, 2H) , 5.73 (broad d, 1H, > 8.8 Hz), 4.47 (d, 1H, > 8.8 Hz), 4.41-4.01 (m, 2H), 1.55 (m, 15H) ppm.

B. Tert-Butyl- (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - [(pyridin-25-ylmethyl) thio] ] propylcarbamate ml, 557 mg (0.0016 mol) of Compound A and 635 mg (0.0049 mol) of dimethylformamide solution containing, diisopropylethylamine were added at room temperature to 912 mg (0.0024 mol) of HATU and after 30 min. 504 mg (0.00176 mol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate. After stirring overnight, the reaction was quenched by the addition of sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography using a 1: 1 mixture of hexane and ethyl acetate as eluent. This gave 466 mg (65%) of Compound B.

1 H-NMR (d 6 acetone) 400 MHz δ 8.46 (d, 1H, > 4.4 Hz), 7.71 (dd, 1H, > 7.6 Hz)

7.48 (d, 1H, > 8.0 Hz), 7.21 (dd, 1H, > 7.6 Hz), 6.25 (broad d, 1H, > 8.4 Hz), 5.60 ( broad d, 1H,> 50.8 Hz), 5.05 (m, 1H), 4.61 (d, 1H, > 8.8 Hz), 4.43-3.83 (m, 4H), 2 , 83-2.52 (m, 2H), 1.50-1.35 (m, 15H) ppm.

C. (2S, 4S) -1 - {(2R) -2-Ammo-3-methyl-3 - [(pyridin-2-ylmethyl) thio] butanoyl} -4-fluoropyrrolidine-220-carbonitrile hydrochloride ml, 314 Trifluoroacetic acid (5 ml) was added to a solution of Compound B in mg (0.00107 mole) of compound B, followed by stirring at room temperature for 16 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The resulting crude solid was subjected to silica gel chromatography, eluting with a mixture of 99% dichloromethane and 1% (v / v) methanol (2M). The pure solid was dissolved in a 1: 1 mixture of acetone and diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The solid formed was filtered off under vacuum and washed with diethyl ether and dried under high vacuum. 127 mg of compound C are obtained.

1 H-NMR (D 2 O) 400 MHz δ 8.54 (d, 1H, > 5.6 Hz), 8.34 (dd, 1H, > 8.0 Hz), 7.92 (d,

1H, > 8.4 Hz), 7.21 (dd, 1H, > 6.4 Hz), 5.44 (broad d, 1H, > 50.4 Hz), 5.02 (d, 1H, > 10 Hz), 4.60 (m, 5H), 2.62 (dd, 1H, > 15.6 Hz), 2.54-2.34 (m, 1H), 1.40 (s, 6H) ppm .

• · ·

- Example 8928 (2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(pyridin-4-ylmethyl) thio] butanoyl} -4-fluoropyrrolidin-2-yl) carbonitrile hydrochloride

A. (2R) -2 - [(tert-Butoxycarbonyl) amino] -3-methyl-3 - [(pyridin-4-ylmethyl) thio] butyric acid, 1 g (0.00401 mol) (2R) -2- To potassium hydroxide containing [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylbutyric acid, to a 1 M aqueous solution was added 4-bromomethylpyridine hydrobromide (1.1 g, 0.00441 mol) at room temperature and after 17 hours. the reaction mixture was diluted with water and washed with diethyl ether. The organic layer was discarded while the aqueous phase was cooled to 0 ° C to 5 ° C and acidified to pH 4.0 with concentrated hydrochloric acid. After extraction with ethyl acetate, the extract was dried over sodium sulfate and evaporated to dryness. 482 mg (35%) of the title compound are obtained as a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 8.48 (d, 2H, > 6.0 Hz), 7.40 (d, 2H, > 5.6 Hz), 5.48 (broad d, 1H, > 9.2 Hz), 4.41 (d, 1H, J = 9.2 Hz), 3.82 (s, 2H) 1.52-1.38 (m, 15H) ppm.

B. Tert-Butyl- (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - [(pyridin-4-ylmethyl) thio] ] propylcarbamate ml, 482 mg (0.00142 mole) of Compound A and 549 mg (0.0042 mole) of N, N-diisopropylethylamine in dimethylformamide are added at room temperature to 810 mg (0.00213 moles) of HATU and after 30 min. 447 mg (0.00156 mol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate. After stirring overnight, the reaction was quenched by the addition of sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography using a 1: 1 mixture of hexane and ethyl acetate as eluent. This gave 476 mg (77%) of Compound B.

1 H-NMR (CDCl 3 ) 400 MHz δ 8.51 (d, 2H, > 4.4 Hz), 7.31 (d, 2H, > 6.4 Hz), 5.43 (broad d, 1H, > 9.6 Hz), 5.43 (broad d, 1H, > 51.2 Hz), 5.01 (d, 1H, > 9.6 Hz), 4.39 (d, 1H, > 9.6 Hz) ), 4.35-3.96 (m, 2H), 3.80 (s, 2H), 2.70 (dd, 1H,> 15.4), 2.46-2.29 (m, 1H) , 1.451.41 (m, 15H) ppm.

C. (2S, 4S) -1 - {(2R) -2-Amino-3-methyl-3 - [(pyridin-4-ylmethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride ml, 476 Trifluoroacetic acid (5 ml) was added to a solution of Compound B in mg (0.00109 mol) of Compound B, followed by stirring at room temperature for 16 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The organic

The -90 phase is separated, dried over sodium sulfate and evaporated to dryness. The crude solid obtained was subjected to silica gel chromatography, eluting with a mixture of 99% dichloromethane and 1% (v / v) methanol (2M ammonia). The resulting pure solid was dissolved in a 1: 1 mixture of acetone and diethyl ether and precipitated with 2M hydrochloric acid in diethyl ether. The solid formed was filtered off under vacuum and washed with diethyl ether and dried under high vacuum. 107 mg of Compound C are obtained.

1 H-NMR (d 4 -MeOH) 400 MHz δ 8.81 (d, 2H, J = 4.8 Hz), 8.08 (d, 2H, > 6.4 Hz), 5.51 (broad d, 1H, 51.2 Hz), 5.10 (d, 1H, J = 9.2 Hz), 4.35-3.96 (m, 4H), 2.65-2.43 (m, 2H) , 1.621.42 (m, 6H) ppm.

Example 29 (2S, 4S) -1 - {(2R) -2-amino-3 - [(4-fluorobenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula XLII

A. (2R) -2 - [(tert-Butoxycarbonyl) amino] -3 - [(4-fluorobenzyl) thio] -3-methylbutyric acid, 1.0 g (0.00401 mol) (2R) -2- [ To potassium hydroxide containing (tert-butoxycarbonyl) amino] -3-mercapto-3-methylacetic acid, 1-bromomethyl-4-fluorobenzene (834 mg, 0.00441 mol) was added to a 1M aqueous solution at room temperature and after 17 hours, the reaction was stirred at room temperature. the reaction mixture was diluted with water and washed with diethyl ether. The organic layer was then discarded and the aqueous phase was cooled to 0 ° C to 5 ° C and then acidified to pH 3.5 with concentrated hydrochloric acid. After extraction with ethyl acetate, the extract was dried over magnesium sulfate and evaporated to dryness. 1.2 g (86%) of Compound A are thus obtained as an oil.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.29-7.26 (m, 2H), 6.99-6.94 (m, 2H), 5.40 (broad d, 1H, J = 8, 0 Hz), 4.40 (broad d, 1H, J = 8.0 Hz), 3.80-3.74 (m, 2H) 1.50-1.40 (m, 15H) ppm.

B. Tert-Butyl (1R) - {[(2S > 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2 - [(4-fluorobenzyl) thio] -2-methylpropylcarbamate, ml, 1.9 g (0.0051 mol) of HATU were added at room temperature to 2 g (0.0034 mol) of Compound A and 1.3 g (0.0101 mol) of il, diisopropylethylamine containing dimethylformamide. after 1.1 g (0.0037 mol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate. After stirring overnight, the reaction was quenched by the addition of sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride, dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue is a column chroma • · · · · · · · · * · ······ ·

-91 was used as a eluent, using a 1: 1 mixture of hexane and ethyl acetate as eluent. 929 mg (61%) of compound B are obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.33 (dd, 2H, J = 8.4 Hz), 6.96 (dd, 2H, > 8.8 Hz), 5.42 (broad d, 1H, > 9.2 Hz), 5.43 (broad d, 1H, > 51.6 Hz), 5.02 (d, 1H, > 9.6 Hz), 4.38 (d, 1H, > 9.2) Hz), 4.34-3.97 (m, 2H), 3.82 (s, 2H), 2.69 (dd, 1H,> 15.4 Hz), 2.46-2.28 (m, 1H), 1.45-1.41 (m, 15H) ppm.

C. Tert-Butyl (1R) -1 [(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2 - [(4-fluorobenzyl) sulfonyl] -2-methylpropylcarbamate

To 100 ml of a 929 mg (0.0019 mol) compound of dichloromethane containing compound B was added 3-chloroperoxybenzoic acid (3.3 g, 0.0111 mol) in 57-86% purity, and the mixture was stirred at room temperature for 16 hours. then neutralized with 2 M aqueous potassium hydroxide solution. The organic phase was then dried over magnesium sulfate and evaporated to dryness. Yield: 678 mg (97%). The resulting off-white solid was used without further purification.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.40 (dd, 2H, &gt; 8.8 Hz), 7.07 (dd, 2H, > 8.6 Hz), 5.52 (broad d, 1H, > 9.2 Hz), 5.43 (broad d, 1H, > 51.2 Hz), 5.03 (d, 1H, > 9.6 Hz), 4.97 (d, 1H, > 9.6) Hz), 4.36-3.74 (m, 4H), 2.70 (dd, 1H,> 15.2 Hz), 2.47-2.28 (m, 1H), 1.72-1, 35 (m,

15H) ppm.

D. (2S, 4S) -1 - {(2R) -2-Amino-3 - [(4-fluorobenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride ml, 678 mg (0 Trifluoroacetic acid (5 ml) was added to a solution of Compound C in dichloromethane (00140 mole), and the resulting mixture was stirred at room temperature for 16 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was then separated, dried over magnesium sulfate and evaporated to dryness. The crude solid obtained was subjected to silica gel chromatography, eluting with a mixture of 99% dichloromethane and 1% (v / v) methanol (2M ammonia). The resulting clear solid was dissolved in a 1: 1 mixture of acetone and diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The solid formed was filtered off under vacuum and then washed with diethyl ether and dried under high vacuum to give 254 mg of compound D as a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.39 (dd, 2H, > 8.4 Hz), 7.08 (dd, 2H, > 8.6 Hz), 5.41 (broad d, 1H, &gt;) 50.8 Hz), 4.94 (d, 1H, > 9.6 Hz), 4.63 (d, 1H, > 13.2 Hz), 4.35-3.55 (m, 4H), 2 , 70 (dd, 1H,> 15.4 Hz), 2.43-2.26 (m, 1H), 1.80-1.39 (m, 8H) ppm.

-9 230. Example 2 (2S, 4S) -1 - {(2R) -2-Amino-3-methyl-3 - [(3-phenoxybenzyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile Liquid chloride (XLIII)

A. (2R) -2 - [(Tert-Butoxycarbonyl) amino] -3-methyl-3 - [(3-phenoxybenzyl) thio] butyric acid, 1.0 g (0.00401 mol) (2R) -2- To a potassium hydroxide containing [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylbutyric acid, 1-chloromethyl-3-phenoxybenzene (964 mg, 0.00441 mol) was added to a 1 M aqueous solution at room temperature, followed by 17 ml. After 1 hour, the reaction mixture was diluted with water and washed with diethyl ether. The organic layer was then discarded while the aqueous phase was cooled to 0 ° C to 5 ° C and then acidified to pH 3.5 with concentrated hydrochloric acid. The reaction mixture was extracted with diethyl ether and the extract was dried over magnesium sulfate and evaporated to dryness. 1.4 g (82%) of Compound A were obtained as a white solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.34-6.98 (m, 8H), 6.85 (dd, III, J = 8.0 Hz), 5.44 (m, 1H), 4 , 38 (m, 1H), 3.80 (m, 2H), 1.50-1.40 (m, 15H) ppm.

B. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - [(3-phenoxybenzyl) thio] propylcarbamate 1.8 g (0.0048 mol) of DMSO was added to a solution of Compound A in 1.4 g (0.0032 mole) of Compound A and 1.3 g (0.0100 M) of N, N-diisopropylethylamine. and after 30 minutes, 1.0 g (0.0035 mol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate. After stirring overnight, the reaction was quenched by the addition of sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography using a 1: 1 mixture of hexane and ethyl acetate as eluent. Yield: 1.1 g (65%) of Compound B.

1 H-NMR (CDCl 3) 400 MHz δ 7.34-6.97 (m, 8H), 6.84 (dd, 1H, > 8.0 Hz), 5.44 (broad d, 1H, > 9, 2 Hz), 5.39 (broad d, 1H, > 51.2 Hz), 5.01 (d, 1H, > 9.6 Hz), 4.36 (d, 1H, > 9.2 Hz), 4.29 - 3.90 (m, 2H), 3.80 (s, 2H), 2.66 (dd, 1H,> 15.4 Hz), 2.43-2.26 (m, 1H), 1.52-1.38 (m, 15H) ppm.

C. Tert-Butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2 - [(3-phenoxybenzyl) sulfonyl] propylcarbamate To a solution of 600 mg (0.0011 mol) of compound B in dichloromethane was added 2.0 g (0.011 mol) of 57-86% 3-chloroperoxybenzoic acid, and the resulting mixture was stirred at room temperature for 16 hours and then 2 mol / L. 1-point aqueous potassium • · ·

THE

It is neutralized with -93 hydroxide solution. The organic phase is then dried over magnesium sulfate and evaporated to dryness. 594 mg (93%) of compound C are obtained. The resulting off-white solid was used in the next step without further purification.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.34-7.00 (m, 9H), 5.40 (broad d, 1H, J = 51.2 Hz), 5.27 (broad d, 1H,> 8.8 Hz), 4.93 (d, 1H, J = 9.6 Hz), 4.62 (d, 1H, > 13.2 Hz), 4.46-3.55 (m, 4H), 2.69 (dd, 1H,> 15.4 Hz), 2.42-2.25 (m, 1H), 1.62-1.43 (m, 15H) ppm.

D. (2S, 4S) -1 - {(2R) -2-Amino-3-methyl-3 - [(3-phenoxybenzyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride

Trifluoroacetic acid (5 ml) was added to a solution of 45 ml (678 mg, 0.00106 mol) of dichloromethane, and the reaction mixture was stirred at room temperature for 16 hours and then neutralized with saturated aqueous sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness. The crude solid thus obtained was purified by chromatography on silica gel using a mixture of 99% (v / v) dichloromethane and 1% (v / v) methanol (2M ammonia). The resulting clear solid was dissolved in 1: 1 acetone / diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The solid formed was filtered off under vacuum and washed with diethyl ether and dried under high vacuum to give 268 mg of Compound D as a white solid.

1 H NMR (d 6 -DMSO) 400 MHz δ 7.42-6.99 (m, 9H), 5.54 (broad d, 1H, > 51.2 Hz),

5.04 (d, 1H, > 9.2 Hz), 4.70 (m, 2H), 4.46 (m, 1H), 4.16-3.79 (m, 2H), 2.55- 2.30 (m, 2H), 1.55 (s, 3H), 1.47 (s, 3H) ppm.

Example 31 (2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(3-phenoxybenzyl) thio] butanoyl} -4-fluoro-pyrrolidine-2-carbonitrile (XLIV) hydrochloride ml, 500 mg (0.0010 mol) of tert-butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2- To a solution of ((3-phenoxybenzyl) thio] propylcarbamate in dichloromethane was added 5 ml of trifluoroacetic acid, and the reaction mixture was stirred at room temperature for 16 hours and then neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over magnesium sulfate and evaporated to dryness. The crude solid thus obtained was subjected to chromatographic purification using 99 volumes of dichloromethane and 1% v / v methanol in 2M ammonia. The resulting clear solid was dissolved in a 1: 1 mixture of acetone and diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The resulting SIL 94 -Land material was filtered in vacuo and washed with diethyl ether and dried under high vacuum to give 132 mg of the title compound.

1 H-NMR (D 2 O) 400 MHz δ 7.17-671 (m, 9H), 5.38 (broad d, 1H,> 50.4 Hz), 5.00 (d, 1H,> 9, 6 Hz), 4.16-3.60 (m, 4H), 2.62-2.30 (m, 2H), 1.38-1.29 (s, 6H) ppm.

EXAMPLE 32 (2S, 4S) -1 - ((2R) -2-Amino-3 - {[(5-chloro-1,1-dioxido-1-benzothien-3-yl) methyl] sulfonyl} - (XLV) 3 metilbutanoiI) -4-fluoropyrrolidine-2-carbonitrile hydrochloride

A. (2R) -2 - [(tert-Butoxycarbonyl) amino] -3 - {[(5-chloro-1-benzothien-3-yl) methyl] thio} -3-methylbutyric acid, 1.0 g (0) (00401 mole) To a potassium hydroxide solution containing (2R) -2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylacetic acid, 1.2 g (0.00441 moles) of 3 g of water are added at room temperature to a 1 M aqueous solution. (bromomethyl) -5-chloro-1-benzothiophene and 10 ml of 1,4-dioxane, and the reaction mixture was diluted with water after 17 hours and washed with diethyl ether. The organic layer was then discarded while the aqueous phase was cooled to 0 ° C to 5 ° C and then acidified to pH 3.5 with concentrated aqueous hydrochloric acid. After extraction with diethyl ether, the extract was dried over magnesium sulfate and evaporated to dryness. 1.0 g (59%) of Compound A were obtained as a tan solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.84 (s, 1H), 7.72 (d, 1H,> 8.4 Hz), 7.39 (s, 1H), 7.30 (d, 1H, > 8.4 Hz), 5.44 (m, 1H), 4.45 (m, 1H, > 7.6 Hz), 4.07-4.00 (m, 2H), 1.55- 1.40 (m,

15H) ppm.

B. Tert-Butyl- (1R) -2 - {[(5-chloro-1-benzothien-3-yl) methyl] thio} -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrole] 1-yl] carbomyl} -2-methylpropylcarbamate, 1.0 g (0.0023 mol) of Compound A and 902 mg (0.007 mol) of N, N-diisopropylethylamine in dimethylformamide are added at room temperature to 1.3 g (0.00345 mole) HATU and after 30 minutes 725 mg (0.025 mol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate. After stirring overnight, the reaction was quenched by the addition of sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography using hexane / ethyl acetate (1: 1) as the eluent. This gave 738 mg (60%) of Compound B.

4

-95'H NMR (CDCl3) 400MHz δ 7.91 (s, lH), 7.72 (d, lH,> 8.8 Hz), 7.47 (s, lH), 7.30 ( d, 1H, > 8.4 Hz), 5.49-5.35 (m, 2H), 5.04 (d, 1H, > 9.6 Hz), 4.41 (d, 1H, > 9, 2 Hz), 4.333.98 (m, 4H), 2.69 (dd, 1H,> 15.2 Hz), 2.46-2.29 (m, 1H), 1.47-1.40 (m Δ5H) ppm.

C. Trict-butyl (1R) -2 - {[(5-chloro-1,1-dioxido-1-benzothien-3-yl) methyl] sulfonyl} -1 - {[(2S, 4S) -2- cyano-4-fluoropyrrolidine-l-yl] carbonyl} -2-metilpropilkarbamát

To 100 ml of dichloromethane solution containing 738 mg (0.0014 mol) of Compound B was added 4.8 g (0.028 mol) of 3-chloroperoxybenzoic acid (57-86%), and the mixture was stirred at room temperature for 16 hours and then stirred for 2 hours. Neutralized with a 0 mol / L aqueous solution of potassium hydroxide. The organic layer was dried over magnesium sulfate and evaporated to dryness. 803 mg (97%) of compound C are obtained. The resulting off-white solid was used in the next step without further purification.

1 H-NMR (CDCl 3 ) 400 MHz δ 8.05 (s, 1H), 7.96 (d, 1H, > 7.6 Hz), 7.48 (m, 3H), 5.45 (broad d , 1H> 10 Hz), 5.44 (broad d, 1H,> 50.8 Hz), 5.02 (d, 1H, > 10 Hz), 4.95 (d, 1H, > 9.6 Hz) , 4.77-3.96 (m, 4H), 2.70 (dd, 1H,> 14.8 Hz), 2.46-2.30 (m, 1H), 1.70-1.37 ( m, ί 5H) ppm.

D. (2S, 4S) -1 - ((2R) -2-Amino-3 - {[(5-chloro-1,1-dioxido-1-benzothien-3-yl) methyl] sulfonyl} -3-methylbutanil ) 4-Fluoropyrrolidine-2-carbonitrile hydrochloride, 5 ml of trifluoroacetic acid, containing 500 mg (0.0010 mol) of dichloromethane, are added, and the reaction mixture is stirred at room temperature for 16 hours and then neutralized with saturated aqueous sodium bicarbonate. . The organic layer was separated, dried over magnesium sulfate and evaporated to dryness. The crude solid obtained was subjected to silica gel chromatography, eluting with a mixture of 99% dichloromethane and 1% (v / v) methanol (2M ammonia). The resulting clear solid was dissolved in a 1: 1 mixture of acetone and diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The precipitate formed is filtered off under vacuum and dried under high vacuum. 132 mg a

Compound D is obtained.

1 H-NMR (D 2 O) 400 MHz δ 7.99 (s, 1H), 7.31-7.56 (m, 3H), 5.44 (broad d, 1H,> 50.4 Hz), 5 , 01 (d, 1H,> 9.6 Hz), 4.19-3.80 (m, 4H), 2.66-2.22 (m, 2H), 1.58 (s, 3H), 1 , 43 (s, 3H) ppm.

-9 633. Example 2 (2S, 4S) -1 - {(2R) -2-amino-3 - [(2,3-benzoxadiazol-5-ylmethyl) thio] -3-methylbutanoyl} -4-fluoropyrrolidin-2-yl carbonitrile hydrochloride

A. (2R) -3 - [(2,1,3-Benzoxadiazol-5-ylmethyl) thio] -2 - [(tert-butoxycarbonyl) amino] -3-methylbutyric acid

To a potassium hydroxide solution (50 ml, 1 g (0.00401 mol) containing (2R) -2 - [(tert-butoxycarbonyl) amino] -3-mercapto-3-methylacetic acid in a 1 M aqueous solution was added 940 mg (0, 00441 mol) 5- (bromomethyl) -2,1,3-benzodioxazole and 5 ml 1,4-dioxane and after 17 hours the reaction mixture is diluted with water and washed with diethyl ether. The organic phase is then discarded, then the aqueous phase is cooled to 0 ° C to 5 ° C and then to water.

Acidify to pH 4.0 with concentrated hydrochloric acid. After extraction with ethyl acetate, the extract was dried over sodium sulfate and evaporated to dryness. 622 mg (41%) of Compound A were obtained as a brown solid.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.76 (d, 1H, J = 9.2 Hz), 7.72 (s, 1H), 7.44 (d, 1H,> 9.2 Hz) , 5.40 (broad d, 1H, > 8.0 Hz), 4.46 (broad d, 1H, J = 8.4 Hz), 3.89 (s, 2H), 1.47-1.40 (m,

15H) ppm.

B. Tert-Butyl- (1R) -2 - [(2,1,3-benzoxadiazol-5-ylmethyl) thio] -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] ] Carbonyl} -2-methylpropylcarbamate ml, 622 mg (0.00163 mole) of Compound A and 632 mg (0.0049 mole) of N, N-diisopropylethylamine in dimethylformamide are added at room temperature to 930 mg (0.00244 mol) of HATU. and after 30 minutes (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (514 mg, 0.00180 mol). After stirring overnight, the reaction was quenched by the addition of sodium bicarbonate and extracted twice with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography using a 1: 1 mixture of hexane and ethyl acetate as eluent. 444 mg (45%) of compound B are obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.78 (s, 1H), 7.76 (d, 1H, > 9.2 Hz), 7.48 (d, 1H, > 9.2 Hz), 5.43 (broad d, 1H, > 9.6 Hz), 5.45 (broad d, 1H, > 50.8 Hz), 5.02 (d, 1H, > 9.6 Hz), 4.44 (d, 1H, > 9.6 Hz), 4.39-3.89 (m, 4H), 2.72 (dd, 1H, > 15.2), 2.48-2.32 (m, 1H ), 1.6030 1.40 (m, 15H) ppm.

C. (2S, 4S) -1 - {(2R) -2-Amino-3 - [(2,1,3-benzoxadiazol-5-ylmethyl) thio] -3-methylbutano} -4-fluoropyrrolidine-2-carbonitrile hydrochloric acid (444 mg, 0.770 mmol) containing dichloromethane was added trifluoroacetic acid (5 mL) and the reaction mixture was stirred at room temperature for 16 h.

-97a and then neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The crude solid obtained was subjected to silica gel chromatography, eluting with a mixture of 99% dichloromethane and 1% (v / v) methanol (2M ammonia). The resulting clear solid was dissolved in 1: 1 acetone / diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The solid formed is filtered off under vacuum and washed with diethyl ether and dried under high vacuum. 105 mg of compound C are obtained.

1 H-NMR (d 6 -DMSO) 400 MHz δ 8.02-7.99 (m, 2H), 7.63 (d, 1H, 3 = 9.6 Hz), 5.55 (broad d, 1H, J = 51.2 Hz), 5.07 (d, 1H,> 9.2 Hz), 4.22-3.98 (m, 5H), 2.58-2.32 (m, 2H), 1 , 48 (s, 3H), 1.40 (s, 3H) ppm.

Example 34 (2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(pyridin-4-ylethyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula (XLVII) ml, 500 mg (0.0011 mol) of tert-butyl (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2- [ To a solution of (pyridin-4-ylmethyl) thio] propylcarbamate in dichloromethane was added 10 ml of trifluoroacetic acid, and the reaction mixture was stirred at room temperature for 16 hours and then 2.0 g (0.00114 mol) of 3-chloroperoxybenzoic acid was added. The reaction mixture was stirred for 4 hours and then neutralized with 2N aqueous sodium hydroxide. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The crude solid obtained was subjected to silica gel chromatography, eluting with a mixture of 99% dichloromethane and 1% (v / v) methanol (2M ammonia). The resulting clear solid was dissolved in a 1: 1 mixture of acetone and diethyl ether and then precipitated with 2M hydrochloric acid in diethyl ether. The solid formed is filtered off under vacuum, washed with diethyl ether and dried under high vacuum. 22 mg of the title compound are obtained.

1 H-NMR (d 4 -CDCl 3 ) 400 MHz δ 8.64 (d, 2H, J = 5.6 Hz), 7.37 (d, 2H, > 5.6 Hz), 5.42 (broad d, 1H, > 51.2 Hz), 4.94 (d, 1H, > 9.6 Hz), 4.77 (d, 1H, > 13.2 Hz), 4.39-3.75 (m , 4H), 2.71 (dd, 1H, > 15.6 Hz), 2.43-2.29 (m, 1H), 2.06-1.86 (br s, 2H), 1.62 ( s, 3H), 1.46 (s, 3H) ppm.

Example 35 (2S, 4S) -1 - [(2S) -2-Amino-3-pyridin-4-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula (XLVIII)

To -9825 ml of dry dimethylformamide was added 705 mg (2.65 mmol) of (2S) -2 - [(tert-butoxycarbonyl) amino] -3-pyridin-4-ylpropionic acid, 1.0 g (2.65 mmol) of HATU. and 0.46 ml (2.65 mmol) of N, N-diisopropylethylamine, followed by stirring at room temperature for 30 minutes (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzene (581 mg, 1.99 mmol). 0.35 ml (1.99 mmol) of Ν, diisopropylethylamine was added. The resulting solution was stirred at room temperature for 12 hours, and then saturated aqueous sodium bicarbonate (100 mL) was added. The aqueous mixture was extracted twice with 100 ml of ethyl acetate, and the combined extract was washed with saturated aqueous sodium chloride (100 ml), dried over magnesium sulfate and evaporated to dryness to give a crude solid. This was then purified by silica gel column chromatography using hexane / ethyl acetate 4: 1 as eluent. The resulting solid was stirred in 20 ml of 4M HCl in dioxane for 2 hours and then diethyl ether (100 ml) was added. The precipitated solid was collected by filtration and dried under high vacuum. 388 mg (1.3 mmol, 65%) of the title compound were obtained as a white solid.

UI-NMR (d 6 -DMSO) 400 MHz δ 8.92 (br s, 3H), 8.84 (d, 2H, J = 6.2 Hz), 7.96 (d, 2H,> 6.2 Hz), 5.45 (d, 1H, > 51Hz), 5.00 (d, 1H, > 8.8 Hz), 4.47 (broad m, 1H), 4.05-3.78 (m, 2H), 3.41-3.36 (m, 2H), 2.42-2.25 (m, 2H) ppm.

Example 36 (2S, 4S) -1 - [(2S) -2-Amino-3-pyridin-3-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride (XLIX) was added to 534 mg (2 ml of anhydrous dimethylformamide). 0 mmol) (2S) -2 - [(tert-butoxycarbonyl) amino] -3-pyridin-3-ylpropionic acid, 0.76 g (2.0 mmol) of HATU and 0.35 ml of 2.0 mmol) And then the mixture was stirred at room temperature for 30 minutes, followed by (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (438 mg, 1.5 mmol) and an additional 0.26 ml. (1.5 mmol) Ν, Ν-diisopropylethylamine was added. The resulting solution was stirred at room temperature for 12 hours, then saturated aqueous sodium bicarbonate (150 mL) was added. The resulting aqueous mixture was extracted three times with 100 ml of ethyl acetate, and the combined extract was washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The crude solid thus obtained was subjected to silica gel chromatography, eluting with a 4: 1 mixture of hexane and ethyl acetate. The resulting solid was stirred for 2 hours with 25 ml of 4M hydrochloric acid in dioxane, and then 200 ml of diethyl ether was added to the reaction mixture, · · · · · · · · · · · · · · · · ··· »* · · E *« * »· * ··

-99hozzá. The precipitated solid was filtered off and dried under high vacuum. 266 mg (0.89 mmol, 59%) of the title compound were obtained as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 8.88 (s, 1H), 5.51 (d, 1H, J = 51Hz), 5.01 (d, 1H, J = 8.8 Hz) , 4.45-4.38 (broad m, 1H), 4.00-3.86 (m, 2H), 3.38-3.27 (m, 2H), 2.42-2.30 (m , 3H) ppm.

Example 37 (2S, 4S) -1 - [(2S) -2-amino-3-piperidin-4-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride of formula L

A. (2S) -2 - [(space c-Butoxycarbonyl) amino] -3-piperidin-4-ylpropionic acid acetate

To a solution of (2S) -2 - [(tert-butoxycarbonyl) amino] -3-pyridin-4-ylpropionic acid (50 ml, 0.69 g, 2.58 mmol) in glacial acetic acid was added 0.35 g (50% w / w). a palladium catalyst with a metal content of about 1% by weight, followed by hydrogenation under a hydrogen atmosphere under a pressure of 4.14 · 10 5 Pa. The reaction mixture was filtered through Celite and the filtrate was evaporated. The resulting white solid was dried under high vacuum to give Compound A as an acetate salt (822 mg, 2.48 mmol, 96%).

¹H NMR (dg-DMSO) 400 MHz δ 10.5 (broad s, 1H), 6.21-6.19 (broad m, 1H), 3.693.62 (m, 1H), 3.19-3, 06 (m, 2H), 2.75-2.65 (m, 2H), 1.92 (s, 3H), 1.80-1.45 (m, 6H), 1.35 (s, 9H) , 1.21-1.05 (m, 1H) ppm.

B. (2S) -2 - [(tert-Butoxycarbonyl) amino] -3- [1- (tert-butoxycarbonyl) piperidin-4-yl] propionic acid

To 150 ml of dichloromethane solution containing (2S) -2 - [(tert-butoxycarbonyl) amino] -3-piperidin-4-ylpropionic acid acetate (1.0 g, 3.00 mmol) was added triethylamine (1.52 g, 815 mmol). Di-tert-butyldicarbonate (786 mg, 3.6 mmol) was added, followed by stirring for 12 hours. Water (50 ml) and dichloromethane (300 ml) were then added and the pH was adjusted to 4 with 1 M aqueous hydrochloric acid. The ethyl acetate layer was then separated, dried over magnesium sulfate, born and the solvent removed in vacuo. The resulting clear oil was dried under high vacuum. 1.06 g (2.86 mmol, 95%) of compound B are obtained as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 12.4 (br s, 1H), 7.08 (d, 1H, J = 8.3 Hz), 3.9830 3.81 (broad m, 3H) ), 2.78-2.59 (broad m, 2H), 1.68-1.42 (m, 6H), 1.39 (s, 16H), 1.02-0.89 (m,

2H) ppm.

·· * ·

- 100C. To (2S, 4S) -1 - [(2S) -2-Amino-3-piperidin-4-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride in anhydrous dimethylformamide was added 0.85 g (2.28 mmol) ( 2S) -2 - [(tert-Butoxycarbonyl) amino] -3- [1- (tert-butoxycarbonyl) piperidin-4-yl] propionic acid, 0.87 g (2.228 mmol) of HATU and 0.40 ml (2 , 28 mmol) Ν, di-diisopropylethylamine, and the resulting mixture was stirred at room temperature for 30 minutes and then (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (500 mg, 1.71 mmol) was added. 0.30 ml (1.71 mmol) of Ν-diisopropylethylamine was added. The resulting solution was stirred at room temperature for 12 hours, and then saturated aqueous sodium bicarbonate (100 mL) was added. The resulting aqueous mixture was extracted twice with 100 ml of ethyl acetate, and the combined extract was washed with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The crude solid obtained was subjected to silica gel chromatography, eluting with a 4: 1 mixture of hexane and ethyl acetate. The resulting solid was stirred in 20 ml of 4M HCl in dioxane for 2 hours and then diethyl ether (100 ml) was added. The precipitate formed is filtered off and dried under high vacuum. Thus, 432 mg (1.26 mmol, 74%) of Compound C is obtained as a white solid.

1 H-NMR (dg-DMSO) 400 MHz δ 9.0-8.83 (br s, 2H), 8.80-8.60 (br s, 311), 5.52 (d, 1H, J = 51Hz) ), 5.06 (d, 1H, J = 8.8 Hz), 4.07-4.01 (broad m, 1H), 3.94-3.81 (m, 2H), 3.23-3 , 20 (m, 2H), 2.87 (s, 1H), 2.74-2.66 (m, 3H), 2.46-2.37 (m, 2H), 1.95-1.91 (m, 1H), 1.77-1.58 (m, 3H), 1.42-1.31 (m, 1H) ppm.

Example 38 (2S, 4S) -1 - [(2S) -2-Amino-3-piperidin-3-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride of formula LI

A. (2S) -2 - [(tert-Butoxycarbonyl) amino] -3-piperidin-3-ylpropionic acid, 0.8 g (3.0 mmol) of (2S) -2 - [(tert-butoxycarbonyl) amino] - To the glacial acetic acid solution containing 3-pyridin-3-ylpropionic acid was added 0.40 g of 50% by weight, 10% by weight of metal-containing palladium catalyst, followed by hydrogenation under a pressure of 4.14 · 10 5 Pa under a hydrogen atmosphere. The reaction mixture was filtered through Celite and the filtrate was evaporated and dried under high vacuum. 946 mg (2.85 mmol, 95%) of Compound A are obtained as the acetate salt.

1 H-NMR (d 6 -DMSO) 400 MHz δ 10.2 (broad s, 1H), 6.15-6.05 (m, 1H), 3.69-2.64 (m, 1H), 3, 21-3.07 (m, 2H), 2.67-2.61 (m, 1H), 2.39-2.31 (broad m, 1H), 1.95 (s, 3H), 1.911.41 (m, 6H), 1.91 (s, 9H), 1.08-1.01 (m, 1H) ppm.

• «·« · «· * · # · · β · · e fc * • · ♦ ··· * # · * · *

- 101 B. (2S) -2 - [(tert-Butoxycarbonyl) amino] -3- [1- (tert-butoxycarbonyl) piperidin-3-yl] propionic acid

To 150 ml of dichloromethane solution containing 1.0 g (3.00 mmol) of Compound A in triethylamine (1.52 g, 15 mmol) and di-tert-butyldicarbonate (786 mg, 3.6 mmol) are added and the mixture is stirred for 12 hours. . The reaction was then quenched by addition of 50 ml of water and 300 ml of dichloromethane. The organic layer was separated and the pH of the aqueous phase was adjusted to 4 with 1M aqueous hydrochloric acid. After extraction with ethyl acetate, the combined organic phases are dried over magnesium sulfate and concentrated in vacuo. The resulting clear oil was dried under high vacuum to give Compound B as a white solid (1.07 g, 2.87 mmol, 95%).

NMR NMR (d6-DMSO) 400 MHz δ 12.15 (broad s, 1H), 7.17 (d, 1H, J = 8.3 Hz), 3.933.87 (broad m, 3H), 2.61 -2.45 (broad m, 2H), 1.73-1.40 (m, 6H), 1.35 (s, 16H), 1.2-0.89 (m, 2H) ppm.

C. (2S, 4) -1 - [(2S) -2-Amino-3-piperidin-3-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride

Compound B, 0.85 g (2.28 mmol), HATU 0.87 g (2.28 mmol) and Ν, diisopropylethylamine (0.40 mL, 2.28 mmol) are added to dry dimethylformamide (25 mL, 25 mL, 2.28 mmol). Stirring at room temperature for 30 minutes. (2S, 4S) -4-Fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (500 mg, 1.71 mmol) and és, diisopropylethylamine (0.30 mL, 1.71 mmol) were added. The resulting solution was stirred at room temperature for 12 hours, and then saturated aqueous sodium bicarbonate (100 mL) was added. The aqueous mixture was extracted twice with 100 ml of ethyl acetate, and the combined extract was washed with saturated aqueous sodium chloride (50 ml), dried over magnesium sulfate and concentrated in vacuo. The crude solid obtained was subjected to silica gel chromatography, eluting with a 4: 1 mixture of hexane and ethyl acetate. The resulting solid was stirred for 2 hours in 20 ml of 4M HCl in dioxane and then diethyl ether (100 ml) was added. The precipitate formed is collected by filtration and then dried under high vacuum. 419 mg (1.23 mmol, 72%) of Compound C were obtained as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 9.0-8.83 (br s, 2H), 8.60-8.50 (br s, 3H),

5.52 (d, 1H, J = 51Hz), 5.02 (d, 1H, J = 8.8 Hz), 4.13-4.08 (broad m, 1H), 3.99-3.87 (m, 2H)

3.37-3.31 (m, 2H), 3.05-3.01 (ni, 1H), 2.87 (m, 2H), 2.46-2.37 (m, 2H), 1, 95-1.91 (m, 5H), 1.22-1.11 (m, 1H) ppm.

·· «« <*> 4 «» * · · * * .1 »

- »· t ♦ · * ♦ W ·> *» «*« * * · ϊ «·

-10 239. Example 2 (2S, 4S) -1 - [(2S) -2-Amino-3-piperidin-2-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride (LII)

A. (2S) -2 - [(tert-Butoxycarbonyl) amino] -3-piperidin-2-ylpropionic acid

To 50 ml of glacial acetic acid solution of (2S) -2 - [(tert-butoxycarbonyl) amino] -3-pyridin-2-ylpropionic acid (1.6 g, 6.0 mmol) was added 0.80 g of 50% w / w. wt% palladium on carbon, followed by hydrogenation under a hydrogen atmosphere of 4.14 × 10 5 is performed under vacuum. The reaction mixture was then filtered through Celite and the filtrate was evaporated and dried under high vacuum. so

951 mg (2.85 mmol, 95%) of Compound C is obtained as the acetate salt.

1 H-NMR (d 6 -DMSO) 400 MHz δ 10.15 (br s, 1H), 6.21-6.19 (m, 1H), 3.69-2.64 (m, 1H), 3 , 61-3.56 (m, 2H), 3.27-3.12 (m, 2H), 2.72-2.65 (m, 1H), 1.89 (s, 3H) 1.81- 1.63 (m, 5H), 1.52-2.42 (m, 1H), 1.91 (s, 9H) ppm.

B. (2S) -2 - [(tert-Butoxycarbonyl) amino] -3- [1- (tert-butoxycarbonyl) piperidin-2-yl] propionic acid

To 150 ml of dichloromethane solution containing 1.5 g (4.50 mmol) of Compound A was added triethylamine (2.27 g, 23 mmol) and di-tert-butyldicarbonate (1.18 g, 5.4 mmol) and then stirred for 12 hours. After stirring for a second time, 50 ml of water and 300 ml of dichloromethane were added and the pH of the reaction mixture was adjusted to 3 with 1 M hydrochloric acid. The organic phase is then separated, dried over magnesium sulfate and concentrated in vacuo. The resulting clear oil was dried under high vacuum to give 1.68 g (4.45 mmol, 95%) of Compound B as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 12.2 (br s, 1H), 7.15 (d, 1H, J = 8.3 Hz), 4.253.99 (broad m, 3H), 3.89 -3.78 (br m, 2H), 2.68-2.58 (m, 1H) 1.79-1.40 (m, 5H), 1.35 (s, 16H), 1.2-1 , 14 (m, 2H) ppm.

C. (2S, 4S) -1 - [(2S) -2-Amino-3-piperidin-2-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride in anhydrous dimethylformamide is added 850 mg (2.28 mmol) of B , HATU 869 mg (2.28 mmol) and Ν, diisopropylethylamine (0.40 mL, 2.28 mmol) and 500 mg (1.71 mmol) (2S) after stirring at room temperature for 30 minutes. 4S) -4-Fluoro-230-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and further 0.30 ml (1.71 mmol) of, diisopropylethylamine. The resulting solution was stirred at room temperature for 12 hours and then 110 mL of saturated aqueous sodium bicarbonate solution was added. The aqueous mixture was extracted twice with ethyl acetate (100-100 mL) and the combined organic layer was washed with saturated aqueous sodium chloride (50 mL) and dried over magnesium sulfate. Solvent in vacuo * ·> * · * · ** · «

After removal of 103, a crude solid was obtained which was subjected to silica gel chromatography, eluting with a 4: 1 mixture of hexane and ethyl acetate. The resulting solid was stirred in 20 ml of 4M HCl in dioxane for 2 hours and then diethyl ether (100 ml) was added. The precipitate formed is filtered off and dried under high vacuum. Compound C was obtained as a white solid (365 mg, 1.07 mmol, 63%).

1 H-NMR (dg-DMSO) 400 MHz δ 9.32-9.10 (broad s, 2H), 8.79-8.53 (br s, 3H), 5.51 (d, 1H, J = 51 Hz), 5.04 (d, 1H, J = 8.8 Hz), 4.25-4.21 (broad m, 1H), 4.19-3.88 (m, 2H), 3.58 -3.46 (m, 1H), 3.42-3.32 (m, 2H), 2.85 (s, 1H), 2.71-2.63 (m, 2H), 2.27-2 , 14 (m, 1H),

2.05-1.97 (m, 1H), 1.81-1.40 (m, 5H) ppm.

Example 40 (2S, 4S) -1 - {(2S) -2-amino-3- | 1- (isopropylsulfonyl) piperidin-4-yl] opanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride

A. (2S) -2 - [(tert-Butoxycarbonyl) amino] -3- [1- (isopropylsulfonyl) piperidin-4-yl] propionic acid

To 150 ml of acetonitrile solution containing Compound A of Example 12 (1.0 g, 3.00 mmol) was added triethylamine (1.52 g, 15 mmol) and isopropylsulfonyl chloride (513 mg, 3.6 mmol) and stirred for 6 h. . The acetonitrile was removed in vacuo and water (50 mL) and ethyl acetate (300 mL) were added to the residue. The ethyl acetate phase is then separated, dried over magnesium sulfate and concentrated in vacuo. The resulting solid was washed with diethyl ether and dried under high vacuum. This gave 860 mg (2.26 mmol, 75%) of Compound A as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 12.4 (br s, 1H), 7.15 (d, 1H, J = 8.3 Hz), 4.374.29 (m, 1H), 3, 99-3.95 (broad m, 1H), 3.85-3.80 (m, 1H), 3.62-3.58 (m, 1H), 2.97-2.92 (m, 1H) , 2.42-2.37 (m, 1H), 1.91-1.89 (m, 1H) 1.87-1.46 (m, 7H), 1.37 (s, 9H), 1, 19-0.89 (d, 4H) ppm.

B. (2S, 4S) -1 - {(2S) -2-Amino-3- [1- (isopropylsulfonyl) piperidin-4-yl] propanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride is added to dry dimethylformamide 1 , 75 g (4.62 mmol) of Compound A, 1.76 g (4.62 mmol) of HATU and 0.80 mL (4.62 mmol) of Ν, di-diisopropylethylamine and then at room temperature for 30 min. After stirring, (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (1.0 g, 3.47 mmol) and Ν, diisopropylethylamine (0.60 mL, 3.47 mmol) were added. The resulting solution was then stirred at room temperature for 12 hours and then 110 ml of saturated aqueous sodium hydrogen carbonate solution were added. The mixture was extracted twice with ethyl acetate (100 ml) and the combined extract was washed with saturated aqueous sodium chloride (50 ml) and dried over magnesium sulfate. The crude solid obtained by removing the solvent in vacuo was purified by chromatography on silica gel using hexane / ethyl acetate (4: 1) as eluent. The resulting solid was stirred with 20 ml of 4M hydrochloric acid in dioxane for 2 hours and then diethyl ether (100 ml) was added. The precipitate formed is filtered off and dried under high vacuum. Thus, 969 mg (2.35 mmol, 68%) of Compound B is obtained as a white solid.

1 H-NMR (dg-DMSO) 400 MHz δ 8.51-8.44 (broad s, 3H), 5.15 (d, 1H, > 51 Hz), 5.06 (d, 1H, > 8.8) Hz), 4.04-4.01 (broad s, 1H), 3.96-3.84 (m, 2H), 3.72-3.61 (m, 2H), 3.51-3.37 (broad m, 2H), 3.35-3.27 (m, 1H), 2.79-2.76 (m, 2H), 1.82-1.69 (m, 5H), 1.17 ( m, 8H) ppm.

Example 41 (2S, 4S) -1 - {(2S) -2-amino-3- [1- (4-methylphenylsulfonyl) piperidin-4-yl] propanoyl} -4-fluoropyrrolidine-2-carbonitrile of formula (LIV) hydrochloride

A. (2S) -2 - [(tert-Butoxycarbonyl) amino] -3- [1- (4-methylphenylsulfonyl) piperidin-4-yl] propionic acid

To 150 ml of acetonitrile solution of Compound A of Example 12 (1.0 g, 3.00 mmol) was added triethylamine (1.52 g, 15 mmol) and toluenesulfonyl chloride (686 mg, 3.6 mmol) followed by stirring for 6 hours. acetonitrile was removed in vacuo. Water (50 ml) and ethyl acetate (300 ml) were added to the residue, and the ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo. The resulting solid was washed with diethyl ether and dried under high vacuum. Thus, 1.09 g (2.56 mmol, 85%) of Compound A is obtained as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz 8 12.4 (br s, 1H), 7.61 (d, 2H, > 8.2 Hz), 7.42 (d, 2H, > 8.2) Hz), 7.13 (d, 1H, > 8.3 Hz), 4.27-4.21 (m, 1H), 3.98-3.95 (m, 1H), 3.58-3, 52 (m, 1H), 2.98-2.91 (m, 1H), 2.42 (s, 3H), 2.21-2.20 (m, 1H), 1.81-1.50 ( m, 6H), 1.39 (s, 9H),

1.21-1.08 (m, 1H) ppm.

B. (2S, 4S) -1 - {(2S) -2-Amino-3- [1- (4-methylphenylsulfonyl) piperidin-4-yl] propanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride in ml of dry dimethylformamide 2.13 g (5.0 mmol) of Compound A, 1.90 g (5.00 mmol) of HATU and 0.87 mL (5.0 mmol) of Ν, 87-diisopropylethylamine are added and then at room temperature for 30 min. (2S, 4S) -4-Fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (1.1 g, 3.75 mmol) and further N, N-diisopropylethylamine (0.65 mL, 3.75 mmol). The resulting solution was stirred at room temperature for 12 hours, and then 110 ml of saturated aqueous sodium bicarbonate was added. Extract twice with 100 ml of ethyl acetate (100 ml) and combine the combined extract with saturated aqueous sodium chloride (50 ml).

- 105, dried over magnesium sulfate and concentrated in vacuo. The crude solid obtained was subjected to chromatographic purification using a 4: 1 mixture of hexane and ethyl acetate. The resulting solid was stirred in 20 ml of 4M HCl in dioxane for 2 hours and then diethyl ether (100 ml) was added. The precipitate formed is filtered off and dried under high vacuum. This gave 1.10 g (2.4 mmol, 64%) of Compound B as a white solid.

1 H-NMR (dg-DMSO) 400 MHz δ 8.21-8.05 (broad s, 3H), 7.60 (d, 2H, > 7.9 Hz), 7.43 (d, 2H, &gt;) 7.9 Hz), 3.91-3.88 (m, 2H), 3.07-2.99 (m, 1H), 2.43 (s, 3H), 2.09-2.03 (m , 1H), 1.94-1.29 (m, 8H), 1.12-1.02 (m, 1H) ppm.

Example 42 (2S, 4S) -1 - {(2S) -2-amino-3- [1- (isopropylsulfonyl] piperidin-3-yl] propanoyl} -4-fluoropyrrolidine-2-carbonitrile hydride of formula (LV)

A. (2S) -2 - [(tert-Butoxycarbyl) amino] -3- [1- (isopropylsulfonyl) piperidin-3-yl] propionic acid

Triethylamine (1.52 g, 15 mmol) and isopropylsulfonyl chloride (513 mg, 3.6 mmol) were added to 150 ml of acetonitrile scar containing the compound of Example 13 (1.0 g (3.00 mmol)) in 150 ml. after stirring, acetonitrile was removed in vacuo. Water (50 ml) and ethyl acetate (300 ml) were added to the residue, and the ethyl acetate layer was separated, dried over magnesium sulfate and concentrated in vacuo. The solid was washed with diethyl ether and dried under high vacuum. Thus, 926 mg (2.43 mmol, 81%) of Compound A is obtained as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 12.2 (broad s, 1H), 7.18 (d, 1H, > 8.3 Hz), 3.933.89 (m, 1H), 3.55-3 49 (broad m 2 H), 3.35-3.30 (m, 2H), 2.89-2.85 (m, 1H), 2.62-2.57 (m, 1H), 1.91 -1.42 (m, 5H), 1.39 (s, 9H), 1.19 (d, 6H) ppm.

B. (2S, 4S) -1 - {(2S) -2-Amino-3- [1- (isopropylsulfonyl] piperidin-3-yl] propanoyl} -4-fluoro-pyrrolidine-2-carbonitrileThydrochloride is added to dry dimethylformamide 1, Compound A, 75 g (4.62 mmol), HATU (1.76 g, 4.62 mmol) and 80, diisopropylethylamine (0.80 mL, 4.62 mmol), followed by stirring at room temperature for 30 minutes (2S, 4S) -4-Fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate (1.0 g, 3.47 mmol) and N, N-diisopropylethylamine (0.60 mL, 3.47 mmol). After stirring at room temperature for 12 hours, an aqueous sodium bicarbonate solution (110 ml) was added and the aqueous mixture was extracted twice with 100 ml of ethyl acetate, and the combined extract was washed with saturated aqueous sodium chloride (50 ml), dried over magnesium sulfate and evaporated to dryness in vacuo. the solid was purified by silica gel chromatography eluting with hexane

- 106 and ethyl acetate using a 4: 1 by volume mixture. The resulting solid was stirred with 20 ml of 4M hydrochloric acid in dioxane for 2 hours and then diethyl ether (100 ml) was added. The precipitate formed is filtered off and dried under high vacuum. This gave 101 g (2.46 mmol, 71%) of Compound B as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 8.42-8.39 (br s, 3H), 5.51 (d, 1H, J = 51 Hz), 5.06 (d, 1H, 5- 8.8 Hz), 4.07-4.01 (broad s, 1H), 3.98-3.84 (m, 2H), 3.52-3.49 (m, 1H), 3.41- 3.27 (broad m, 4H), 3.09-3.02 (m, 1H), 2.98-2.80 (m, 1H), 2.65-2.61 (m, 1H), 1 , 77-1.63 (m, 6H), 1.18 (m, 8H) ppm.

Example 43 (2S, 4S) -1 - {(2S) -2-amino-3- [1- (4-methylphenylsulfonyl) piperidin-3-yl] propanoyl} -4-fluoropyrrolidine-2-carbonitrile of formula (LVI) hydrochloride

A. (2S) -2 - [(tert-Butoxycarbonyl) amino] -3- [1- (4-methylphenylsulfonyl) piperidin-3-yl] propionic acid

To 150 ml of acetonitrile solution of Compound A in Example 13 (1.0 g, 3.00 mmol) was added triethylamine (1.52 g, 15 mmol) and toluenesulfonyl chloride (686 mg, 3.6 mmol) followed by 6 hours. after stirring, acetonitrile was removed in vacuo. Water (50 mL) and ethyl acetate (300 mL) were added and the ethyl acetate layer was separated, dried over magnesium sulfate, and the solvent removed in vacuo. The resulting solid was washed with diethyl ether and dried under high vacuum. Thus, 946 mg (2.22 mmol, 74%) of Compound A are obtained as a white solid.

1 H NMR (d6-DMSO) 400 MHz δ 12.4 (br s, 1H), 7.61 (d, 2H,> 8.2 Hz), 7.41 (d,

2H, > 8.2 Hz), 7.15 (d, 1H, > 8.3 Hz), 3.98-3.91 (m, 1H), 3.45-3.41 (m, 2H), 2.42 (s, 3H), 2.21-2.20 (m, 1H), 2.05-1.95 (m, 1H), 1.87-1.45 (m, 6H), 1, 42 (s, 9H), 1.21-1.08 (m, 1H) ppm.

B. (2S, 4S) -1 - {(2S) -2-Amino-3- [1- (4-methylphenylsulfonyl) pipendin-3-yl] propanoyl} -4-fluoro-pyrrolidine-2-carbonitrile hydrochloride ml 2.13 g (5.0 mmol) of Compound A, 1.90 g (5.00 mmol) of HATU and 0.87 mL (5.0 mmol) of Ν, di-diisopropylethylamine are added to dry dimethylformamide and then at room temperature for 30 min. After stirring for 1 minute, 1.1 g (3.75 mmol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and further 0.65 ml (3.75 mmol) of N, N-diisopropyl30 are added. amine. The resulting solution was stirred at room temperature for 12 hours, and then 110 ml of saturated aqueous sodium bicarbonate was added. The aqueous mixture was extracted twice with 100 ml of ethyl acetate, and the combined extract was washed with 50 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness. The crude solid obtained was purified by silica gel chromatography eluting with hexane and ethyl acetate 4: 1.

Using a mixture of volume-107. The resulting solid was stirred with 20 ml of 4M hydrochloric acid in dioxane for 2 hours and then diethyl ether (100 ml) was added. The precipitate was collected by filtration and dried under high vacuum. 1.17 g (2.55 mmol, 51%) of the title compound are obtained as a white solid.

1 H-NMR (dg-DMSO) 400 MHz δ 8.50-8.43 (br s, 3H), 7.61 (d, 2H, J = 7.9 Hz),

7.43 (d, 2H, > 7.9 Hz), 5.51 (d, 1H, J = 51Hz), 5.07 (d, 1H, > 8.8 Hz), 4.07-4.01 (broad m, 1H), 3.91-3.83, (m, 1H), 3.48-3.40 (m, 2H), 3.17-3.05 (m, 2H), 2.57 -2.51 (m, 1H), 2.38 (s, 3H), 1.84-1.23 (m, 8H), 1.07-1.05 (m, 1H) ppm.

Example 44 (2S, 4S) -1 - [(2S) -2-amino-3- (1-benzothien-3-yl) propanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride of formula LVII (2S) -3- (1-benzothien-3-yl) -2 - [(tert-butoxycarbonyl) amino] propionic acid (1.92 g, 6.0 mmol) was added, 2.28 g (6.0 mmol) of HATU and 1.05 mL (6.0 mmol) of Ν, iz-diisopropylethylamine and then stirring at room temperature for 30 minutes (2.31 g, 4.5 mmol) of (2S, 4S) -4-fluoro-2- pyrrolidinecarbonitrile-4-methylbenzenesulfonate and further 0.78 ml (4.5 mmol) of Ν, diisopropylethylamine. The resulting solution was then stirred at room temperature for 12 hours, and then 110 ml of saturated aqueous sodium bicarbonate was added. The aqueous mixture was extracted twice with 100 ml of ethyl acetate, and the combined extract was washed with saturated aqueous sodium chloride (50 ml), dried over magnesium sulfate and evaporated to dryness to give a crude precipitate. This was then purified by silica gel chromatography eluting with a 4: 1 mixture of hexane and ethyl acetate. The resulting solid was stirred with 20 ml of 4M hydrochloric acid in dioxane for 2 hours and then diethyl ether (100 ml) was added. The precipitate formed is filtered off and dried under high vacuum. 1.0 g (2.84 mmol, 63%) of the title compound were obtained as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 8.70-8.61 (br s, 3H), 8.05-8.00 (m, 2H), 7.457.36 (m, 3H), 5, 21 (d, 1H, > 51 Hz), 5.01 (d, 1H, > 8.8 Hz), 4.23-4.20 (m, 1H), 3.71 (ddd, 1H, > 41.1) , 12.3, 3.2 Hz), 3.55-3.51 (m, 1H), 3.30-3.24 (m, 1H), 2.73 (q, 1H, > 12.1 Hz) , 2.392.14 (m, 2H) ppm.

Example 45 (2S, 4S) -1 - {(2S) -2-amino-3-methyl-3- [4- (trifluoromethyl) phenyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride (LVIII)

108 A. 2-Methyl-2- [4- (trifluoromethyl) phenyl] propanol ml, 5.54 g (26.0 mmol), J. Am. Chem. Soc., 122, 712 (2000) To a solution of 2-methyl-2- [4- (trifluoromethyl) phenyl] propanenitrile, prepared as described above, in a toluene solution cooled to -78 ° C, 26 ml of a 1.5 M solution of DIBAL in toluene (39.0 mmol) was added, followed by the addition of toluene. The solution was stirred at -78 ° C for 2.5 hours. The reaction was then quenched with a solution of 6.6 g of sodium acetate and 6.6 ml of acetic acid in a mixture of tetrahydrofuran (105 ml) and water (20 ml). After 5 minutes, the cooling bath was removed and stirring was continued at room temperature for 20 minutes. The reaction mixture was then treated with Celite filtration aid and diethyl ether, and after stirring for 30 minutes, the hetero10 gene solution was filtered through a pad of Celite filtration aid. The filter layer was rinsed thoroughly with diethyl ether, and the aqueous layer was separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified by column chromatography eluting with 5% ethyl acetate in hexane. 4.22 g (19.5 mmol, 75%) of Compound A are thus obtained as pure oil.

1 H-NMR (CDCl 3 ) 400 MHz δ 9.52 (s, 1H), 7.63 (d, 2H, > 8.2 Hz), 7.39 (d, 2H, > 8.2 Hz), 1.49 (s, 3H) ppm.

B. To 2-Amino-3-methyl-3- [4- (trifluoromethyl) phenyl] butanitrile, 1.87 g (8.66 mmol) of Compound A in methanol

1.2 ml of a 30% aqueous solution of ammonium hydroxide and 6 ml of water plus 592 mg (9.09 mmol) of potassium cyanide. Ammonium chloride (510 mg, 9.53 mmol) was added to the resulting solution at room temperature, and after one hour, the solution was kept at 70 ° C for 6 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and water. After drying over magnesium sulfate, the solvent was removed in vacuo and the residue was purified by column chromatography using a 3: 2 by volume mixture of ethyl acetate and hexane. 1.52 g (6.27 mmol, 72%) of compound B are obtained.

1 H-NMR (CDCl 3 ) 400 MHz δ 7.63 (d, 2H, J = 8.4 Hz), 7.55 (d, 2H,> -8.5 Hz), 3.80 (t, 1H) ,> 7.9 Hz), 1.56 (s, 3H), 1.53 (s, 3H), 1.40 (broad d, 2H, > 6.9 Hz) ppm.

C. 2-Amino-3-methyl-3- [4- (trifluoromethyl) phenyl] butyric acid hydrochloride

To 2.96 g (12.2 mmol) of Compound B was charged with 10 mL of acetic acid followed by 60 mL of concentrated aqueous hydrochloric acid and the resulting solution was refluxed overnight. Then most of the solvent was removed in vacuo and the remaining white solid was triturated with ether-hexane 2: 1 mixture of k-1

-109 is triturated and finally separated by vacuum filtration. After drying under high vacuum, 3.13 g (10.5 mmol, 86%) of Compound C were obtained as a white solid.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.69-7.68 (m, 4H), 4.33 (s, 1H), 1.57 (s, 3H), 1.53 5 (s, 3H) ppm.

D. 2 - [(Tert-Butoxycarbonyl) amino] -3-methyl-3- [4- (trifluoromethyl) phenyl] butyric acid in ml of dioxane and 7 ml of water containing 3.05 g (10.2 mmol) of Compound C To this solution was added 12.8 ml of a 2.0 M aqueous sodium hydroxide solution (25.6 mmol) at room temperature and then di-tert-butyl dicarbonate (3.13 g, 14.4 mmol). The resulting solution was stirred overnight, then poured into saturated aqueous sodium bicarbonate solution and washed with diethyl ether. The diethyl ether layer was washed with saturated aqueous sodium bicarbonate solution and the aqueous layers were combined. After acidification with 1M aqueous hydrochloric acid, the mixture was extracted twice with ethyl acetate, and the combined extract was dried over magnesium sulfate and concentrated in vacuo. 3.58 g (9.92 mmol, 97

to give Compound D as a white solid.

! 1 H-NMR (CDCl 3 ) 400 MHz δ 7.57 (d, 2H, > 8.2 Hz), 7.49 (d, 2H, > 8.3 Hz), 4.99 (broad d, 1H, &gt;) 9.2 Hz), 4.63 (broad d, 1H, > 9.3 Hz), 1.45 (s, 3H), 1.44 (s, 3H), 1.36 (s, 9H) ppm.

E. Tert-Butyl (1S) - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-methyl-2- [4- (trifluoromethyl] phenylphenylpropylcarbamate, 2, To a dimethylformamide solution containing Compound D (0 g, 5.54 mmol) at room temperature was added 8, diisopropylethylamine (788 mg, 6.09 mmol) followed by HATU (2.21 g, 5.82 mmol). After stirring for 30 minutes, 27 ml, 1.66 g (5.82 mmol) of (2S, 4S) -4-fluoro-2-pyrrolidinecarbonitrile-4-methylbenzenesulfonate and 752 mg (5.82 mmol) of N, N25 diisopropylethylamine were added. After stirring overnight, the reaction mixture was diluted with ethyl acetate and washed once with water, once with saturated aqueous sodium bicarbonate solution and once with 1M aqueous hydrochloric acid, after drying over magnesium sulfate, the solvent was removed in vacuo and the solvent was evaporated. the residual dark oil was purified by column chromatography eluting with hexane, ethyl acetate and dichloromethane (5: 4: 1). Thus, a low Rf material is obtained in an amount of 610 mg (1.37 mmol), which is a single stereoisomer according to 1 H-NMR and liquid chromatography. There is also obtained a high Rf value of 335 mg containing the desired product, but contaminated with another compound. The low Rf value in the in vitro test is the (S) -diastereomer.

Low Rf Diastereomer:

1 H-NMR (CDCl 3 ) 400 MHz δ 7.65-7.60 (m, 2H), 7.59-7.55 (m, 2H), 5.29 (d, 1H, 5> 9.9 Hz) ), 5.06 (dt, 1H, > 51.1.3.3 Hz), 4.85 (d, 1H, > 9.4 Hz), 4.34 (d, 1H, > 9.9 Hz) , 3.55 (ddd, 1H, > 3.4, 12.1, 36.2 Hz), 2.70 (dd, 1H, > 12.3, 17.8 Hz), 2.48 (t, 1H ,> 15.4 Hz), 2.15 (m, 1H), 1.53 (s, 3H), 1.51 (s, 3H), 1.40 (s, 9H) ppm.

F. (2S, 4S) -1 - {(2S) -2-Amino-3-methyl-3- [4- (trifluoromethyl) phenyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride

To trifluoroacetic acid (1.65 g, 14.4 mmol) at room temperature was added 10 ml of 643 mg (1.44 mmol, low Rf isomer) containing dichloromethane. After 1 hour an additional 5 equivalents of trifluoroacetic acid was added and after a total of two hours the solvent was removed in vacuo and the residual oil dissolved in 5 ml of dioxane. To the resulting solution was added 10 ml of 4M hydrochloric acid in dioxane and the solvent was removed in vacuo. Dichloromethane and diethyl ether were added to the residue. This procedure is repeated three times until a solid solid is formed. This was then isolated by vacuum filtration to give 406 mg (1.03 mmol, 72%) of Compound F.

1 H-NMR (d 4 -MeOH) 400 MHz δ 7.74-7.66 (m, 4H), 5.13 (broad d, 1H, > 51.3 Hz),

4.97 (d, 1H, > 9.3 Hz), 4.25 (s, 1H), 3.52 (m, 1H), 2.74 (dd, 1H, > 22.0, 11.9 Hz) ), 2.47-2.22 (m, 2H), 1.67 (s, 3H), 1.60 (s, 3H) ppm.

Example 46 (3R) -3-Amino-4 - [(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] -2-methyl-4-oxobutane-2-sulfonic acid (LIX)

A. (4R) -2,2,5,5-Tetramethyl-1,3-thiazolidine-4-carboxylic acid

To a suspension of L-penicillamine (0.300 g, 2.01 mmol) in methanol (2 mL) was added acetone (4 mL, 54.5 mmol), when the solution became clear and refluxed after about 3 hours. Evaporation of this solvent gave 0.377 g (99%) of Compound A as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 3.74 (s, 1H), 2.48 (m, 2H), 1.54 (m, 6H), 1.43 (s, 3H), 1.18 (s, 3H) ppm.

- 111 B. (2S, 4S) -4-Fluoro-1 - {[(4R) -2,2,5,5-tetramethyl-1,3-thiazolyl-4-yl] carbonyl} pyrrolidine-2-carbonitrile

Compound A, 0.256 g (1.35 mmol), (2S, 4S) -4-fluoropyrrolidine-2-carbonitrile tosylate (0.387 g, 1.35 mmol), 1-hydroxybenztriazole hydrate (0.182 g, 1.35 mmol), 0.279 g (1.35 mmol)

A solution of N, N-diisopropylethylamine (0.280 mL, 1.63 mmol) in tetrahydrofuran (13 mL) was stirred for about 48 hours and then concentrated. The residue was taken up in ethyl acetate and filtered. The filtrate was washed with aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The resulting crude mixture was purified by silica gel chromatography using a mixture of 5% v / v methanol and 95% v / v chloroform as eluent. Yield: 0.171 g (44%) of the title compound as a white solid.

1 H-NMR (d 6 -DMSO) 400 MHz δ 5.48 (d, J = 50 Hz, 1H), 5.02 (m, 1H), 4.05-3.85 (m, 3H), 3.48 (m, 1H), 2.42 (m, 1H), 1.54 (m, 5H), 1.47 [s, 3H), 1.22 (s, 3H) ppm.

C. (2S, 4S) -1 - [(2R) -2-Amino-3-mercapto-3-methylbutanoyl] -4-fluoropyrrolidine-2-carbonitrile-15-hydrochloride

To a solution of Compound B (0.143 g, 0.501 mmol) in water and methanol (50:50) in 20 mL was added 0.550 mL of a 1 M aqueous hydrochloric acid solution (0.550 mmol) and the resulting solution was about 35 mbar at about 35 ° C. Stir at C for about one hour. The solution was concentrated and then taken up in tetrahydrofuran, dried over magnesium sulfate and evaporated again. This gave 0.163 g (100%) of Compound C as an off-white solid.

1 H NMR (d 6 -DMSO) 400 MHz δ 8.61 (s, 1H), 5.54 (d, J = 52 Hz, 1H), 5.05 (d, J = 9 Hz, 1H), 4 , 28-3.89 (m, 4H), 2.47 (m, DMSO overlap, 1H), 174 (m, 3H), 1.43 (m, 6H), 1.33 (s, 3H), ppm.

D. tert-Butyl- (1R) -1 - {[(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] carbonyl} -2-mercapto-2-methylpropylcarbamate

To a solution of Compound C (0.141 g, 0.501 mmol) and N, N-diisopropylethylamine (0.090 mL, 0.526 mmol) in dichloromethane (3 mL) was added di- tert -butyl dicarbonate (0.120 g, 0.551 mmol) followed by 0.100 mL (0.584 mmol). Ν, Ν-diisopropylethylamine. The resulting solution was stirred for about 2 hours and then concentrated. The crude mixture was subjected to silica gel chromatography, eluting with a mixture of 2% methanol and 98% chloroform. 0.088 g of Compound D were obtained as an oil which crystallized as a white solid (51% yield).

-112 1 H-NMR (d 6 -DMSO) 400 MHz δ 6.99 (d, J = 9 Hz, 1H), 5.53 (d, 51 Hz, 1H), 4.97 (d,> 7 Hz, 1H), 4.37-3.74 (m, 311), 2.95 (s, 1H), 2.40 (m, 1H), 1.35 (m, 15H) ppm.

E. (3R) -3-Amino-4 - [(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] -2-methyl-4-oxobutan-2-sulfonic acid

To a solution of Compound D (4.412 g, 12.8 mmol) in methanol (18 mL) was added 5.9 mL of 30% aqueous hydrogen peroxide solution, and the resulting mixture was stirred for nearly 30 hours, concentrated, lyophilized and about 40 for phosphorus pentoxide. Dry at a temperature of at least 12 hours. The resulting crude mixture was taken up in a mixture of 20% v / v methanol and 80% v / v chloroform, and the precipitate was filtered off. Thus, 0.607 g (16%) of Compound E is obtained as a pink solid.

1 H-NMR (dg-DMSO) 400 MHz δ 8.12 (s, 3H), 5.50 (d,> 50 Hz, 1H), 5.07 (d,> 9

Hz, 1H), 4.27-3.30 (m, 6H), 2.30 (m, DMSO overlap, 1H), 1.26 (s, 3H), 1.15 (s, 3H) ppm.

Biological data

Materials:

The H-Ala-Pro-pNA-HCl peptide (L-1115) used in the experiments was purchased from BACHEM Bioscience Inc.. 500 mM stock solution was prepared with dimethyl sulfoxide and stored at -20 ° C. The Gly-Pro-AMC peptide (product AMC-39) was purchased from Enzyme System Products and stored at -20 ° C as a stock solution of 10 mM dimethyl sulfoxide. The test compounds were dissolved in 10 mM in dimethylsulfoxide and the resulting solutions were used as stock solutions for DPP-IV titration studies. The purified human DPP-IV enzyme was purchased from Athens Research and Technology, Inc.. This company uses this material by DeMeester et al., J. Immunol. Methods, 189, 99-105 (1996), isolates it from human prostate glands.

DPP-IV Test:

Dilute serial dilutions of the test compounds with 100% dimethyl sulfoxide in 96-well polystyrene flat plates (available from Costar 9017). We used the average enzyme activity from wells that did not contain dimethylsulfoxide but did not contain the test compound as the control value for the% inhibition. DPP-IV enzyme at a concentration of 20 ng / ml was mixed in microtiter plates with test compounds, substrate and assay buffer so that 100 µl of H-Ala-Pro-pNA-HCl in a solution of 25 mM potassium chloride for Tris was added. and 140 mM sodium chloride, and a pH of 7.5. The intact peptide contains p-nitrophenylanilide which, when hydrolyzed by DPP-IV, releases p-nitrophenylaniline absorbent. The

Absorbence 1, 113 was determined at 20 minute intervals at 387 nm using a SpectraMax 250 plate absorbance meter from Molecular Devices. The enzymatic activity is determined by estimating the best line that fits the data. The values of the enzymatic activity were determined directly from this linear fitting line using appropriate software for the plate reader.

Analyze the results:

The enzymatic activity was determined by estimating the best linear line that fits the data. We used Microsoft Excel RoboSage to calculate the data.

Determination of IC5Q values: enzymatic activity was plotted against the concentration of the test compound, including [I] = 0, and the IC5Q was calculated from these values using equation (2) below:

ratio = V max ! (1 + ([I] / IC 50 )] (2)

V max = estimated value best suited for maximum enzymatic activity

Determination of Ki values: Kj values were calculated from IC5Q based on equation (3), assuming a competitive model.

S

Ki = IC 50 * [l-] (3) (S + K m )

Apparent pKi values are greater than 5.0 for each compound of the example.

DPP-II Study:

The intermediate plate contained 5.3 µΐ of the test compound in duplicate serial dilution along the plate. To each well of the intermediate plate was added 209 μΐ puff (pH 5.5 containing 100 mM sodium acetate), which buffer contained the H-Lys-Ala-pNA-2HCl substrate purchased from BACHEM Bioscience Inc., L-2085. After addition, stirring was performed in each well, and the reaction was initiated by measuring 180 µΐ of substrate or test compound in wells containing 20 µΐ of enzyme test plate. The final concentrations for the enzyme were 100 nM for the enzyme and 1000 μΜ for 100 mM sodium acetate for the substrate, at pH 5.5, and for the final volume of 200 μΐ at 2.5% dimethylformamide. «» * «·><

-114lett. Absorbance was measured every 20 minutes at 387 nm using a Molected Devices SpectraMax 250 plate absorbance meter.

Analyze the results:

The enzymatic activity was determined by estimating the best 5 linear lines matching the data. We used Microsoft Excel RoboSage to calculate the data.

Determination of IC5Q values: enzymatic activity was plotted against the concentration of the test compound, including [I] = 0, and the IC50 value was calculated from these values from equation (2) below:

ratio = V max / (l + ([I] / IC 50 )] (2)

V max = estimated value best suited for maximum enzymatic activity

Determination of Ki values: AK; values were calculated from IC5Q based on equation (3), assuming a competitive model.

S

Ki = IC 50 * [l-] (3) (S + K m )

Some of the compounds of the present invention exhibit activity for the DPP-II enzyme, such as pKi of less than 6.0, while other compounds have shown selectivity for DPP-IV as previously mentioned.

In carrier studies:

Balanced male CDI mice with age and body weight were kept at 72 ° F and 50% relative humidity for 12 hours light / dark cycles. Animals were administered a test compound at a dose of 0.5% methylcellulose support (surfactant 0.1% Tween 80) at a dose of 10 ml / kg, or 1 mg / kg in the same carrier. The animals were then anesthetized with isofluorane and blood samples were collected at defined intervals between 0 and 6 hours. In plasma, DPP-IV activity was measured with 50 μΜ of Gly-Pro-AMC fluorogenic substrate in Enzyme System Products (Livermore, California, USA).

United States) manufacturer specification. The substrate was mixed with 50 mM Tris buffer at pH 7.8 and 20% blood plasma. The samples were then incubated for 20 minutes at 30 ° C and fluorescence measured with a so-called cytofluor spectrophotometer equipped with 360 nm excitation and 460 nm emission filters.

· «·· · · ♦ · <· · *

- 115 Comparative Examples

The compounds of the invention exhibit a number of advantageous properties. Without any limitation, such advantageous properties of the compounds of the present invention are believed to be due to the unexpected benefits of changing the substitution characteristics of the compounds of formula (I). The results of the comparative studies described below illustrate many surprising and unexpected benefits. In particular, comparative studies show that the compounds of the present invention exhibit the following effects: (i) increased efficacy as characterized by DPP-IV inhibition activity in blood plasma; (ii) increased selectivity; (iii) increased duration of action; and / or (iv) an enhanced safety profile.

In the comparative examples, the following compounds are used:

Comparative Example 1 - Compound (LX)

Comparative Example 2 = Compound (LXI)

Comparative Example 3 = Compound (LXII)

Comparative Example 4 = Compound (LXIII)

Comparative Example 5 = Compound (LXIV)

Comparative Example 6 = Compound (LXV)

Comparison I - Duration of Effect / Effect

Surprisingly, for the inhibition of dipeptidyl peptidases, in particular DPP-IV, compounds that exhibit high affinity for this enzyme, i.e., are effective, do not necessarily have a duration of time sufficient for therapeutic efficacy. In the present context, the duration of the effect is the ability of the compound to maintain its efficacy, preferably its therapeutic efficacy over a given period of time. A compound having a preferred duration of action has a therapeutic efficacy with a once-daily administration. As this drug is widely used, i.e. widely accepted by physicians, once daily administration may be advantageous over multiple daily administrations for patient cooperation and convenience. Thus, preferred compounds should not only exhibit satisfactory efficacy, but should also have a sufficient duration of effect.

As is well known to those skilled in the art, there is no unnecessary correlation between efficacy and duration of action. In other words, although a given compound may exhibit high affinity for DPP-IV, the same compound may not be effective for a sufficient period of time to be administered preferably once a day. In the following, we will describe the lack of correlation between efficacy and duration of effect. The following information is> «

-116, however, are not to be construed as limiting the invention.

Balanced male CD rats with age and body weight were kept separate at 72 ° F and 50% relative humidity for 12 hour light / dark cycles5. Experimental animals were administered test compound (10 mM acetic acid) or 1 mg / kg in the same vehicle. Six hours after administration of the compound, the rats were anesthetized with isofluorane to take a blood sample from the heart. The activity of DPP-IV in blood serum was measured using a 50 µjú concentration of Gly-Pro-AMC fluorogenic substrate (Enzyme System).

Products, Livermore, California, USA. The substrate was mixed with 50 mM Tris at pH 7.8 in the presence of 20% final blood plasma, and the samples were incubated for 5-20 minutes at 30 ° C. DPP IV activity was determined by measuring the fluorescence with a cytofluor spectrophotometer equipped with 360 nm wavelength excitation and 460 nm wavelength filters. In each group (number of animals = 3), averages and standard deviations were calculated using a student t-test and compared with results from vehicle-treated rats for the calculation of% inhibition, as shown in Table 1 below.

Table 1

Experimental compound IC 50 (nM) human DPP-IV DPP-IV% inhibition after 6 hours in rats
Comparative Example 1 1.3 32 ± 3
Comparative Example 2 3 32 ± 3
Comparative Example 4 5.6 2.8 ± 0.1
Comparative Example 5 3 71 ± 13
Example 2 22 68 ± 4
Example 9 72 64 ± 12

As can be seen, the compounds of Comparative Examples 1, 2 and 4 are highly effective, each having an ICI of less than 5.6 nM. Exemplary compounds of Examples 2 and 9, exemplified by the compounds of the present invention, exhibit satisfactory efficacy, and have a potency (C ^ of 22 and 72, respectively. If the compounds of Comparative Examples 1, 2 and 4 for duration of action are tested for a weak duration of action

- 117 points. The compounds of the invention, although less effective, are preferred over the duration of the action, and thus have a complete therapeutic profile. The compound of Comparative Example 5 further demonstrates that the relationship between efficacy and duration of action is unpredictable. In particular, for Compound Example 5, both the binding affinity and the duration of action are high. Therefore, the relationship between efficacy and duration of effect cannot be characterized as strictly as a parallel or inverse relationship; rather, this relationship is not predictable.

This lack of correlation between efficacy and duration of action also means that there is no predictability for dipeptidyl peptidases, specifically for compounds that inhibit DPP-IV. This unpredictability has not yet been recognized. As can be seen from the foregoing, the binding data alone may or may not be sufficient to determine the therapeutic utility of such compounds. However, the compounds of the present invention demonstrate appropriate levels of efficacy and duration of action in addition to the other features discussed below.

II. Comparison - β-substitution and cyclization

As can be seen from the foregoing, the compounds of the invention have at least two identical β-substituents, wherein R 1 and R 2 have the same meaning. For example, the compounds of Examples 1 and 10 are represented by formulas (XIV) and (XXIII), both disubstituted at the β-carbon atom. Thus, for example, with reference to the compound of Example 10, in a preferred embodiment R 1 and R 2 are both alkyl, more preferably C 1-6 alkyl, most preferably methyl. Another preferred embodiment is a compound of Example 1, wherein R 1 and R 2 are both aryl, more preferably phenyl, and such an example is represented by the compound of Example 2, wherein the phenyl is substituted with a halogen atom, preferably a fluorine atom. In general, di-P-substituted compounds, such as the compounds of the invention, are not prone to cyclization with the nitrile moiety present in their molecule by formation of a cyclic amine, such compounds being considered stable.

On the other hand, mono-substituted compounds such as those of Comparative Examples 3 and 4, where the β-carbon does not carry two identical substituents, tend to cyclize and therefore have a relatively short stability, i.e. a half-life, tj / 2 .

·· ·· .10

In general, however, compounds that are doubly substituted on the β-carbon atom also exhibit increased selectivity.

Stability studies with potent compounds for DPP-IV

Typically, 0.2 to 0.5 mg of the test compound is dissolved in 1 ml of phosphate buffered saline (PBS) in a high-resolution chromatography vessel and placed in a thermostatically controlled automatic sampler at 37 ° C. First, determine the initial point of the high-performance liquid chromatography (HPLC) chromatogram and then prepare the chromatograms 24 hours, 48 hours, 72 hours.

The HPLC method used for the test is as follows:

column:

Mobile Phase A:

Mobile Phase B:

flow rate: gradient:

wavelength of ultraviolet detection:

Phenomenex Luna Cl8 (2), 3 μ, 100 · 4.6 mm, temperature controlled at 40 ° C and acetonitrile 95: 5, 0.2% trifluoroacetic acid water and acetonitrile 5:95, 0.2% trifluoroacetic acid containing 1 ml / min.

215 nm

For each chromatogram, the peak area caused by the drug is compared to the initial area, and then plotted as a percentage of the initial time (ίθ).

When comparing the half-life (tj / 2 ) of the cyclization / degradation reaction of the test compounds, it can be stated that the di-β-substituted compounds, such as the compounds of Examples 2 and 9, show increased stability. Increased t 1/2 is directly related to the increased stability of the compound.

Table 2

Compound

Example 9

Example 2

Comparative Example 4

Comparative Example 3, Ti / 2 at 37 ° C, 1733 hours

266 hours

33.5 hours (calculated *) hours at 23 ° C

I

-119 * Note: in the case of Comparative Example 3, the thermostat was not controlled thermostatically, but simply left at ambient temperature. Typically, an increase of 10 ° C increases the reaction rate by two, thereby reducing the value of tj / 2 by two times. It will be appreciated by those skilled in the art that for a compound of Comparative Example 3, an acceptable calculated tp 2 value is half or less at 23 ° C, i.e. room temperature.

Thus, in addition to the efficacy and duration of action, the compounds of the present invention also show desirable stability.

III. Comparison - Safety Profile

The dog is a common non-rodent species commonly used in drug licensing experiments. Considering the general pathology of this strain and the effect of the various active agents, the hunter picker was chosen to examine the safety of the compounds of the invention. 9-12 months or 5-12 kg, a

Dogs from Marshall Farms Inc. (North Rose, New York, U.S.A.) were administered a carrier (10 mM acetic acid, pH 3.3) or a test compound in the carrier via a gastric tube at a dose of 10 mL / kg / day. Each dosing is washed with about 10 ml of water, once a day for 24-48 hours between successive doses. When limited gastrointestinal toxicity was not observed, the dose was increased threefold not earlier than about 24 hours after the previous dose. Symptoms of limited gastrointestinal toxicity include diarrhea, soft or artificial stool, blood in the stool, and / or dying of intestinal epithelium. Clinical observations were made at least three times a day during treatment (once prior to drug administration, one hour after drug administration and once in the afternoon viability test). In serum, the activity of DPP-IV was performed using the Gly-Pro-AMC (50 mM) fluorogenic substrate as required by the producer, i.e. Enzyme System Products (Livermore, California, USA). The substrate was mixed with 50 mM Tris pH 7.8 in blood serum (providing a volume of 20% by volume) followed by 30 ° C samples.

Incubated for 5-20 minutes. DPP-IV activity was determined by measuring the fluorescence with a cytofluor spectrophorometer with filters set to 360 nm excitation and 460 nm emission.

Compound of Comparative Example 5 above contains, in relative terms, a small P2 moiety as defined by the molecular weight. Thus, this is comparative example 5

X

Compounds of Formula 120 and compounds of the present invention containing a large P2 moiety, such as those of Examples 2 and 9, were tested in the assays described above with increased dose.

Based on the dose-escalation studies performed in dogs, it can be concluded that the compound of Comparative Example 5 causes loose or artificial stone feces at a dose of 0.3 mg / kg with blood stains, while the compound of the invention is a compound of Example 9 mg / kg does not cause such adverse effects. However, by increasing the dose to 3 mg / kg, the compound of Example 9 also causes a loose or artificial stone containing feces.

In contrast, the compound of Comparative Example 5, when administered orally at 0.2 mg / kg, inhibited the DPP-IV enzyme by 2% 12 hours after administration. Surprisingly, in the same dose, the compound of Example 9 inhibited the DPP-IV enzyme by 76%, suggesting that the compound of Example 9 significantly inhibited DPP-IV activity in blood serum.

Similarly, for the other compounds of the invention, the compound of Example 2 does not cause adverse gastrointestinal toxicity at 10 mg / kg, and the same compound at 0.5 mg / kg 12 hours after oral administration of DPP-IV. inhibits by%.

Based on the above studies, it can be established that the compounds of Examples 2 and 9 containing the compounds of the invention, and more particularly the higher molecular weight P2, are preferred.

ARC. comparison - fluorinated versus non-fluorinated

When the compounds of the present invention were tested in vivo for periods between 0 and 10 hours, the fluorinated compounds of the present invention showed a significant increase in \ t

DPP-IV enzyme inhibition compared to the corresponding non-fluorinated compounds. Thus, the compounds of the present invention exhibit an unexpected efficacy that was not predictable, for example, comparing the compound of Example 2 with its non-fluorinated variant, i.e., the compound of Comparative Example 6, the advantage of the 4-fluoro substituent. Surprisingly, the fluoro substituent at position 4 dramatically increases the durability of the enzyme inhibitor complex, and results in a significant increase in efficacy. These advantageous properties were not predictable.

• · · · · · * * ······

- 121 Table 3

Experimental compound IC 50 (nM) human DPP-IV DPP-IV% inhibition after 6 hours in rats
Example 2 22 68 ± 4
Comparative Example 6 151 15 ± 1

All of the above-mentioned studies are based on the principles of laboratory animals (NIH publication, 85-23, revised in 1985) and Glaxo.

They complied with SmithKline's experimental animal regulations.

Although some specific embodiments of the invention have been described in detail above, it will be appreciated by those skilled in the art that it is not intended to limit the scope of the invention. These preferred embodiments and embodiments are exemplary only, and should not be construed as limiting the invention in any way. Certain modifications will be apparent to those skilled in the art, and if these modifications do not depart from the spirit of the invention, they will fall within the scope of the following claims.

- 122 -

Claims (2)

Claims
1) protected aminocarboxylate, coupling reagents
Scheme 1
Compounds of formula (I), and salts, solvates and pharmaceutically active derivatives thereof, wherein X is fluorine or hydrogen;
R 1 and R 2 are independently (i) hydrogen, (ii) alkyl; or (iii) optionally substituted aryl or heteroaryl; or (iv) together form a ring system of 3 to 14-membered, optionally one or more heteroatoms and optionally one or more unsaturated bonds;
when R 1 and R 2 are as defined in (iii) above, R 3 is hydrogen or alkyl;
when R 1 and R 2 are as defined in (i), (ii) or (iv) above, R 3 is a group of formula III wherein n is an integer from 0 to 5;
m is an integer from 0 to 12;
Y is an oxygen atom, a chemical bond or an alkylene, alkylene, alkenylene or alkynylene group, or a group of the formula -S (O) p-, wherein p is 0, 1 or 2;
r 4 is R 3 when Y is a bond or a sulfur or oxygen atom or an alkylene, alkenylene or alkynylene group, wherein R 3 is optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclic group; and
R 4 is R 3 when Y is a sulfmyl or sulfonyl group, wherein R 1 is an optionally substituted alkyl, aryl, cycloalkyl, heteroaryl, amino, alkylamino, arylamino, heteroarylamino, cycloalkylamino or hydroxy group.
Compounds according to claim 1, wherein the optional substituent is one or more halogen or alkyl, alkoxy, aryloxy, haloalkyl, cyano, alkylsulfonyl or aryl.
The compound of claim 1, wherein the optional substituent is one or more fluoro or chloro or C 1-6 alkyl, C 1-6 alkoxy, phenoxy, benzoxy, C 1-6 carbon haloalkyl, cyano, C 1-6 alkylsulfonyl, phenyl or benzyl.
- 123
4. A compound according to claim 1, wherein R and R 2 each represent an aryl group and R3 is hydrogen.
The compound of claim 4, wherein each aryl is phenyl.
The compound of claim 5, wherein each phenyl is substituted with a halogen atom.
Compounds according to claim 6, wherein each halogen atom is fluorine.
Compounds according to claim 1, wherein R 1 and R 2 are each alkyl and R 2 (III).
Compounds according to claim 8, wherein each alkyl group is C 1-6 alkyl.
The compound of claim 9, wherein each alkyl group is methyl.
The compound of claim 10, wherein n is 0, m is 1, and Y is -S (O) p-.
The compound of claim 11, wherein p is 0, R 4 is R 6 and R 1 is optionally substituted aryl.
13. A compound of claim 12 wherein R 6 is alkoxy substituted phenyl.
14. The compound of claim 13, wherein the alkoxy group is methoxy.
The compound of claim 11, wherein p is 1 or 2, R 4 is R 6 and R 6 is optionally substituted aryl.
16. The compound of claim 15, wherein R 6 is alkoxy substituted phenyl.
17. The compound of claim 16, wherein the alkoxy group is methoxy.
18. The compound of claim 17, wherein p is 1.
19. The compound of claim 17, wherein p is 2.
The compound of claim 1, wherein the amino group is cis-position relative to the cyano group.
The compound of claim 1, wherein the amino group is trans-positioned relative to the cyano group.
22. A compound according to claim 1 wherein A is hydrogen.
24. Compounds of formula (I), and salts, solvates, and pharmaceutically active derivatives thereof, wherein X is fluorine or hydrogen;
-124 R 1 and R 2 independently represent an optionally substituted aryl or heteroaryl group; and
R 3 is hydrogen or alkyl.
25. Compounds of formula (I), and salts, solvates, and pharmaceutically active derivatives thereof, of formula (I):
X is fluoro or hydrogen;
R 'and R 2 are independently (i) alkyl; or (ii) together form a ring system of 3 to 14-membered, optionally one or more heteroatoms and optionally one or more unsaturated bonds;
R 3 is a group of formula III wherein n is an integer from 0 to 5; m is an integer from 0 to 12;
Y is an oxygen atom, a chemical bond or an alkylene, alkylene, alkenylene or alkynylene group, or -S (O) p -, wherein p is 0, 1 or 2;
R 4 is R 3 when Y is a chemical bond or a sulfur or oxygen atom or an alkylene, alkenylene or alkynylene group, wherein R 3 is optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl- or a heterocyclic group; and
R 4 is R 1 when Y is sulphinyl or sulfonyl, wherein R 1 is optionally substituted alkyl, aryl, alkylalkyl, heteroaryl, amino, alkylamino, arylamino, heteroarylamino, cycloalkylamino or hydroxy .
26. The compound of claim 25, wherein p is 1 or 2.
27. The compound of claim 26, wherein p is 2.
28. The compound of claim 25, wherein R 3 and R 2 are each independently alkyl.
The compound of claim 28, wherein R 3 and R 2 are independently C 1-6 alkyl.
30. The compound of claim 29 wherein R 3 and R 2 are both methyl.
31. A compound according to claim 1 having the formula (IV) and (V).
32. A compound according to claim 1 having the formula VI, VII and VIII.
33. A compound according to claim 1 wherein:
125 (25.45) -1 - [(2S) -2-amino-3,3-diphenylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - [(2S) -2-Amino-3,3-bis (4-fluorophenyl) propanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - [(2S) -2-amino-5- (4-fluorophenyl) -3,3-dimethylpentanoyl] -4-fluoro-2-pyrrolidinecarbonitrile 5-hydrochloride;
(2S, 4R) -l - [(2S) -2-amino-4- (4-fluorophenyl) -3,3-dimethylbutanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3 - [(4-methoxybenzyl) thio] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(2S, 4S) -l - {(2R) -2-amino-3-methyl-3 - [(3-phenylpropyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(2-phenylethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - ((2R) -2-amino-3 - {[3- (4-fluorophenyl) propyl] thio} -3-methylbutanoyl) -4-fluoropyrrolidine-215-carbonitrile hydrochloride;
(2S, 4S) -1 - {(2R) -2-amino-3 - [(4-methoxybenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3 - [(4-methoxybenzyl) sulfinyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(2S, 4S) -l - ((2R) -2-amino-3-methyl-3 - {[4- (trifluoromethyl) benzyl] thio} butanoyl} -4-fIuorpirrolidin-2-carbonitrile hydrochloride;
(25.45) -1 - [(2S) -2-amino-2- (1-vinylcyclopentyl) ethanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - [(2S) -2-amino-5- (4-methoxyphenyl) -3,3-dimethylpentanoyl] -4-fluoropyrrolidine-225-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(3-phenylpropyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile;
(2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(4-methylbenzyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile;
(2S, 4S) -1- ((2R) -2-amino-3 - {[4- (benzyloxy) benzyl] sulfonyl} -3-methylbutanoyl) -4-fluoropyrrolidine-2-carbonitrile;
(2S, 4S) -1 - {(2R) -2-amino-3 - [(4-cyanobenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile;
· * ··· ♦ · · · ♦ · · · «» »·« * »· * * ···» * *
126 (25.45) -1 - ((2R) -2-amino-3-methyl-3 - {[4- (methylsulfonyl) benzyl] sulfonyl} butanoyl) -4-fluoropyrrolidine-2-carbonitrile;
(2S, 4S) -1 - {(2S) -2-amino-2- [1- (4-fluorobenzyl) cyclopentyl] ethanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(2S, 4S) -l - ((2S) -2-amino-2- {l- [4- (trifluoromethyl) phenyl] cyclopentyl} ethanoyl) -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2S) -2-amino-2- [1- (4-fluorobenzyl) cyclopropyl] ethanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3- (benzylsulfonyl) -3-methylbutanoyl] -4-fluoropyrrolidine-2-carbonitrile-10-hydrochloride;
(25.45) -1 - {(2R) -2-amino-3 - [(3-methoxybenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3 - [(1,1'-biphenyl-4-ylmethyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(2S, 4S) -1 - {(2R) -2-amino-3 - [(2-methoxybenzyl) sulfonyl] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(pyridin-3-ylmethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile;
(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(pyridin-2-ylmethyl) thio] butanoyl} -4-fluoropyrrolidine-220-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(pyridin-4-ylmethyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3 - [(4-fluorobenzyl) sulfonyl] -3-methylbutanoyl) -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(2S, 4S) -1 - {(2R) -2-amino-3-methyl-3 - [(3-phenoxybenzyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3-methyl-3 - [(3-phenoxybenzyl) thio] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - ((2R) -2-Amino-3 - {[(5-chloro-1,1-dioxido-1-benzothien-3-yl) methyl] sulfonyl} -3-methyl-3-butanoyl) 4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-amino-3 - [(2,1,3-benzoxadiazol-5-ylmethyl) thio] -3-methylbutanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2R) -2-Amino-3-methyl] -3 - [(pyridin-4-ylmethyl) sulfonyl] butanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
* ί "
127 (25.45) -1 - [(2S) -2-amino-3-pyridin-4-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - [(2S) -2-Amino-3-pyridin-3-ylpropanoyl] -4-fluoro-pyridine-2-carbonitrile hydrochloride;
(25.45) -1 - [(2S) -2-amino-3-piperidin-4-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride;
(2S, 4S) -l - [(2S) -2-amino-3-piperidin-3-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride;
(25.45) -1 - [(2S) -2-amino-3-piperidin-2-ylpropanoyl] -4-fluoropyrrolidine-2-carbonitrile dihydrochloride;
(25.45) -1 - {(2S) -2-amino-3- [1- (isopropylsulfonyl) piperidin-4-yl] propanoyl} -4-fluoropyrrolidine-10-carbonitrile hydrochloride;
(25.45) -1 - {(2S) -2-amino-3- [1- (4-methylphenylsulfonyl) piperidin-4-yl] propanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2S) -2-amino-3- [1- (isopropylsulfonyl) piperidin-3-yl] propanoyl} -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(2S, 4S) -l - {(2S) -2-amino-3- [l- (4-methylphenylsulphonyl) pipendin-3-yl] propanoyl} -4-fiuorpirrolidin-2-carbonitrile hydrochloride;
(25.45) -1 - [(2S) -2-amino-3- (1-benzothien-3-yl) propanoyl] -4-fluoropyrrolidine-2-carbonitrile hydrochloride;
(25.45) -1 - {(2S) -2-Amino-3-methyl-3- [4- (trifluoromethyl) phenyl] butanoyl} -4-fluoropyrrolidin-2-carboxylate; and (3R) -3-amino-4 - [(2S, 4S) -2-cyano-4-fluoropyrrolidin-1-yl] -2-methyl-4-oxobutane-2-sulfonic acid.
34. A pharmaceutical composition comprising the active ingredient as defined in claims 1-33. A compound according to any one of claims 1 to 5.
35. The pharmaceutical composition of claim 34, further comprising a carrier and / or other excipient commonly used in the pharmaceutical formulation.
36. Use of a compound according to any one of claims 1 to 3 for the preparation of a pharmaceutical composition for inhibiting post-proline / analin cleavage protease.
The use of claim 36, wherein the post proline / analin cleavage protease is a serine protease.
The use of claim 37, wherein the serine protease is a dipeptidyl peptidase.
The use of claim 38, wherein the dipeptidyl peptidase is DPP-II.
The use of claim 38, wherein the dipeptidyl peptidase is DPP-IV.
41. Use of a compound according to any one of claims 1 to 4 for metabolic disorders, gastrointestinal disorders, viral diseases, inflammatory disorders.
-128 illnesses, diabetes, obesity, hyperlipidemia, dermatological or mucosal membrane disorders, psoriasis, intestinal distress, constipation, autoimmune disorders such as cerebrovascular inflammation, complement mediated diseases such as glomerulonephritis, fat metabolism and tissue damage, and psychosomatic , depressive and neuropsychiatric diseases such as anxiety, depression, insomnia, schizophrenia, epilepsy, spasms and chronic pain, HIV infection, allergic diseases, inflammatory diseases, arthritis, transplant rejection, hypertension, congestive heart failure, tumors and stress for the treatment or prevention of abortion-induced abortions.
42. A compound according to any one of claims 1 to 4 for use as an active therapeutic agent.
43. A compound according to any one of claims 1 to 4 for use in the manufacture of a pharmaceutical composition for inhibiting serine protease.
44. Referring to FIGS. A compound according to any one of claims 1 to 4, metabolic disorders, gastrointestinal disorders, viral diseases, inflammatory diseases, diabetes, obesity, hyperlipidemia, dermatological or mucosal membrane disorders, psoriasis, intestinal distress, constipation, autoimmune disorders such as cerebrovascular inflammation, complement mediated diseases, for example glomerulonephritis, fatty tissue metabolism and tissue damage, as well as psychosomatic, depressive and neuropsychiatric diseases such as anxiety, depression, insomnia, schizophrenia, epilepsy, spasms and chronic pain, HIV infection, allergic diseases, inflammatory diseases, arthritis, transplants rejection, hypertension, congestive heart failure, tumors and stress-induced abortions suitable for use in the manufacture of a pharmaceutical composition for the prevention of the disease.
Instead of the notifier, the proxy:
Our number: 99770-5194-JG
Ρ 04 Ö0 3 2 1
MeO (Fruit)
R (IX) (X) (XI) pTOH
CN (XIII) (XII)
Ρ04 00321 (XVI) (xx) (XXI) (XXIV)
EXHIBITION EXAMPLE (XXIII) (XXVIII)
F (XXX) «·
Ρ04 0032 (XXXIX) (XLI)
EXAMPLE OF DISCLOSURE ^ 7 (XLVIII) ( XLIX >
• «· • · ···
Ρ04 00321 (LIX)
Shall be made, examples Jí7 y
2) deprotection reagents
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