IL184725A - 3-aryl-2-amino-propionic acid amides, 3-heteroaryl-2-amino-propionic acid amides for use in treating pain or stimulating the immune system of a mammal - Google Patents

Description

- 3 - >ηΝποπ - 3 msoin \y ΟΠΌΝ ,jw avi-> - WO - 2 - >opm»n -3 - N 3- nunm i>\y ΟΠΌΝ ΐΓο^ιη'οσυια'Ν IN/I TPOJ!¾N m 'va in yn nnwp mniDnni ,η υοηο-ιΐΌΝ - 2 - >opwnn 3-ARYL-3-HYDR0XY-2-AMIN0-PR0PI0NIC ACID AMIDES, 3-HETER0AYRYL-3-HYDR0XY-2-AMIN0-PR0PI0NIC ACID AMIDES AND RELATED COMPOUNDS HAVING ANALGESIC AND/OR IMMUNOSTIMULANT ACTIVITY ALLERGAN, INC.

C: 62641 3-ARYL-3-HYDROXY-2-AMINO-PROPIONIC ACID AMIDES, 3- HETEROARYL-3-HYDROXY-2-AMINO-PROPIONIC ACID AMIDES AND RELATED COMPOUNDS HAVING ANALGESIC AND/OR IMMUNO STIMULANT ACTIVITY BACKGROUND OF THE INVENTION Claim Of Priority: The present application claims the priority of United States provisional application serial number 60/647,271 filed on January 26, 2005. Field of the Invention The present invention relates to derivatives of 3-aryl-3-hydroxy-2-amino-propionic acid amides, 3 ietei ai7l-3-hydi xy-2-amino-propionic acid amides and to related compounds having analgesic and in some cases immuno stimulant activity.

The present invention also relates to pharmaceutical compositions containing these compounds as active ingredient for alleviating or eliminating pain in mammals and/or stimulating the immune system in mammals and to methods of using said pharmaceutical compositions as analgesics and or immuno stimulants.

Background Art Several compounds falling within one or more of the general definitions as "derivatives of 3-aryl-3-hydroxy-2-amino-propionic acid amides, of 3-heteroaryl-3-hydroxy-2-amino-propionic acid amides, of l-aryl-l-hydroxy-2,3-diamino-propyl amines, l-heteroaryl-l-hydiOxy-2,3-diamino-propyl amines" are blown in the patent and scientific literature.

For example, United States Patent Application Publications US 2003/0153768; US 2003/0050299 disclose several examples of the above- mentioned known compounds. The N-acyl compounds of these references are said to be useful as N-acylsphingosine glucosyltransferase inhibitors, the amide and the reduced compoimds are described as intermediates in their preparations. Illustrative specific examples of compounds of these references are shown below: The publication Shin et al. Tetrahedron Asymmetry, 2000, 11, 3293-3301 discloses the following compounds: 3 184725/2 (1 R,2fi)-2-((S)-1-phenylethylamino)-3- (1R,2ft)-2-amino-3-morpholino-1- morpholino-1-phenylpropan-1-ol phenylpropan-1-ol L-threo-PDMP [N(( 1 S,2S)- 1 -hydroxy-3-morpholino- 1 -phenylpropan-2-yl)decanamide] and some other known compounds used in the methods of this invention are commercially available, in pure enantiomeric and racemic forms, as applicable, from Matreya, LLC Pleasant Gap, Pennsylvania.

United States Patent Nos. 5,945,442; 5,952,370; 6,030,995 and 6,051,598, which are all related to each other as being based on same or related disclosures, shown above. The compounds of these U.S. patent references are said to be inhibitors of the enzyme glucosylceramide (GlcCer) synthethase.

A publication in Journal of Labelled Compounds & Radiopharmaceuticals (1996), 38(3), 285-97 discloses the compound of the formula Published PCT application WO 01/38228 discloses in connection with a chromatographic method.

Kastron et al in Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija (1965) (4), 474-7 disclose the following compound.

DL-erythro Significantly, according to the best knowledge of the present inventors, none of the compounds of the prior art which are struQturally similar to the novel compounds of the present invention are known in the prior artias analgesics or immunostimulants.

SUMMARY OF THE INVENTION The present invention is directed to compounds of Formula 1 5 184725/2 Formula 1 where Ri is H or alkyl of 1 to 6 carbons, R2 is H, alkyl of 1 to 6 carbons or the R\ and R2 groups together with the nitrogen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, cyano or halogen groups or with one or two alkyl groups having 1 to 6 carbons, or one or two carbons of said rings being attached to an oxygen to form keto groups and said 4, 5, 6 or 7 membered ring optionally being condensed with an aromatic or non-aromatic 5 or 6 membered ring that optionally includes 1 or heteroatoms selected from N, O and S; R3 is independently selected from H, alkyl of 1 to 20 carbons, cycloalkyl of 3 to 6 carbons, aryl or heteroaryl, aryl-alkyl, aryl-(hydroxy)alkyl, heteroaryl-alkyl or hetero-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 6 carbons, or R3 is CO-R7, SO2R7 or CO-0-R7 where R7 is H, alkyl of 1 to 20 carbons, alkyl of 1 to 20 carbons substituted with and NH2 group or with an NH-COalkyl group where the alkyl group has one to 6 carbons, aryl or heteroaryl, aryl-alkyl or heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 6 carbons; R4 is. H, alkyl of 1 to 6 carbons or CO-Rs where R8 is alkyl of 1 to 6 carbons; the wavy lines represent bonds connected to carbons having R or S configuration; the dashed lines represent a bond or absence of a bond witli the proviso that the ring containing the dashed lines is aromatic; m, 11 and q are integers independently . selected from 0, 1, 2 or 3 with the proviso that the sum of m, n and q is 2 or 3; s is zero (0) or when X is N then s is zero (0) or 1; W, X and Y independently represent a CH, CR5, CRe or a heteroatom selected independently of N, O and S, and R5 and R^ are independently selected from H, halogen, alkyl of 1 to 6 carbons, halogen substituted allcyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 6 carbons, phenyl, or R5 and R<5 together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; said carbocyclic or heterocyclic ring jointly formed by R5 and Re being optionally substituted witli 1 to 6 R9 groups where R9 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 6 carbons or a pharmaceutically acceptable salt of said compound with the proviso that Formula 1 does not cover compounds where R4 is H, R\ and R2 jointly witli the nitrogen form a pyrrolidino or moipholino ring, the sum of m, 11 and q is 3, and none of W, X and Y represent a heteroatom witli the further proviso that the formula does not cover the compounds of the formula below: DL-erythro The present invention is also directed to the compounds of Formula 2 Formula 2 where Ri is H or alkyl of 1 to 6 carbons, R2 is H, alkyl of 1 to 6 carbons or the Rj and R2 groups together with the nitrpgen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, C¾OH, OH, B(OH)2, cyano or halogen groups or with one or two alkyl groups having 1 to 6 carbons, or one or two carbons of said rings being attached to an oxygen to form keto groups and said 4, 5, 6 or 7 membered ring optionally being condensed with an aromatic or non-aromatic 5 or 6 membered ring that optionally includes 1 or heteroatoms selected from N, O and S; R3 is independently selected from H, alkyl of 1 to 20 carbons, cycloalkyl of 3 to 6 carbons, aryl or heteroaryl, aryl-alkyl, aiyl-(hydroxy)alkyl, heteroaryl-alkyl 8 184725/2 or hetero-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 6 carbons, or R3 is CO-R7, SO2R7 or CO-O-R7 where R7 is H, alkyl of 1 to 20 carbons, alkyl of 1 to 20 carbons substituted with an NH2, NHCOR7 or NHCOOR7 group, aryl or heteroaryl, aryl-alkyl or heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 6 carbons; the wavy lines represent bonds connected to carbons having R or S configuration; the dashed lines represent a bond or absence of a bond with the proviso that the ring containing the dashed lines is aromatic; R9 and R)0 are independently H, alkyl of 1 to 6 carbons or ORi 1 , or R9 and Ri0 jointly represent NORn with the proviso that when the dashed lines between carbons 2 and 3 of the propionic acid moiety represents a bond then R)0 does not exist and R9 is not OR] 1 with the further proviso that when R9 is ORi 1 then Rio is not hydrogen; Rn is H, alkyl of 1 to 6 carbons or CO-R12 where Rj2 is alkyl of 1 to 6 carbons; m, n and q are integers independently selected from 0, 1, 2 or 3 with the proviso that the sum of m, n and q is 2 or 3; s is zero (0) or when X is N then s is zero (0) or 1; W, X and Y independently represent a CH, CR5, CR^ or a heteroatom selected independently of N, O and S, and R5 and R<; are independently selected from H, halogen, alkyl of 1 to 6 carbons, halogen substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and tliioxy of 1 to 6 carbons, phenyl, or R5 and Rg together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, 0 and S; said carbocyclic or heterocyclic ring jointly formed by R5 and R The present invention is also directed to pharmaceutical compositions containing the above-noted novel compound to be used as analgesics and/or immunostimulants in mammals, and to methods of using said pharmaceutical compositions as analgesics or imiiiunostimulants.

DETAILED DESCRIPTION OF THE INVENTION A general description of the compounds of the invention is provided in the Summary Section of the present application for patent. Most compounds of the invention contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. In fact, most of the compounds of the present invention have two asymmetric carbons adjacent to one another and therefore can exist in eiythro or threo form, with each of these two forms having dextrorotatory (D) or levorotary (L) enantiomers. Although the threo form is generally preferred in accordance with the present invention for analgesic activity, unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and diastereomeric or racemic mixtures. In light of the foregoing, it should be 10 184725/2 clearly understood that the designation "DL" or "(+/-)" or "(±)" in this application includes the pure dextrorotatory enantiomer, the pure levorotatory enantiomer and all racemic mixtures, including mixtures where the two enantiomers are present in equal or in unequal proportions. Moreover, for simplicity sake in many of the structural formulas, such as in the example below, only one of the enantiomers is actually shown but when the designation or "(+/-)" or "(±)" appears it also includes the enantiomeric form (mirror image) of the structure actually shown in the formula.

For Example: HCI DL-threo (Only one enantiomer shown) Thus, in the example above, only one enantiomer is shown, but because the designation "DL" (or "(+/-)" or "(±)") appears below the formula, its optical isomer HCI DL-threo (the other enantiomer shown) and all racemic mixtures of the two optical isomers are also included.

In the case of some compounds of the present invention one enantiomer of the threo, and in some cases of the erythro, enantiomers is significantly more active as an analgesic than the other enantiomer of the same pair. For this reason the isolated enantiomer which is significantly more active than the other is considered a novel and inventive composition even if Hie racemic mixture or tlie other opposite enantiomer of the same compound have already been described in the prior art.

Some of the novel compounds of tlie present invention contain three or more asymmetric centers. An example is the following compound Compound 214 named Compound 214 in the description. The formula shown in the description for Compound 214 indicates two compounds of the threo isomer, but tl e two compounds indicated are not mirror images of each other, they are diastereomers. Another isomer pair is shown and described as Compound 215. (2S.3R) & (2R.3S) Compound 215 Keeping the foregoing examples in mind the reader one of ordinary skill in the art should readily understand tlie scope of each described example, although in a broad sense all isomers, enantiomers and racemic mixtures are within the scope of the invention.

The term "alkyl" in the general description and definition of the compounds includes straight chain as well as branch-chained alkyl groups.

Generally speaking the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds of Formula 1 and of Formula 2 are also witliin the scope of the invention.

Referring now to the novel compounds of Formula 1, in a class of preferred compounds of the invention none of the W, X and Y groups is a heteroatom. Within this class, compounds are preferred where the sum of m, n and q is 3 and the aromatic group is unsubstituted or substituted with one or more halogen, alkyl of 1 to 6 carbons, or halogen substituted alkyl of 1 to 6 carbons. Compounds within this class are also preferred where the R5 and R6 groups form a carbocyclic ring, or a heterocyclic ring.

In another class of preferred compounds in accordance with Formula 1 one of the variables , X and Y represents a heteroatom, preferably nitrogen and the sum of m, n and q is 3.

In still another class of preferred compounds in accordance with Formula 1 one or two of the variables W, X and Y represent a heteroatom, selected from N, 0 or S and the sum of m, u and q is 2.

Referring still to the compounds of Formula 1, compounds are preferred where R4 is H or an acyl group, more preferably H.

With reference to the variables R3, compounds in accordance with Formula 1 are preferred where both R3 groups are Hand where one R3 group is H and the other is benzyl, monohalogeno, dihalogeno, methyl or methoxy substituted benzyl, cyclohexyl, an allcyl of 1 to 7 carbons, COR7, COOR7 where . R7 is allcyl of 1 to 15 carbons, benzyloxy, phenyl, methoxyphenyl, monohalogen or dihalogeno substituted phenyl, a 2-hydroxy-l-phenylethyl group or an allcyl group of 1 to 20 carbons itself substituted with an NH2, NHCOR7, or NHCOOR7 group.

Referring now to the variables Rj and R2 in the compounds of Formula 1, compounds are preferred in accordance with the invention where R\ and R2 jointly form a pyrrolidine, a 3-fluoro or a 3,3-difluoro or an 3-hydroxy substituted pyrrolidine, a morpholine, a thiomorpholine, a piperazine, an all yl substituted piperazine where the alkyl group has 1 to 6 carbons, an azetidine, a tetral ydrothiazole, an indoline, or a 2H-pyrrol ring or R\ and R2 are two alkyl groups of 1 to 3 carbons.

Referring now to the novel compounds of Formula 2, with respect to the variables W, X, Y, m, n, q, Rj, 2, R5, e, R3 compounds are gerenerally preferred in which these variables have the same preferences as in compounds of Formula 1.

With respect to R9 and Rjo, compounds are generally preferred where R9 and R10 are both hydrogen, where one of these two variables is hydroxy and the other is alkyl of 1 to 6 carbons, where the R9 and Ri0 groups jointly form an NORu group, and where R9 is hydrogen, the dashed line between carbons 2 and 3 represent a double bond and Ri0 does not exist. With respect to Rn compounds of Formula 2 are preferred where Rn is H, or COR12 where R12 is , alkyl of 1 to 3 carbons.

Presently still more preferred are Compounds of Formula 2 where Ri and R2 jointly with the nitrogen form a five-membered ring, where both R3 groups are hydrogen and where one of the R3 groups is hydrogen and the other is formyl.

The presently most preferred novel compounds of the invention are disclosed with their structural formulas in the ensuing Tables and or description, showing activity of exemplary compounds relevant to their ability to act as analgesics and/or immunostimulants.

BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION The novel compounds of the invention have analgesic and/ or immunostimulant activity in mammals. Some of the compounds described in the introductory section which per se are known in the art, have been discovered by the present inventors to also have analgesic effect in mammals. To the best of the knowledge of the present inventors the analgesic or immunostimulant biological activity of the known compounds was not known before the present discovery.

An art-accepted model or assay for measuring an analgesic effect · of a compound in clironic pain (in particular peripheral neuropathy) is the model known as Kim and Chung 1992, Pain 150, pp 355-363 {Chung model). This model involves the surgical ligation of the L5 (and optionally the L6) spinal nerves on one side in experimental animals,. Rats recovering from the surgery gain weight and display a level of general activity similar to that of normal rats. However, these rats develop abnormalities of the foot, wherein the hindpaw is moderately everted and the toes are held together. More importantly, the hindpaw on the side affected by the surgery appears to become sensitive to low-threshold mechanical stimuli and will perceive pain instead of the faint sensation of touch. This sensitivity to normally non-painful touch, called "tactile allodynia", develops within the first week after surgery and lasts for at least two months. The allodynia response includes lifting the affected hindpaw to escape from the stimulus, licking the paw and holding it in the air for many seconds. None of these responses is normally seen in the control group.

To produce the tactile allodynia, rats are anesthetized before surgery. The surgical site is shaved and prepared either with betadine or Novacaine. Incision is made from the thoracic vertebra Xlll down toward the sacrum.

Muscle tissue is separated from the spinal vertebra (left side) at the L4 - S2 levels. The L6 vertebra is located and the transverse process is carefully removed with a small rongeur to expose the L4 - L6 spinal nerves. The L5 and L6 spinal nerves are isolated and tightly ligated with 6-0 silk thread. The same procedure is done on the right side as a control, except no ligation of the spinal nerves is performed.

After a complete hemostasis is confirmed, the wounds are sutured. A small amount of antibiotic ointment is applied to the incised area, and the rat is transferred to the recovery plastic cage under a regulated heat-temperature lamp.

On the day of the experiment, at least seven days after the surgery, typically six rats per test group are administered the test drugs by intraperitoneal (i.p.) injection or oral gavage (p.o.). For i.p. administration, the compounds are formulated in H2O and given in a volume of 1 ml/kg body weight by injecting into the intraperitoneal cavity. For p.o. adiriinistration, the compounds are formulated in H2O and given in a volume of 1 ml/leg body weight using an 18-gauge, 3 inch gavage needle that is slowly inserted through the esophagus into the stomach.

Tactile allodynia is' assessed via vo Frey hairs, which are a series of fine hairs with incremental differences in stiffness. Rats are placed in a plastic cage with a wire mesh bottom and allowed to acclimate for approximately 30 minutes. To establish the pre-drug baseline, the von Frey hairs are applied perpendicularly through the mesh to the mid-plantar region of the rats' hindpaw with sufficient force to cause slight budding and held for 6-8 seconds. The applied force has been calculated to range from 0.41 to 15.1 grams. If the paw is sharply withdrawn, it is considered a positive response. A normal animal will not respond to stimuli in this range, but a surgically ligated paw will be withdrawn in response to a 1-2 gram hair. The 50% paw withdrawal threshold is detennined using the method of Dixon, W.J., Ann. Rev. Pharmacol. Toxicol. 20:441-462 (1980) hereby incorporated by reference. Tactile allodynia is measured prior to and 15, 30, and 60 minutes after drug administration. The post-drug threshold is compared to the pre-drug threshold and the percent reversal of tactile sensitivity is calculated based on a normal threshold of 15.1 grams.

Table 1 below indicates the degree of pain reversal obtained in the Chung model with exemplary compounds of the invention. The intraperitonial (i.p.) and/or intravenous (iv) administration of the compoimds was in doses ranging from 1 μg/kg to 300 μg/kg or 3 mg/kg PO and the peak percentage of reversal of allodynia was measured at 15, 30 or 60 minutes after administration, as is indicated in the table. Data are expressed as the highest % allodynia reversal (out of 3 time points: 15 min, 30 min, or 60 min. post-dmg) with a minimum of a 20% allodynia reversal in the rat Chung model. Comparisons between groups (drug treated vs. saline treated) were made using a two-tailed, 2-sample, impaired t-test. Compounds that are not shown which were not statistically analgesic following an IP dose of 300 ug/kg, but may still be analgesic.

Compounds that do not exhibit significant analgesia at 100 mg/kg are not considered to be analgesic.

TABLE 1 23 184725/2 An art accepted method for measuring immiino stimulation comprises systemic administration of compounds to assay for the ability to stimulate the immune system, possibly due to nonspecific upregulation of the hemolymphoreticular system. This upregulation could result in increased numbers of lymphocytes of both T- and B-cell lineage. Altliough applicant does not wish to be bound by the biological tlieory of the immunostimulation, actual immunostimulatory efficacy of the compounds can be demonstrated in vivo by assaying splenic size in response to adrainstration of the test compound to laboratory test species rats. Animals dosed at 200 mg/kg of Compound 22 of this invention exhibited a twentyfive percent increase in spleen size which demonstrates immunostimulatory potential of the compound. Generally speaking any compound that exhibits splenic enlargement following dosing of 200 mg/kg or less may be considered an immunostimulant.

Modes of Administration: The compounds of the invention may be administered at pharmaceutically effective dosages. Such dosages are normally the minimum dose necessary to achieve the desired therapeutic effect; in the treatment of · chromic pain, this amount would be roughly that necessary to reduce the discomfort caused by the pain to tolerable levels. For human adults such doses generally will be in the range 0.1-5000 mg/day; more preferably in the range 1 to 3000 mg/day, still more preferably in the range of 10 mg to 1000 mg/day. However, the actual amount of the compound to be administered in any given case will be determined by a physician talcing into account the relevant circumstances, such as the severity of the pain, the age and weight of the patient, the patient's general physical condition, the cause of the pain, and the route of administration.

The compounds are useful in the treatment of pain in a mammal; particularly a human being. Preferably, the patient will be given the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like. However, other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, intraperitonial, parenteral, subcutaneous, intranasal, intrathecal, intramuscular, intravenous and intrarectal modes of delivery. Another aspect of the invention is drawn to therapeutic compositions comprising the novel compounds of the invention and pharmaceutically acceptable salts of these · compounds and a pharmaceutically acceptable excipient. Such an excipient may be a earlier or a diluent; this is usually mixed with the active compound, or permitted to dilute or enclose the active compound. If a diluent, the carrier may be solid, semi-solid, or liquid material that acts as an excipient or vehicle for the active compound. The formulations may also include wetting agents, emulsifying agents, preserving agents, sweetening agents, and/or flavoring agents. If used as in an ophthalmic or infusion format, the formulation will usually contain one or more salt to influence the osmotic pressure of the formulation.

In another aspect, the invention is directed to methods for the treatment of pain, particularly clironic pain, through the acmiinistration of one or more of the novel or otherwise known compounds of the invention, or of pharmaceutically acceptable salts thereof to a mammal in need thereof. As indicated above, the compound will usually be formulated in a form consistent with the desired mode of delivery.

Compounds of the invention which are immunostimulants are administered subject to the same basic principles as the compounds having analgesic activity, in doses which are best detennined on a case-by-case and/or species-by-species and, in case of humans, at times on a patient-by-patient basis. Generally speaking the effective dose will be in the range of 10 μg/kg to 200 mg/kg. 29 184725/2 In this regard it is noted that the compounds of the threo configuration are more likely to have the analgesic activity, compounds of the erythro configuration are more likely to have immunostimulant activity, and among the erythro compounds those with an S configuration at carbon 2 of the propionic acid moiety are likely to have stronger immuno stimulant activity.

SYNTHETIC METHODS FOR OBTAINING THE COMPOUNDS OF THE INVENTION, EXPERIMENTAL The compound of the invention can be synthesized by utilizing the synthetic methods described in the experimental below, or such modifications of the below described experimental methods which will become readily apparent to those skilled in the art in light of the present disclosure.

GENERAL Ή NMR ( Nuclear Magnetic resonance) spectra were recorded at ambient temperature with an Avance 300 (Bruker) spectrometer. The compounds were analyzed by reverse phase high performance liquid chromatography (HPLC) using a Waters Autopurification System equipped with a Waters 2525 Pump, a Waters 2696 photodiode array detector, and a XTerra column (Part. No. 186000482, 5 μιη, CI 8, 4.5 x 50 mm).

The HPLC method used was a gradient of 5 % solvent B to 100 % in 7 min. Solvent A was H20 with 0.05 % TFA and solvent B was CH3CN with 0.05 % TFA (trifluoroacetic acid) (Method A).

Melting points were measured with a Biichi B-545 melting point apparatus and were uncorrected. To isolate reaction products the solvent were removed by evaporation using a vacuum rotatory evaporator, the water bath temperature not exceeding 40 °C.

Absolute configuration of compounds of the invention, where applicable, can generally speaking be determined in accordance with metliods Icnown in the state of the ait, such as X-ray christallography. Compounds 203 and 204 are mentioned as examples for which the absolute configurations were determined by X-ray christallography analysis of the corresponding (lS)-camphanylamide D-(10) camphorsulfouic acid salt. As a result Compound 204 was assigned (2S, 3R). Its enantiomer, Compound 203 was assigned by default the (2R, 36) absolute configuration.

GENERAL SYNTHETIC ROUTES The compound of the invention can be synthesized by utilizing the synthetic methods described in a general sense immediately below and in more detail in the experimental section of the present application, or by such modifications of the below described experimental methods which will become readily apparent to those skilled in the art in light of the present disclosure.

A general synthetic route to the novel compounds of the invention which are amides of substituted (+/-)-i/ireo-3-hydroxy-2-aminbpropionic acid of the Generalized Structure 1 is described below.

General Structure 1 In General Structure 1, for the sake of simplicity of description R* substantially corresponds to the 5, 6, or 7 membered ring structure on the left side of Formula 1 (as the formula is depicted in the Summary and in the instant claims) and R** substantially corresponds to the Ri groups in Formula methylisocyanoacetate "amine" 2-Isocyano-l-(subst-amino)ethnnone R* -CHO strong base "aldehyde" (KOH) {+l-)-threo ira/is-oxazoline General Structure 1 (major isomer (major isomer) General Reaction Scheme 1 Thus, in accordance with General Scheme 1, methyl isocyanoacetate (or ethyl isocyanoacetate available commercially) is reacted with an "amine" which includes the R** groups to provide the 2-isocyanoacetic acid amide derivative shown in the general scheme. Typical examples for me amines used in the reaction are pyrrolidine, piperidine, azetidine, morpholine, 2,5-dihydro-lH-pyrrole, dialkylamines such as diethylamine, 3-fluoro-, 3,3-difluoro or 3-hydroxy substituted pyrrolidines. Specific examples of these "amines" abound in the experimental description. The 2-isocyanoacetic acid amide derivative is then reacted in the presence of base (such as KOH) with an "aldehyde" which includes the R* group to provide a trans "oxazoline" with high diastereoselectivity (trans'.cis ratios generally > 97:3) as shown in the general reaction scheme 1. The trans, oxazolme is then treated with a strong acid, such as HC1, to open the ring and to provide the i/ireo-3-substituted-3-hydi xy-2-amino-propionic acid amides (with threo:erythro ratios generally > 97:3) of the invention as shown in General Scheme 1.

Compounds of Formula 1 where the amino group of formula NH(R**)2 is a weaker nucleophile, such as indoline, thiomorpholine and the like, can be made as illustrated in Reaction Scheme 2 for the synthesis of (±)-threo-2-aniino-3-hydroxy- 1 -(indol i- 1 -yl)-3-(pyridin-4-yl)propan- 1 -one dihydrochloride Compound 243 and (-fc)-t/ireo-2-amino-3-hydroxy-l-(thiazoUdin-3-yl)-3-(pyridiii-4-yl)propan-l-one dihydrochloride Compound 242.

Compound 242 a) KOH, MeOH; b) Indol!ne, EDCI, TEA, HOBT, CH2CI2. c) HCI (1M) In MeOH d) I. Silica Gel Chromatography.!! HCI (0.1 M) In /-PrOH e) BOC20, NaOH, Dioxane. f) Thlazolldlne, EDCI, TEA, HOBT, CH2CI2; g) Silica Gel Chromatography g) HCI (1 ) In MeOH.

Reaction Scheme 2 lii Reaction Scheme 2 EDCI stands for l-(3-dimethylaiTrinopropyl)-ethylcarbodiimide hydrochloride; HOBT stands for 1-hydroxybenzotriazole; BOC2O stands for di-i-butyl-dicarbonate and TEA stands for hiethylamine.

As it will be readily understood by those skilled in the art, for a more general synthetic route, such as the one shown in Reaction Scheme 2, the 4- pyridyl group can be substituted with an R* group (as defined in connection with Scheme 1) and the indoline can be susbstituted with other weak nucleophilic amines of the formula NH(R**)2 (R** defined as in connection with Reaction Scheme 1) to provide other compounds of Formula 1 analogous to compounds 242 and 243.

Ispmerically pure and/or enantiomerically pure compounds and further derivatives of the 3-substituted-3-hydroxy-2-amino-propionic acid amides are obtained by separation techniques and reactions which, per se, are well known to the synthetic chemist. The experimental section of the present invention abounds in examples of such separation techniques and reactions. Some of the typical separation techniques and reactions are generally described below.

Separation of threo and erythro isomers, when both are formed in the reactions leading to the compounds of the invention, can typically be separated by chromatographic methods. The more abundantly formed threo isomers can also be converted into the erythro isomers by oxidizing to the ketone level the hydroxyl group in the 3 position of the propanoic acid moiety and subsequently reducing the resulting ketone to the hydroxyl level. (See, for example, the preparation of Compound 219).

Separation of enantiomeric mixtures can be performed on Cliiralpack columns which are well known in the art. (See, for example, the preparation of Compound 204).

The amino function in the 2-position of the propanoic acid moiety is, generally speaking, more reactive towards acylation and carbamoylation than the hydroxyl group in the 3 position. Therefore, acylated derivatives of the 2- amino function can be prepared by using acyl chlorides such as acetyl chloride and hexanoyl chloride. (See, Method G and the preparation of Compound 51). Carbamate derivatives of the 2-amino function can be obtained by using chloroformates, such as benzylchloroformate. (See, for example, the preparation of Compound 58). The tertiary butyl carbamoyl function can also serve as a removable protecting group of the 2-amino function, (see for example tlie preparation of Compounds 219 and 224). When the 2-amino function of tlie compounds of the invention is already acylated or bears a carbamoyl group, then the 3-hydroxy group of tlie propanoic acid moiety can be subjected to acylation by reagents such as acetic anhydride. (See for example the preparation of Compound 217).

Alkylation of the 2-amino function is readily performed by condensing the compound bearing the 2-NH2 group with an aldehyde to obtain a Schiff base intermediate which can be reduced, without isolation* to provide the N-alkyl, arylalkyl or heteroaryl-alkyl compound. The procedure described for preparing Compound 234 can be generalized to make compounds of the invention where Hie 2-amino function bears an aryl( hydroxy)alkyl or heteroaryl(hydroxy)alkyl group.

Several compounds of the invention of Formula 2 can be obtained by derivatization of compounds of Formula 1, or by such modification of the synthetic routes leading to compounds of Formula 1 which will become readily apparent to those skilled in the art in light of the present disclosure. For example, compounds of Formula 2 where R9 is OH or ORn and R10 is all yl can be made by using a "ketone" bearing the Ri0 group, instead of the "aldehyde" in General Reaction Scheme 1.

Compounds of Formula 2 where the R9 and Rj0 groups jointly form an oxime (ΝΟΗ) group can be obtained by oxidizing the 3-hydroxyl group of the propanoic acid moiety to the ketone stage and reacting the resulting ketone with hydroxylamine.

Another general synthetic route for making several compounds of Formula 2 is illustrated in Synthetic Scheme 3 adapted for synthesizing (R)-2-amino-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one dihydrochloride, Compound 236. of the present invention.

S Compound 236 As it will be readily understood by those skilled in the art, for a more general synthetic route, such as the one shown in Reaction Shyntetic Scheme 3, the 4-pyridyl group can be substituted with an R* group (as defined in connection with Scheme 1) and the pyrrolidine can be substituted with amines of the formula NH(R**)2 (R** defined as in connection with Reaction Scheme 1) to provide other compounds of Formula 2 analogous to compound 236 or to its enantiomer (5)-2-amino-3-(pyridin-4-yl)-l -(pyrrolidin- 1 -yl)propan- 1 -one dihydrochloride Compound 240.

DETAILED DESCRIPTION OF THE SYNTHESIS OF PREFERRED COMPOUNDS (EXPERIMENTAL) Preparation of compound 12 2-Isocvano-l-fpyrrolidin-l-yl)emanone BLE 04098.

To stirred and cooled (0 °C) methyl isocyanoacetate (96 % technical grade, 5.0 g, 47.8 mmol) was slowly added in 0.75 h pyrrolidine (6.5 niL, 78 mmol). The mixture was stirred for 1.5 h with continued cooling and then concentrated. The resulting oil was co-evaporated twice from CHaC^ exane to remove residual pyrrolidine. 2-Isocyano-l-(pyrrolidin-l-yl)etlianone BLE 04098 was obtained as a yellow solid (6.85 g, 98 % yield) and used in the next step without purification.

BLE 04098 MW: 138.17; Yield: 98 %; yellow solid; Mp (°C) = 73.9. 1H-NMR (CDC13, δ): 1.81-2.08 (m, 4H, 2xCH2), 3.35-3.45 (m, 2H, -NCH2), 3.50-3.60 (m, 2H, -NC¾ , 4.23 (s, 2H, CH2CO). tm«.y- 4.5-DihvdiO-5-("2.3-dihvdrobeiizo[biri.41dioxin-6-yl oxazol-4-yl¥pynOlidin-l-v memanone BLE 04100.

To a stirred and cooled (0°C) solution of potassium hydroxide (0.43 mg, 7.60 mmol) in MeOH (6.5 mL). were added successively l,4-benzodioxan-6- carboxaldehyde (1.31 g, 7.96 mmol) and 2-isocyano-l-(pyrrolidin-l- yl)ethanone BLE 04098 (1.0 g, 6.57 mmol). The solution was stirred 3 h at 0°C and then concentrated. The residue was partitioned between EtOAc (100 mL) 38 184725/2 and water. The organic layer was combined with 2 additional EtOAc extracts (2 x 100 mL), washed with brine, dried over MgS04, filtered and evaporated. Concentration afford to a crude product which was purified by column chromatography on silica (EtOAc) to yield, after evaporation and drying, to fra«s-4,5-dihydro-5-(2,3-dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)(oxazol-4-yl)(pyrrolidin-l-yl)methanone BLE 04100 as a colourless oil (1.76 g, 89 % yield).

BLE 04100 MW: 440.49; Yield: 89 %; colorless oil. 1 H-NMR (CDC13, δ): 1.75-2.10 (m, 4H, 2xCH2), 3.40-3.59 (m, 3H, 1.5xCH2N), 3.85-4.00 (m, 1H, 0.5xCH2N), 4.26 (s, 4H, CH20), 4.59 (dd, 1H, J= 7.5 Hz, J= 2.2 Hz, CH-N), 6.00 (d, 1H, J= 7.5 Hz, CH-O), 6.75-6.90 (m, 3H, ArH), 7.00 (d, 1H, .7= 2.2 Hz, CH=N). trans-( 4,5-Dihvdro-5-('4-methoxyphenvnoxazol-4-yl (pyrrolidin- 1 -vDmethanone SLA 07074.

To a stirred and cooled (0°C) solution of potassium hydroxide (0.37 g, 6.57 mmol) in methanol (30 mL) was added a mixture of 4-methoxy-benzaldehyde (0.88 mL, 7.23 mmol) and 2-isocyano-l-(pyrrolidin-l-yl)ethanone BLE 04098 (1.0 g, 6.57 mmol). The solution was stirred 4 h with continued cooling and then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was combined with additional ethyl acetate extracts, washed with aqueous sodium chloride and dried over MgS04. Concentration afforded a crude product as a glassy solid. Flash chromatography over silica (ethyl acetate) yielded to /ra«jr-(4,5-diliydiO-5-(4-metlioxyphenyl)oxazol-4-yl)(pyiTolidin-l-yl)methanone SLA 07074 yellow solid (1.2 g, 90.5 %).

SLA 07074 MW: 274.32; Yield: 90.5 %; pale yellow sohd; Mp (°C): 91.2.

R :0.30 (EtOAc). 1 H-NMR (CDC13, δ): 1.75-2.08 (m, 4H, 2xCH2), 3.40-3.58 (in, 3H, CH2N), 3.52 (ss 3H, CH3O), 3.88-3.98 (m, 1H, CH2N), 4.59 (dd, 1H, J= 7.6 Hz, J= 2.2 Hz, CH-N), 6.06 (d, 1H, J= 7.6 Hz, CH-O), 6.90 (d, 2H, J= 8.7 Hz, ArH), 7.01 (d, 1H, J= 2.2 Hz, CH=N), 7.25 (d, 2H, J= 8.7 Hz, ArH).

MS-ESI rn/z (% rel. Int.): 275.1 ([MH]+, 10), 247.1 (100).

HPLC: Method A, detection UV 280 rail, SLA 07074 RT = 5.2 min, peak area 92 %.

DL-^reo-2-AnTino-3-hydroxy-3-(4-methoxyphenyl -l-^yrrolidin-l-yl')propan-1-one hydrochloride SLA 07078.

To a stirred solution of ira/i1s-(4,5-dihydro-5-(4-methoxyphenyl)oxazol-4-yl)(pyriOlidin-l-yl)methanone SLA 07074 (1.61 g, 5.93 mmol) in methanol (13 mL) was added hydrochloric acid (lmL). After heating at 50 °C for 3h tlie mixture reaction was concentrated and the resulting yellow oil was co-evaporated twice with ethyl acetate before solidifying. Trituration (ethyl acetate) and drying afforded DL-iAreo-2-amino-3-hydroxy-3-(4- 40 184725/2 methoxypheny 1)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one hydrochloride SLA 07078 as a white solid (1.64 g, 93 %).

SLA 07078 MW: 300.78; Yield: 93 %; white Solid; Mp (°C): 177.0.

'H-NMR (CD3OD, *): 1.32-1.50 (m, 1H, 0.5xCH2), 1.50-1.88 (m, 3H, 1.5xCH2), 2.15-2.28 (m, 1H, CH2N), 3.15-3.42 (m, 3H, 1.5xCH2N), 3.79 (s, 3H, CH3O), 4.06 (d, 1H, J= 9.2 Hz, CH-N), 4.78 (d, 1H, J= 9.2 Hz, CHO), 6.94 (d, 2H, J= 8.5 Hz, ArH), 7.34 (d, 2H, J= 8.5 Hz, ArH). ,3C-NMR (CD3OD, *): 24.8, 26.6, 47.2, 47.6, 55.9, 59.6, 73.9, 115.0 (2xC), 128.9 (2xC), 132.5, 161.7, 166.4.

DL-f/zreo-2-amino-3-(2,3-dihydrobenzorb1 Γ 1 ,41 dioxin-6-vD-3 -hydroxy- 1 -(pyrrolidin- l-yl)propan-l -one hydrochloride Compound 12.

To a stirred solution of £r Compound 12 MW: 328.79; Yield: 95.0 %; White Solid; Mp (°C): 176.2. 1H-NMR (CD3OD, δ): 1.42-1.58 (m, 1H, 0.5xCH2), 1.58-1.70 (m, 1H, 0.5xCH2), 1.70-1.88 (m, 2H, CH2), 3.20-3.45 (m, 4H, 2xN-CH2), 4.06 (d, 1H, J = 9.1 Hz, CH-N), 4.25 (s, 2H, OC¾), 4.75 (d, 1H, J= 9.2 Hz, CH-O), 4.89 (s, 2H, OCH2), 6.82-6.95 (m, 3H, ArH). l3C-NMR (CD3OD, δ): 24.9, 26.7, 47.3, 47.6, 59.5, 65.7, 73.6, 116.4, 118.3, 120.3, 133.7, 145.1, 145.6, 166.4.

Preparation of Compound 18.

Method B: ' To a stirred and cooled (0 °C) solution of potassium hydroxide (380 mg, 5.80 mmol) in MeOH (5 mL) were added successively aldehyde (5.80 mmol) and 2-isocyano-l-(pyiTolidin-l-yl)ethanone BLE 04098 (0.8 g, 5.8 mmol). The solution was stirred 3 h at 0 °C and then concentrated. The residue was partitioned between CH2CI2 (100 mL) and water. The organic layer was washed with brine, dried over MgS04, filtered and evaporated. Concentration afford to a crude product which was purified by column chromatography on silica (cyclohexane:EtOAc = 70:30 to 0:100) to yield, after evaporation and drying, to an intermediate oxazoline. To a stirred solution of oxazoline in methanol (15 mL) was added hydrochloric acid (1 mL, 12 mmol). After heating at 60 °C for 2 h, the mixture reaction was then concentrated and the resulting yellow oil was coevaporated twice with MeOH before solidifying. Trituration in EtOAc:MeOH = 10:1 followed by filtration gave title compound as a white solid.

DL-t/trgo-2-Arnino-3-fbiphenyl-4-ylV3-hvdiOXv- 1 -fpyrrolidin- 1 -vDpropan- 1 -one hydrochloride Compound 18.

The compound was prepared according to method B with 4-phenylbenzaldehyde (1.05 g, 5.78 mmol). DL-t/ireo-2-Amino-3-(biphenyl-4-y^-S-hydroxy-l-^yrrolidin-'l-y^propan-l-'one hydrochloride Compound 18 was obtained as a pale brown solid (0.55 g, 28 % yield).

Compound 18 MW: 346.85; Yield: 28 %; Pale Brown Solid; Mp (°C): 197.3. 1H-NMR (CD3OD, δ): 1.25-1.42 (m, 1H, 0.5xCH2), 1.50-1.60 (m, 1H, 0.5xCH2), 1.60-1.80 (m, 1H, 0.5xCH2), 2.20-2.30 (m, 2H, N-CH2), 3.15-3.30 (m, 2H, N-CH2), 3.30-3.45 (1H5 m, N-CH2), 4.13 (d, 1H, J= 9.2 Hz, CH-N), 4.85-4.95 (rri, 1H, CH-O), 7.32 -7.38 (m, 1H, ArH), 7.46 (dd, 2H, 7= 7.1 Hz, J = 7.8Hz, ArH), 7.52 (d, 2H, J= 8.3 Hz, ArH), 7.58-7.70 (m, 4H, ArH). 13C-NMR (CD3OD, δ): 24.8, 26.5, 47.2, 47.6, 59.5, 78.7, 127.9, 128.1, 128.2, 128.8, 130.0, 139.7, 141.6, 143.3, 166.3.

MS-ESI m/z (% rel. Int.): 311.2 ([MH]+, 60).

HPLC: Method A, detection UV 254 nm, Compound 18 RT = 4.50 min, pealc area 99.9 %. 43 184725/2 Preparation of 2-isocvano derivatives: SLA 071 16B, SLA 07116C. SLA 071 18.

SLA 07130A, SLA 07178. and SLA 07184A 2-Isocy ano- 1 -(piperidin- 1 -vDethanone SLA 071 16B .

Prepared in accordance with Method B with methyl isocyanoacetate (2.46 g, 24.63 mmol) and piperidine (3.22 mL, 37.85 mmol). The reaction mixture was stirred 1 h at RT and then concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10 % aqueous citric acid (2 x 25 mL), dried over MgS04, filtered and evaporated. 2-Isocyano-1 -(piperidin- l-yl)ethanone SLA 07116B was obtained as an orange solid (3.13 g, 83 % yield).

SLA 07116B MW: 152.19; Yield: 83 %; Orange Solid; Mp (°C): 81.6. Ή-NMR (CDC13, *): 1.56-1.74 (m, 6H, CH2C), 3.33 (t, 2H, J = 5.7 Hz, CH2N), 3.58 (t, 2H, J= 5.7 Hz, CH2N), 4.29 (s, 2H, CH2CO). tert- u yl 4-(2-isocyanoacetyl piperazine-l-carboxylate SLA 071 16C.

Prepared in accordance with Method B with methyl isocyanoacetate (2.51 g, 25.29 mmol) and piperazine-l-carboxylic acid tert-butyl ester (6.28 g, 33.85 mmol). The reaction mixture was stirred 1 h at RT and then concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10 % aqueous citric acid (2 x 25 mL), dried over MgS04, filtered and evaporated. tert-Butyl 4-(2-isocyanoacetyl)piperazine-l-carboxylate SLA 07116C was obtained as a colorless oil (0.41 g, 6.5 % yield).

SLA 07116C MW: 253.14; Yield: 6.5 %; Colorless oil. 1H-NMR (CDC13) δ): 1.47 (s, 9H, tBu), 3.38 (t, 2H, J= 5.3 Hz, CH2N), 3.45-3.53 (m, 4H, CH2N), 3.62 (t, 2H, J= 5.5 Hz, CH2N), 4.32 (s, 2H, CH2CO). ■ 2-Isocvano- 1-morpholinoethanone SLA 07118.

Prepared in accordance with Method B with methyl isocyanoacetate (2.51 g, 25.30 mmol) and morpholine (3.30 mL, 38.05 mmol). The reaction mixture was stirred 24 h at RT and then concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10 % aqueous . citric acid (2 x 25 mL), dried over MgS04, filtered and evaporated. 2-Isocyano-1-morpholinoethanone SLA 07118 was obtained as'a brown oil (2.28 g, 58 % yield).

SLA 07118 MW: 154.17; Yield: 58 %; Brown Oil.

Rf: 0.20 (EtOAcxyclohexane = 50:50). 1H-NMR (CDC13, δ): 3.42 (t, 2H, J= 4.9 Hz, CH2N), 3.65 (t, 2H, J= 5.1 Hz, CH2N), 3.73 (t, 4H, J= 5.0 Hz, CH20), 4.31 (s, 2H, CH2CO). 2-Isocyano-l-tiiiomorpholmoemanone SLA 07130A.

Prepared in accordance with Method B with methyl isocyanoacetate (2.50 g, 25.28 mmol) and tliiomorpholine (4.25 mL, 37.85 mmol). The reaction mixture was stirred 22 h at RT and then concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10 % aqueous citric acid (2 x 25 mL), dried over MgS04, filtered and evaporated. 2-Isocyano-l-thiomorpholinoetlianone SLA 07130A was obtained as a yellow solid (3.05 g, 71 % yield).

SLA 07130A MW: 170.23; Yield: 71 %; Yellow Solid; Mp (°C): 144.4.

R/: 0.35 (EtOAc yclohexane = 50:50). 1H-NMR (CDC13, δ): 2.68 (m, 4H, 2xCH2S), 3.67 (m, 2H, N-CH2), 3.90 (m, 2H, N-CH2), 4.31 (s, 2H, COCH2). 2-Isocvano-l-r2H-pyrrol-lf5H-vnethanone SLA 07178.

Prepared in accordance with Method B with methyl isocyanoacetate (1.00 g, 10.10 mmol) and dihydro-lH-pyrrole (1.01 mL, 15.15 mmol). The reaction mixture was stirred 5 h at 50 °C and concentrated. The residue was dissolved in dichloromethane (50 mL) and the organic layer was washed with 10 % aqueous citric acid (2 x 25 mL), dried over MgS04, filtered and evaporated. 2-Isocyano- l-(2H-pyriOl-l(5H)-yl)ethanone SLA 07178 was obtained (1.0 g, 73 % yield) as a yellow solid.

SLA 07178 MW: 136.15; Yield: 73 %; Yellow Solid.

R : 0.35 (EtOAc yclohexane = 50:50). 1H-NMR (CDC13, δ): 4.23 (s, 4H, 2xCH2N), 4.31 (s, 2H, CH2N), 5.80-5.86 (m, 1H, CH=C), 5.90-5.95 (m, 1H, CH=C).

N.N-Diethyl-2-isocvanoacetarnide SLA 07184A.

Prepared in accordance with Method B with methyl isocyanoacetate (2.50 g, 25.29 mmol) and diethylamine (1.96 mL, 37.94 mmol). The reaction mixture was stirred 5 h at 50 °C and concentrated. The residue was dissolved in dicliloromethane (50 mL) and the organic layer was washed with 10 % aqueous citric acid (2 x 25 mL), dried over MgS04, filtered and evaporated. N ^l-Diethyl-2-isocyanoacetamide SLA 07184A was obtained (1.213 g, 34 % yield) as a brown oil.

SLA 07184A MW: 140.18; Yield: 34 %; Brown Oil.

Ry: 0.35 (EtOAc:cyclohexane = 50:50). 1H-NMR (CDC13, δ): 1.15-1.26 (m, 6H, CH3), 3.21-3.30 (m, 2H, CH2N), 3.38- 3.45 (m, 2H, CH2N), 4.26 (s, 2H, CH2CO).

Preparation of oxazolines: BLE 04110B. SLA 07122A. SLA 07124A. SLA 07124B. SLA 07132. BLE 04110A. Compound 19. BLE 04124A. BLE 04124B. BLE 04124C. BLE 04124D. BLE 04130B. BLE 04130C. BLE 04130D. BLE 04136B. BLE 04136C. BAL 01016. BLE 04136D. BAL 01014. SLA 07194A. SLA 07174. BAL 01028A. BLA 01028B. SLA 07158 and SLA 07180.

BLE 04110B.

General Method D for oxazolines formation: ' To a stirred and cooled (0 °C) solution of potassium hydroxide (0.55 g, 9.80 mmol) in methanol (10 mL) were added a mixture of 3-pyridine carboxaldehyde (1.03 mL, 10.84 mmol) and 2-isocyano-l-(pyrrolidin-l-yl)ethanone BLE 04098 (1.50 g, 10.86 mmol). The solution was stirred 3 h at 0 °C and then concentrated. The residue was partitioned between ethyl acetate (100 mL) and water. The organic layer was combined with two additional ethyl acetate extracts (2x100 mL), washed with aqueous sodium chloride and dried over MgSO-j, filtered and evaporated. Concentration afforded a crude product which was purified by column chromatography on silica (CH2Cl2:MeOH = 98:2) to yield to /r fw-(4,5^ydTO-5-(pyridm-3-yl)ox yl)methanone BLE 04110B (0.95 g, 39 % yield) as a pale yellow pale solid.

BLE 04110B W: 245.28; Yield: 39 %; Yellow Pale Solid; Mp (°C): 107.0. 1H-NMR (CDC13, δ): 1.78-2.10 (m, 4H, 2xCH2), 3.40-3.61 (m, 3H, CH2N), 3.90-4.04 (m, 1H, C¾N), 4.59 (dd, 1H, /= 7.7 Hz, J= 2.2 Hz, CH-N), 6.21 (d, 1H, J= 7.7 Hz, CH-O), 7.04 (d, 1H, J= 2.2 Hz, 0-CH=N), 7.33 (m, 1H, ArH), 7.64 (m, 1H, ArH), 8.59 (d, 2H, J= 2.8 Hz, ArH). ,3C-NMR (CDCI3, δ): 24.2, 26.0, 46.4, 46.6, 75.7, 79.3, 123.7, 133.5, 135.3, 147.6, 149.9, 155.2, 166.2. ara-(4.5-Dihvdro-5-(pyridin-4^ 07122A.

SLA 07122A was prepared in accordance with method method D using 2-isocyano-l- piperidin-l-yl)euianone (0.4 g, 26.3 mmol), potassium hydroxide (0.15 g, 26.7 mmol) in methanol (5 mL) andpyridine-4-carbaldehyde (0.37 mL, 40.9 mmol). The solution was stirred 20 h at 0 °C. ira/w-(4,5-Dihydro-5-(pyridin-4-yl)oxazol-4-yl)(pi^ SLA 07122A was obtained as a yellow solid (0.353 g, 52 % yield).

SLA 07122A MW: 259.30; Yield: 52 %; Yellow Solid; Mp (°C): 111.7. 0.80 (MeOH:C¾Cl2 = 10:90). 1H-NMR (CDCI3, δ): 1.55-1.78 (m, 6H, 3xCH2), 3.45-3.60 (m, 2H, CH2 ), 3.70-3.85 (m, 2H, CH2N), 4.60 (dd, 1H, = 7.8 Hz, J= 2.3 Hz, CH-N), 6.27 (d, IH, J= 7.8 Hz, CH-O), 7.01 (d, IH, = 2.3 Hz, CH-N), 7.23 (dd, 2H, J= 4.5 Hz, J= 1.6 Hz, ArH), 8.61 (dd, 2H, J= 4.5 Hz, J= 1.5 Hz, ArH). .ra/w-(4.5-Dilivdro-5-fpyri(un^^ 07124A.

SLA 07118 was prepared in accordance with method D using 2-isocyano-1-morpholinoethanone (0.40 g, 25.95 mmol), potassium hydroxide (0.146 g, 26.0 mmol) in methanol (5 mL) and pyridine-4-carbaldehyde (0.36 mL, 40.4 mmol). The solution was stirred 22 h at 0 °C. ira^-(4,5-Dmydro-5-(pyridin-4-yl)oxazol-4-yl)(mo^holmo)methanone SLA 07124A was obtained as a yellow solid (0.168 g, 25 % yield).

SLA 07124A MW: 261.28; Yield: 25 %; Yellow Solid; Mp (°C): 90.5. fy: 0.30 (EtOAc:.cyclohexane = 20:80). 1H-NMR (CDC13, δ): 3.46-4.02 (m, 8H, 2xCH20, 2xCH2N), 4.56 (dd, IH, J= 7.8 Hz, J= 2.3 Hz, CH-N), 6.27 (d, IH, J= 7.9 Hz, CH-O), 7.02 (d, IH, J 2.3 Hz, CH=N), 7.24 (dd, 2H, J= 4.6 Hz, J= 1.4 Hz, ArH), 8.63 (dd, 2H, J= 4.5 Hz, 7= 1.6 Hz, ArH). fraws-(4.5-D vdro-5-(pyridm-4-vB^ piperazm-l-yllmethanone SLA 07124B.

SLA 07124B was prepared in accordance with method D using tert-butyl 4-(2-isocyanoacetyl)piperazine-l-carboxylate SLA 07116C (0.41 g, 16.20 mmol), potassium hydroxide (0.91 g, 16.2 mmol) in methanol (5 mL) and pyridine-4-carbaldehyde (0.227 mL, 25.2 mmol). The solution was stirred 22 h at 0 °C. frfln5-(4,5-Dmydro-5 (pyridin-4-yl)oxazol-4-yl)(4-tert-butyloxycarbonyl-piperazin-l-yl)methanone SLA 07124B was obtained as a pale yellow solid (0.335 g, 58 % yield).

SLA 07124B MW: 360.41; Yield: 58 %; Pale Yellow Solid; Mp (°C): 157.2°C.

JH-NMR (CDC13, δ): 1.47 (s, 9H, tBu), 3.25-4.02 (m, 8H, CH2N), 4.58 (dd, IH, J= 7.8 Hz, J= 2.3 Hz, CH-N), 6.27 (d, IH, J= 7.8 Hz, CH-O), 7.01 (d, IH, /= 2.3 Hz, CH=N), 7.24 (dd, 2H, J= 4.6 Hz, J= 1.4 Hz, ArH), 8.62 (dd, 2H, J= 4.5 Hz, J= 1.6 Hz, ArH).

SLA 07132 was prepared in accordance with method D using 2-Isocyano-1-thiomorpholinoethanone SLA 07130A (0.752 g, 4.41 mmol), potassium hydroxide (0.250 g, 4.45 mmol) in methanol (10 mL) and pyridine-4-carbaldehyde (0.436 mL, 4.85 mmol). The solution was stirred 24 h at 0 °C.

SLA 07132 was obtained as a yellow foam (1.01 g, 83 %).

SLA 07132 MW: 277.35; Yield: 83 %; Yellow Foam.

R,: 0.80 ( eOH:CH2Cl2 = 10:90). 1H-NMR (CDC13> δ): 2.53-2.92 (m, 4H, .ZxCHa), 3.58-3.70 (m, IH, CEfeN), 3.78-3.88 (m, IH, CH2N), 4.15-4.30 (m, 2H, CHjN), 4.56 (dd, J= 7.8 Hz, 7= 2.3 Hz, 2Η, CH-N), 627 (d, IH, J= 7.8 Hz, CH-O), 7.02 (d, IH, J- 2.3 Hz, N-CH-O), 7.22 (d, 2H, J= 6.1 Hz, ArH), 8.61 (dd, 2H, 6.1 Hz, ArH). ,3C-NMR (CDC13> δ): 27.3, 28.0, 45.4, 48.6, 74.9, 79.6, 120.0 (2xC), 148.5, 150.3 (2xC), 154.8, 166.2. trans-( 4.5-Dihvdro-5-fpvridm-2-vDoxazol-4-^ BLE 04110A.

BLE 04110A was prepared in accordance with method D using 2-pyridine carboxaldehyde (1.02 mL, 10.84 mmol). 7 ww-(4,5-dihydro-5-(pyridin-2-yl)oxazol-4-yl)(pyrrolidin- 1 -yl)methaiione BLE 04110A was obtained as a yellow pale oil (0.45 g, 19 % yield).

BLE 04110A MW: 245.28; Yield: 19 %; Yellow Pale Oil. 1H-NMR(CDC13, δ): 1.73-2.08 (m, 4H, 2χΟ¾), 3.35-3.70 (m, 3H, CH2N), 3.85-4.00 (m, 1H, C¾N), 5.05 (dd, 1H, J= 6.9 Hz, J- 2.2 Hz, CH-N), 6.18 (d, 1H, J= 6.9 Hz, CH-O), 7.02 (d, 1H, ./= 2.1 Hz, 0-CH=N), 7.25 (m, 1H, ArH), 7.43 (d, 1H, J= 7.8 Hz, ArH), 7.69 (dt, 1H, J= 7.8 Hz, 7= 1.8 Hz ArH), 8.62 (m, 1H, ArH). 13C-NMR (CDCI3, δ): 24.2, 25.9, 46.3, 46.5, 73.4, 81.3, 121.5, 123.2, 136.8, 149.8, 154.8, 158.0, 166.9.

Compound 19.

SLA 07092 was prepared in accordance with method D using pyridine-4-carbaldehyde (1.88 mL, 19.76 mmol), KOH (1.01 g, 18.00 mmol) in methanol (18 mL) and 2-isocyano-l-(pynOlidin-l-yl)ethanone BLE 04098 (2.73 g, 19.76 mmol). The residue was partitioned between ethyl acetate (200 mL) and water (150 mL). The organic layer was combined with additional ethyl acetate extracts (2 x 150 mL), washed with aqueous sodium chloride (2 x 150 mL) and dried over MgS0 , filtered and evaporated. 7>anj-(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(pyrrolidin-l-yl)methanone Compound 19 was obtained as a white solid (4.32 g, 98 % yield).

Compound 19 MW: 245.28; Yield: 98 %; White Solid; Mp (°C) 0.65 (MeOH:CH2Cl2 = 10:90). 1H-NMR (CDC13, δ): 1.78-2.06 (m, 4H, 2xC¾), 3.44-3.60 (m, 3H, CH2N), 3.90-4.01 (m, IH, CH2N , 4.52 (dd, 1H,7= 7.9 Hz, 7= 2.2 Hz, CH-N), 6.19 (d, 7= 7.9 Hz, IH, CH-O), 7.03 (d, IH, 7= 2.2 Hz, N=CH-0), 724 (dd, 2H, 7= 4.5 Hz, J= 1.5 Hz, ArH), 8.61 (dd, 2H, 7= 4.5 Hz, J = 1.5 Hz, ArH). fra?ij-f4.5-Dihvdro-5-(thioph∞^ BLE 04124A.

BLE 04124A was prepared in accordance with method D using thiophen-3-carboxaldehyde (0.475 mL, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano- 1 -(pyrrolidin- 1 -yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue obtained was recristallized from ethyl acetate to obtain after filtration traw-(4,5-dihydro-5-(thiop en-3-yl)oxazol-4-yl)(pyrrolidin-l-yl)methanone BLE 04110A as a yellow pale solid (0.498 g, 40 % yield).

BLE 04124A MW: 250.32; Yield: 40.5 %; Yellow Pale Solid; Mp (°C): 105.9.

!H-NMR (CDCI3, δ): 1.78-2.10 (m, 4H, C¾), 3.42-3.61 (m, 3H, CH2N), 3.90-4.02 (m, IH, CH2N), 4.63 (dd, IH, J= 7.4 Hz, /= 2.2 Hz, CH-N), 6.20 (d, IH, J= 7.4 Hz, CH-O), 6.98 (d, IH; J= 2.2 Hz, 0-CH=N), 7.03 (dd, IH, 7= 5.0 Hz, 7= 1.3 Hz, CH=C). 7.30 (dt, IH, 7= 3.0 Hz, 7= 1.3 Hz, CH=C), 7.36 (dd, IH, 7= 5.0 Hz, 7= 3.0 Hz, CH=C). ,3C-NMR (CDCI3, δ): 24.2, 26.0, 46.4, 46.6, 74.6, 77.9, 122.7, 125.1, 127.3, 140.4, 155.3, 166.7.

MS-ESI m/z (% rel. Int.): 251.0 ([MH]+, 17), 223 (40), 179.9 (60), 151.9 (63), 123.9 (100).

HPLC: Method A, detection UV 254 nm, BLE 04124A, RT = 4.4 min, peak area 98.0 %. fra^4.5-D vdro-5-ftMop en-2^^ BLE 04124B.

BLE 04124B was prepared in accordance with method D using thiophen-2-carboxaldehyde (0.507 mL, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-l^ynOlidin-l-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue obtained was purified by column chromatography (EtOAc) to led after evaporation to ira/is-(4,5-dihydro-5-( tWophen-2-yl)oxazol-4-yl)(pyrroUdm-l-yl)methanone BLE 04124B as a yellow pale solid (0.713 g, 58 % yield).

BLE 04124B MW: 250.32; Yield: 58 %; Yellow Pale Solid; Mp (°C): 71.3. 1H-NMR (CDC13) δ): 1.78-2.10 (m, 4H, CH2), 3.42-3.62 (m, 3H, CH2 ), 3.90-4.03 (m, IH, CH2 ), 4.76 (dd, IH, J= 7.3 Hz, J= 2.2 Hz, CH-N), 6.37 (d, IH, J= 7.3 Hz, CH-O), 6.96 (d, IH, J= 2.2 Hz, 0-CH=N), 7.00 (dd, IH, J= 5.0 Hz, 7= 3.5 Hz, CH=Q, 7.11 (d, IH, 7= 3.1 Hz, CH=C), 7.33 (dd, IH, = 5.0 Hz, J = 0.7 Hz, CH=C). 13C-NMR(CDC13, δ): 24.2, 26.0, 46.4, 46.6, 75.5, 77.6, 126.3 (2xC), 127.1, 142.0, 154.9, 166.3.

MS-ESI m/z (% rel. Int): 251.0 ([MHf , 15), 223 (100).

HPLC: Method A, detection UV 254 nm, BLE 04124B, RT = 3.8 rnin, peak area > 90 %. fra»g-(4.5-I¾fovdro-5-flM^ol-2^ 04124C.

BLE 04124C was prepared in accordance with method D using 2-thiazolecarboxaldehyde (0.476 mL, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano- 1 -(pyrrolidin- 1 -yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-υρ the residue obtained was purified by column chromatography (EtOAc) to led after evaporation to fra/w-(4,5-dihydro-S-itWazol^-yQoxazoM-y^ipyffoUdin-l- ^metha one BLE 04124C as a colourless oil (0.564 g, 45.5 % yield).

BLE 04124C MW: 251.3; Yield: 45.5 %; colourless Oil. 1H-NMR (CDCI3, δ): 1.80-2.10 (m, 4H, CH2), 3.47-3.70 (m, 3H, C¾N), 3.91-4.02 (m, IH, CH2N), 5.18 (dd, IH, J= 6.4 Hz, J= 2.2 Hz, CH- ), 6.40 (d, IH, J= 6.4 Hz, CH-O), 6.97 (d, IH, = 2.2 Hz, 0-CH= ), 7.38 (d, IH, 7= 3.3 Hz, CH=C), 7.81 (d, IH, 7= 3.3 Hz, CH=Q- 13C-NMR (CDC13, δ): 24.2, 26.0, 46.4, 46.5, 73.7, 78.2, 120.1, 143.3, 154.3, 166.1, 168.2.

MS-ESI m/z (% rel. Int.): 252.0 ([MH]+, 18), 225 (30), 198.9 (37), 153.9 (48), 143.0 (100).

HPLC: Method A, detection UV 254 nm, BLE 04124C, RT = 3.5 rnin, peak area > 90 %. vnmethanone BLE 04124D.

BLE 04124D was prepared in accordance with method D using thianaphtene-3-carboxaldehyde (0.88 g, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano- l-(pyrrolidin- 1 -yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue obtained was purified by column chromatography (EtOAc) to led after evaporation to trans-(5-(benzo[&] ophen-3-yl)-4,5-dmydi^ BLE 04124D as a white solid (1.12 g, 75.5 % yield).

BLE 04124D MW: 300.38; Yield: 75.5 %; White Solid; Mp (°Q: 92.2.

'H-NMR (CDC13, δ): 1.75-2.08 (m, 4H, C¾), 3.36-3.49 (m, IH, C¾N), 3.50-3.62 (m, IH, CH2N), 3.89-4.00 (m, IH, C¾N), 4.75 (dd, IH, J= 7.6 Hz, J= 2.2 Hz, CH- ), 6.54 (d, IH, J= 7.6 Hz, CH-O), 7.08 (d, IH, J 2.2 Hz, O-CH=N), 7.35 (m, 2H, ArH), 7.45 (s, IH, C=CH-S), 7.67-7.75 (m, IH, ArH), 7.84-7.92 (m, IH, ArH). ,3C-NMR (CDC133 δ): 24.2, 26.0, 46.5, 46.6, 73.3, 77.7, 121.8, 123.1, 124.1, 124.6, 124.8, 134.0, 136.4, 141.0, 155.4, 166.6.

MS-ESI m/z (% rel. Int): 301.0 (|MH]+, 30), 273.0 (100).

HPLC: Method A, detection UV 254 nm, BLE 04124D, RT = 42 min, peak area 92.0 %. trans-( 5-(7 iran-3-ylV4.5-dihvdrooxazo.-4-^^ BLE 04130B.

BLE 04130B was prepared in accordance with method D using 3-furaldehyde (0.453 g, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-l-(pyrrolidin-l-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue was washed with a minimum of ethyl acetate to led, after filtration and drying, to tra^-(5-(furan-3-yI)-4,5-dLhydrooxazol-4-yl)(pyrrolidin-l-yl)methanone BLE 04130B as a white solid (0.837 g, 72.5 % yield).

BLE 04130B MW: 234.25; Yield: 72.5 %; White Solid; Mp (°C): 136.7. 1H-NMR (CDC13, δ): 1.80-2.10 (m, 4H, CH2), 3.47-3.58 (m, 3H, α¾Ν), 3.91- 4.02 (m, IH, CH2N), 4.61 (dd, IH, 7.3 Hz, 7= 2.1 Hz, CH-N), 6.10 (d, IH, J= 7.3 Hz, CH-O), 6.36 (dd, IH, /= 1.6 Hz, / « 0.6 Hz, CH=C), 6.95 (d, IH, J = 2.1 Hz, 0-CH=N), 7.44 (t, IH, J= 1.6 Hz, OCH=C); 7.50 (d, IH, J= 0.6 Hz, OCH=C). 13C-NMR (CDC13, δ): 24.2, 26.0, 46.4, 46.6, 70.0, 74.0, 108.1, 124.0, 140.4, 144.2, 155.3, 166.6. frawg-f4.5-Dmvdro-5-(naphth CT^ BLE 04130C.

BLE 04130C was prepared in accordance with method D using 2- naphtaldehyde (0.847 g, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-l-(pyrrolidin-l-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue was washed with a minimum of ethyl acetate to led, after filtration and drying, to tra/tf-(4,5-dihydro-5-(naphtbalen-3-yl)oxazol-^yl)(pyrrolidin-l-yl)methanone BLE 04130C as a white solid (0.791 g, 54.5 % yield).

BLE 04130C MW: 294.35; Yield: 54.5 %; White Solid; Mp (°C): 117.9. 1H-NMR (CDCI3, δ): 1.78-2.07 (m, 4H, CH2), 3.37-3.49 (m, 1H, CHjjN), 3.49-3.61 (m, 2H, CH21S , 3.88-3.99 (m, 1H, C¾N), 4.67 (dd, 1H, J= 7.7 Hz, J= 2.2 Hz, CH-N), 6.31 (d, 1H, J= 7.7 Hz, CH-O), 7.10 (d, 1H, J= 2.2 Hz, O-CH=N), 7.38 (dd, 1H, J= 8.5 Hz, J= 1.7 Hz, ArH); 7.45-7.54 (m, 2H, ArH), 7.79-7.90 (rn, 4H, ArH). 13C-NMR(CDC13, d): 23.8, 25.7, 46.1, 46.2, 75.3, 81.4, 122.7, 124.9, 126.1, 126.2, 127.4, 127.7, 128.7, 132.8, 132.9, 136.5, 155.2,166.4.

MS-ESI m/z (% rel. Int.): 295.1 ([MH]+, 40), 267.1 (100).

HPLC: Method A, detection UV 254 nm, BLE 04130C, RT = 4.2 min, peak area 92.0 %. fl7i.y-f4.5-Dmvdro-5-(naphthal^ BLE 04130D.

BLE 04130D was prepared in accordance with method D using 1-naphtaldehyde (0.736 mL, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-l-(pyrroli BLE 04130D MW: 294.35; Yield: 58.5 %; Colorless gum. 1H-NMR (CDC13, δ): 1.75-2.02 (m, 4H, C¾), 3.25-3.37 (m, 1H, CHaN), 3.52-3.67 (m, 2H, CH2 ), 3.82 -3.93 (m, 1H, CH2 ), 4.62 (dd, 1H, 7.0 Hz, J= 2.0 Hz, CH-N), 6.89 (d, 1H, J= 7.0 Hz, CH-O), 7.16 (d, 1H, /= 2.0 Hz, O-CH=N), 7.44-7.58 (m, 4H, ArH), 7.80-7.90 (m, 3H, ArH). ,3C- M (CDC13, 6): 24.2, 25.9, 46.5 (2xQ, 75.3, 79.2, 122.5, 123.0, 125.4, 126.0, 126.8, 128.7, 129.0, 129.9, 133.9, 135.5, 155.5,166.9.

MS-ESI m/z (% rel. Int.): 295.1 ([MH]+, 50), 267.1 (100).

HPLC: Method A, detection UV 254 nm, BLE 04130D, RT = 4.2 min, peak area 95.0 %. fra^-f4.5-Dmvdro-5-(Qumolm-2-v oxazol-4-yl¥pmoHdm^ BLE 04136B was prepared in accordance with method D using 2-quinoline carbaldehyde (0.852 g, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano- 1 -(pyrrolidin- 1 -yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue was purified by column chromatography on silica (EtOAc) to led, after evaporation, to trans-(4,5-dihydro-5-(quinolin-2-yl)oxazol-4-yl)(pyrroHdin-l-yl)methanone BLE 04136B as a yellow pale solid (0.966 g, 60.3 % yield).

BLE 04136B MW: 295.34; Yield: 60.3 %; Yellow Pale Solid; Mp (°C): 93.8. 1H-NMR (CDCI3, δ): 1.85-2.10 (m, 4H, C¾), 3.50-3.66 (m, 2H, CH2N), 3.67-3.80 (m, 1H, C¾N), 3.92-4.03 (m, 1H, CH2 ), 5.32 (dd, 1H, J= 7.8 Hz, = 2.1 Hz, CH-N), 6.31 (d, 1H, J= 7.8 Hz, CH-O), 7.06 (d, 1H, 2.1 Hz, O-CH= ), 7.51-7.60 (m, 2H, ArH); 7.72 (t, 1H, J= 8.4 Hz, ArH), 7.83 (t, 1H, J= 8.1 Hz, ArH), 8.07 (d, 1H, 7= 8.4 Hz, ArH), 8.20 (d, 1H, J= 8.4 Hz, ArH). ,3C-NM (CDCI3, 6): 24.3, 26.2, 46.5, 46.7, 73.0, 82.1, 119.2, 126.9, 127.7, 127.8, 129.5, 129.9, 137.2, 147.7, 155.0, 1582, 167.3. frgw3-(4.5-I¾hvdro-5-fisoqumol^ BLE 04136C.

BLE 04136C was prepared in accordance with method D using 4-quinoline carbaldehyde (0.852 g, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-l-(pyiToUdm-l-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue was washed with a minimum of EtOAc to led, after filtration and drying, to r««i-(4,5-0 hydro-5-(isoqumolin-4- yl)oxazol^yl)(pyrroKdin-l-yl)methanone BLE 04136C as a white solid (0.640 g, 40 % yield).

BLE 04136C MW: 295.34; Yield: %; White Solid; Mp (°C): 152.0.

'H- MR (CDCI3, δ): 1.85-2.08 (m, 4H, CH2), 3.28-3.40 (m, IH, CH2 ), 3.54-3.69 (m, 2H, CH2N), 3.84-3.95 (m, IH, CH2 ), 4.57 (dd, IH, J= 6.8 Hz, 2.1 Hz, CH-N), 6.93 (d, IH, 6.8 Hz, CH-O), 7.15 (d, IH, J= 2.1 Hz, 0-CH=N), 7.41 (d, IH, J= 4.5 Hz, ArH); 7.59 (m, IH, ArH), 7.76 (m, IH, ArH), 7.91 (d, IH, J= 8.3 Hz, ArH), 8.16 (d, IH, J= 8.3 Hz, ArH), 8.92 (d, IH, = 4.5 Hz, ArH). 13C- MR (CDCI3, δ): 24.2, 25.9, 46.7 (2xQ, 75.6, 77.8, 116.4, 123.1, 124.8, 127.5, 129.6, 130.5, 145.5, 148.4, 150.3, 155.0, 166.0. frflw.fr(4.5-Dihvdro-5-(qumoKn^ BAL 01016.

To a stirred and cooled (0 °C) solution of KOH (0.31 g, 5.43 mmol) in 5 mL MeOH were added successively qumoline-3-carboxaldehyde (0.85 g, 5.43 mmol) and 2-isocyano- 1-pyrrolidin- 1-yl-ethanone BLE 04134 (0.75 g, 5.43 mmol). The mixture was stirred at 0 °C until precipitation and concentrated. The mixture was partitioned between EtOAc (50 mL) and H20 (25 mL). The aqueous layer was extracted twice with EtOAc (25 ml). The EtOAc fractions were combined, washed twice with brine (2x25 mL), dried over MgSC>4 and filtered. After evaporation and drying ^a w-(4)5-dmydro-5-(qumolin-3- yl)oxazoM-yl)(pyrrolidin-l-yl)methanone BAL 01016 was obtained (0.96 g, 60 % yield) as a white solid.

(+/-) BAL 01016 MW: 295.34; Yield: 60 %; White Solid; Mp (°C): 144.4.

R/*: 0.15 (EtOAc). 1H NMR (CDC13, δ): 1.75-2.10 (m, 4H, 2xCH. , 3.40-3.62 (m, 3 H, CH2N), 3.90-4.05 (m, 1 H, CH2N), 4.70 (dd, 1H, 7.8 Hz, J= 2.2 Hz, CH-N), 6.40 (d, 1H, J= 7.8 Hz, CH-O), 7.10 (d, 1H, J= 2.2 Hz, OCH=N), 7.58 (dt, 1H, .7= 1.1 Hz, J= 8.0 Hz, ArH) ), 7.73 (dt, 1H, J= 1.4 Hz, J= 6.9 Hz, ArH), 7.83 (dd, 1H, J= 1.2 Hz,J= 8.2 Hz, ArH), 8.12 (m, 2H, ArH), 8.87 (d, 1H, J= 2.2 Hz, ArH). 13C-NMR (CDC13, δ): 24.2, 26.0, 46.6, 46.6, 75.8, 79.7, 127.3, 127.5, 127.9, 129.4, 130.0, 132.3, 133.2, 148.1, 148.4, 155.3, 166.2.

MS-ESI m/z (% rel. Int): 296.1 ([MH]+, 5), 314.1 (100). 04136D.

BLE 04136C was prepared in accordance with method D using 2-furaldehyde (0.449 mL, 5.42 mmol), KOH (0276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-l-(pyiiOhdin-l-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue was purified by column chromatography on silica (cyclohexane:EtOAc = 100:0 to 0:100) to led, after evaporation, to trans-(5-(furan-2-yl)-4,5-dmydrooxazol-4-yl)(pynoli(hn-l-yl)methM 04136D as a yellow pale oil (0.742 g, 58.5 % yield).

BLE 04136D MW: 234.25; Yield: 58.5 %; Yellow Pale Oil. Ή-NMR (CDCI3, δ): 1.80-2.10 (m, 4H, CH2), 3.47-3.60 (m, 3H, CH2N), 3.94-4.06 (m, 1H, CH2N), 4.94 (dd, 1H, = 7.4 Hz, 2.2 Hz, CH-N), 6.14 (d, 1H, J= 7.4 Hz, CH-O), 6.37 (dd, 1H, J= 3.3 Hz, J= 1.8 Hz, CH=C), 6.48 (d, 1H, = 3.3 Hz, CH=C), 6.93 (d, 1H, J= 2.2 Hz, 0-CH=N), 7.44 (d, 1H, J= 1.8 Hz, OCH=C). 13C-NMR (CDCI3, δ): 24.2, 26.0, 46.4, 46.5, 71.3, 74.5, 110.2, 110.5, 143.6, 150.4, 155.0, 166.3. frfl/ij-(4 -Dihydro-5-(2-methoxyp^ yrhnethanone BAL 01014.

BAL 01014 was prepared in accordance with method D using 2-methoxy-3-pyridinecarboxaldehyde (0.64 ml, 5.43 mmol), KOH (0.305 mg, 5.43 mmol) in methanol (5 mL) and 2-isocyano-l-(pyrroUdm-l-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up tra/w-(4,5-dihydro-5-(2-methoxypyridin-3-yl)oxazol-4-yl)(pyrroUdm-l-yl)methanone BAL 01014 was obtained (0.74 mg, 50 % yield) as a white solid.

BAL 01014 MW: 275.30; Yield: 50 %; White Solid; Mp (°C): 110.1. f 0.25 (EtOAc). 1H MR (CDC13, δ): 1.82-2.10 (m, 4H, 2xCH2), 3.40-3.62 (m, 3 H, CH2N), 3.80-3.90 (m, 3 H, CH2N), 3.93 (s, 3H, OMe), 4.61 (dd, IH, J= 7 Hz, /= 2 Hz, CH-N), 6.14 (d, IH, J= 7 Hz, CH-O), 6.90 (dd, IH, J= 7.3 Hz, /= 5 Hz, ArH), 7.02 (d, IH, 2 Hz, OCH=N), 7.60 (dd, IH, 7= 7.3 Hz, J= 1.7 Hz, ArH) ), 8.13 (dd, IH, , J= 5 Hz, = 1.8 Hz, ArH). 13C-NMR (CDC13, δ): 24.3, 26.1, 46.3, 46.6, 53.5, 73.5, 78.1, 116.8, 122.2, 135.2, 146.5, 155.3, 160.5 and 167.4.

MS-ESI m/z (% rel. Int.): 276.1 ([ΜΗ]+, 42).

HPLC: Method A, detection UV 254 nm, BAL 01014 T = 3.63 min, peak area 97.2 °/o. 07194A.

SLA 07194A was prepared in accordance with method D using pyridine-4-carbaldehyde (1.14 mL, 9.52 mmol), KOH (0.54 g, 9.60 mmol) in methanol (5 mL) and \r,N-diethyl-2-isocyanoacetamide SLA 07184A (1.21 g, 8.65 mmol). After work-up and column chromatography on florisil (ethyl acetate) 07194A was obtained as a brown oil (0.25 g, 12 % yield).

(+/-) SLA 07194 A MW: 247.29; Yield: 12 %; Brown Oil.

R : 0.15 (AcOEt= 100). 65 184725/2 'H-NMR (CDCI3, *): 1.16-1.34 (m, 6H, CH3), 3.30-3.80 (m, 4H, CH2N), 4.60 (dd, 1H, J= 7.7 Hz, J= 2.2 Hz, CH-N), 6.22 (d, 1H, J= 7.7 Hz, CH-O), 7.06 (d, J= 2.2 Hz, CH=N), 7.23 (d, 2H, J= 5.8 Hz, ArH), 8.61 (d, 2H, J= 6.0 Hz, ArH).

Preparation of 2-chloropyridine-4-carbaldehyde SLA 07156.

Methyl 2-chloropyridine-4-carboxylate SLA 07150. 2-Chloro-isonicotinic acid (5.10 g, 32.38 mmol) was dissolved in methanol (150 mL). Thionyl chloride (12 mL) was added. This suspension was stirred 5 h at 70 °C and concentrated in vacuo. The residue was dissolved in dichloromethane (250 mL) washed with a solution of 10 % aqueous K2CO3 (2 x 150 mL) dried with MgS04, filtered and evaporated. Methyl 2-chloropyridine-4-carboxylate SLA 07150 was obtained as a yellow solid (5.06 g, 91 %).

SLA 07150 MW: 171.58; Yield: 91 %; Yellow Solid; Mp (°C): 33.0.

Rf: 0.80 (MeOH:CH2Cl2 = 10:90).

'H-NMR (CDCI3, *): 3.98 (s, 3H, CH3), 7.78 (dd, 1H, J= 5.1 Hz, J= 1.3 Hz, ArH), 7.89 (d, 1H, J= 0.6 Hz ArH), 8.55 (dd, 1H, J= 5.1 Hz, J= 0.6 Hz, ArH). (2-Chloropyridin-4-yl methanol SLA 07152.

Methyl 2-chloropyridine-4-carboxylate (2.50 g, 14.60 mmol) was dissolved in anhydrous Tetrahydrofuran (THF, 50 mL) and this solution was cooled to -78°C under N2 atmosphere. Durobutylaliramium hydride 1.0 M in hexanes (63.3 mL, 63.30 mmol) was added dropwise stabilizing the temperature between -50 °C and -70 °C. The reaction mixture was stirred 1.5 h at -78 °C and allowed to stand at room temperature for 3 h. A solution of aqueous 10 % NH4CI was slowly added and the mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with water (3 x 20 mL), brine (2 x 20 mL), dried over MgS04, filtered and evaporated. (2-Chloropyridin-4-yl)methanol SLA 07152 was obtained as a yellow oil (1.97 g, 94 % yield).

SLA 07152 MW: 143.71; Yield: 94 %; Yellow Oil. : 0.35 (EtOAc:cyclohexane = 30:70). 1H-NMR (CDCI3, δ): 2.95 (s broad, IH, OH), 4.75 (s, 2H, CH20), 7.21 (dd, IH, J= 5.1 Hz, = 1.2 Hz, ArH), 7.37 (d, IH, J~ 1.2 Hz ArH), 8.29 (d, IH, 7= 5.1 Hz, ArH).

MS-ESI m/z (rel. int.): 144.0 ([MH]+, 100).

HP LC: Method A, detection UV 254 nm, SLA 07152 RT = 3.45 rnin, peak area 99.9 %. 2-Chloropyridine-4-carbaldehvde SLA 07156.

In a 250 mL tricol equipped with a low temperature thermometer and two equalizing dropping funnels was charged oxalyl dichloride (1.24 g, 9.81 mmol) in dichloromethane (15 mL) and this solution was stirred under N2 at -78 °C. The irst equalizing dropping funnel was connected to a nitrogen flow line and was charged with a solution of (2 liloropyridin-4-yl)methanol SLA 07152 (0.94 g, 6.54 mmol) with dichloromethane (15 mL). The other was charged with a solution of dimethyl sulfoxide anhydrous (1.7 mL, 19.63 mmol) in dichloromethane (2 mL) and this solution was added dropwise (25 min) in order to stabilize the temperature between -60 °C and -70 °C. At the end of the addition the reaction solution was warmed to -60 °C over a period of 20 min then the solution of (2-cUoropyridin-4-yl)methanol SLA 07152 was added dropwise (50 min) keeping the temperature between -50 °C and -60 °C in the reactor then the mixture reaction was warmed to -45 °C over a period of 30 min. The dropping funnel was washed with dichloromethane (2 x 5 mL) and charged with a solution of triemylamine (480 μΐ, 6.51 mmol) in dichloromethane (4 mL) which was added (10 min) to the reaction mixture and finally the reaction flask was allowed to warm to 0 °C over 10 min. The reaction solution was transferred to a 500 mL separatory funnel charged with 130 mL of a 5 % aqueous NH4CI solution. The two phases were separated the aqueous phase was extracted with dichloromethane (3 x 50 mL) and the combined organic phases were washed with 1 M aqueous phosphate buffer (pH = 7; 4xl00mL), then dried over MgS04, filtered and evaporated.2-C¾loropyridme-4-carbaldehyde SLA 07156 was obtained as an orange solid (0.740 g, 76 % yield).

SLA 07156 MW: 141.57; Yield: 76 %; Orange Solid. fy: 0.35 (EtOAc:cyclohexane = 30:70). 1H-NMR (CDC13, δ): 7.65 (dd, IH, J= 5.0 Hz, /= 1.3 Hz, ArH), 7.75 (d, IH, J = 1.3 Hz, ArH) 8.66 (d, IH, J= 5.0 Hz, ArH), 10.05 (s, IH, CHO). vDmethanone SLA 07174.

SLA 07174 was prepared in accordance with method D using 2-cWoropyridine-4-carbaldehyde SLA 07156 (0.12 g, 1.05 mmol), KOH (0.06 g, 1.05 mmol) in methanol (10 mL) and 2-isocyano- 1 -(pyrrolidin- 1 -yl)ethanone BLE 04098 (0.146 g, 1.05 mmol). The solution was stirred 24 h with continued cooling. After work-up ^a^(5-(2-chlc«Opyridin-4-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin-l-yl)methanone SLA 07174 was obtained as a yellow solid (0.19 g, 66 % yield).

(+/-) SLA 07174 MW: 279.72; Yield: 66 %; Yellow Solid; Mp (°C): 116.3. 1H-NMR (CDCI3, δ): 1.86-2.07 (m, 4H, C¾), 3.45-3.62 (m, 3H, CH2N), 3.93-4.01 (m, IH, CH2N), 4.50 (dd, J= 8.0 Hz, /= 2.3 Hz, IH, CH-N), 6.19 ( d, IH, J= 8.0 Hz, CH-O), 7.02 (d, IH, J<= 2.3 Hz, CH=N), 7.17 (td, IH, 7= 5.1 Hz J= 0.9 Hz, J= 0.4 Hz, ArH), 7.29 (d, IH, 7= 0.7 Hz, ArH), 8.38 (d, IH, J= 5.1 Hz, ArH). l3C-NMR (CDCI3, δ): 22.5, 24.4, 44.9, 45.0, 74.3, 77.3, 117.2, 119.0, 148.6, 150.4, 150.6, 153.1, 164.0. trans-( 5~( 3-Bromopyrio n-4-yl .5-dijv0^ooxazol-4-ylXpYrrnHHiTi- 1 - vDmethanone BAL 01028A.

BAL 01028A was prepared in accordance with method D using 3-bromo- 4-pyridinecarboxaldehyde (1.010 g, 5.43 mmol), KOH (0.305 g, 5.43 mmol) in methanol (5 mL) and 2-isocyano- 1 -pyrrolidin- 1 -yl-ethanone BLE 04134 (0.75 g, 5.43 mmol). The mixture was stirred at 0 °C until precipitation and concentrated. The mixture was partitioned between EtOAc (50 ml) and H20 (25 ml). The aqueous layer was extracted twice with EtOAc (25 mL). The EtOAc fractions were combined, washed twice with brine (2x25 mL), dried over MgS0 and filtered. After evaporation and /r /w-(5-(3-bromopyridin-4-yl)-4,5-0 hydrooxazol-4-yl)(pyiToUdin-l-yl)methanone BAL 01028A was obtained (1.20 g, 68 % yield) as a white solid.

(+/-) BAL 01028A MW: 324.17; Yield: 68 %; White Solid; Mp (°C): 160.8.

R/: 0.25 (EtOAc = 100). 1H NMR (CDC-3, δ): 1.82-2.08 (m, 4H, 2xCH2), 3.45-3.65 (m, 3H, CHaN), 3.80-3.92 (m, 1H, CH2 ), 4.60 (dd, 1H, 7= 2.1 Hz, J= 6.1 Hz, CH-N), 6.30 (d, 1H, J= 6.1 Hz, CH-O), 7.10 (d, 1H, J= 2.1 Hz, OCH=N), 7.30(d, 1H, /= 5.0 Hz, ArH) ), 8.55 (d, 1H, J= 5.0 Hz, ArH), 8.72 (s, 1H, ArH). ,3C-NMR (CDCI3, δ): 24.3, 26.0, 46.4, 46.6, 74.5, 79.6, 118.6, 121.1, 148.3, 148.8, 152.1, 155.1, 166.2.

MS-ESI m/z (% rel. Int.): 324.1/326.1 ([MH]+, 50/50), 239.0 (100).

HPLC: Method A, detection UV 254 nm, BAL 01028A RT = 3.50 min, peak area 96.8 %. vflmethanone BAL 01028B.

BAL 01028B was prepared in accordance with method D using 2-isocyano-l-pyrrolidin-l-yl-ethanone BLE 04134 (0.75 g, 5.43 mmol), KOH (0.305 g, 5.43 mmol) in methanol (5 mL) and 3-chloro-isonicotinaldehyde (0.769 g, 5.43 mmol). The solution was stirred 3 h at 0 °C. iro/w-(5-(3-CUorcpyridm-4-yl)-4,5-dihydrooxazol-4-yl)(pynOUdm^ 1 -yl)methanone BAL 01028B (1.20 g, 65% yield) was obtained as a white solid.

(+/-) BAL 01028B MW: 279.72; Yield: 65 %; White Solid; Mp (°C): 162.

Rf: 0.25 (EtOAc = 100). 1H NMR (CDCI3, δ): 1.82-2.08 (m, 4H, CH2), 3.45-3.65 (m, 3H, C¾N), 3.82-3.93 (m, IH, CH2N), 4.62 (dd, IH, J= 2.1 Hz, /= 6.1 Hz, CH-N), 6.38 (d, IH, J= 6.1 Hz, CH-O), 7.08 (d, IH, J= 2.1 Hz, OCH=N), 7.33 (d, IH, 7= 5.0 Hz, ArH), 8.52 (d, IH, /= 5.0 Hz, ArH), 8.59 (s, IH, ArH). ,3C-NMR(CD3OD, δ): 24.3, 26.0, 46.4, 46.6, 74.4, 77.9, 120.6, 128.8, 146.6, 148.3, 149.7, 155.0, 166.1.

MS-ESI m/z (% rel. Int.): 280.1/282.1 ([MH]+, 39/14).

HPLC: Method A, detection UV 254 nm, BAL 01028B RT = 3.47 min, peak area 97.2 %. tranj-f5-f2-Chlorcrovridin-4-vlV4.5-dfo^ vDmethanone SLA 07158.

SLA 07158 was prepared in accordance with method D using 2-chloropyridine-4-carbaldehyde SLA 07156 (0.47 g, 3.31 mmol), KOH (0.184 g, 3.33 mmol) in methanol (10 mL) and 2-Isocyano- 1 -(2H-pyrrol- 1 (5H)~ yl)ethanone SLA 07178 (0.410 g, 3.01 mmol). The solution was stined 2 h with continued cooling. After work-up and column chromatography on florisil (EtOAc), fr «j-(5-(2-chloropyridm-4-yl)-4,5-dmydrooxazol-4-yl)(2i^ l(5H)-yl)methanone SLA 07158 was obtained as a yellow solid (0.597 g, 84 %).

SLA 07158 MW: 277.71; Yield: 84 %; Yellow Solid; Mp (°C): 90.2.

R^: 0.10 (EtOAc). 1H-NMR (CDC13, δ): 4.26-4.37 (m, 3H, CH2N), 4.48-4.52 (dd, 1H, 7= 2.3 Hz, J = 8.0 Hz, CH-N), 4.75-4.85 (m, 1H, CH2N), 5.80-5.95 (m, 2H, CH=CH), 6.20 (d, 1H, J= 8 Hz, CH-O), 7.02 (d, J= 2.3 Hz, CH=N), 7.17 (td, 1H, J= 5.1 Hz, J = 0.8 Hz, J= 0.6 Hz, ArH), 7.30 (t, 1H, J= 0.6 Hz, ArH), 8.38 (d, 1H,J= 5.1 Ηζ, ΑτΗ). ,3C-NMR (CDC13, δ): 53.4, 53.9, 75.8, 78.9, 118.9, 120.7, 125.2, 125.4, 150.3, 151.9, 152.3, 154. aw-(4.5-Dmydro-5-foyridin-4-^^^ SLA 07180.

SLA 07158 was prepared in accordance with method D using pyridine-4-carbaldehyde (0.293 mL, 2.40 mmol), KOH (0.13 g, 2.32 mmol) in methanol (10 mL) and 2-isocyano-l-(2i7-pyn:ol-l(5/ -yl)ethanone SLA 07178 (0.301 g, 2.20 mmol). The solution was stirred 2 h with continued cooling. After work-up and column chromatography on florisil (EtOAc), tranj-(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(2i -pyrrol-l(5f -yl)methanone SLA 07180 was obtained (0.284 g, 53 % yield) as a yellow oil.

SLA 07180 MW: 243.26; Yield: 53 %; Yellow Oil. 0.15 (AcOEt). 1H- MR (CDC13, 6): 4.28-4.33 (m, 3H, CH2 ), 4.52-4.56 (dd, IH, J= 7.8 Hz, J - 2.2 Hz, CH-N), 4.73-4.82 (m, IH, CH2N), 5.80-5.93(m, 2H, CH=CH), 6.18 (d, IH, J- 7.8 Hz, CH-O), 7.08 (d, J= 2.2 Hz, CH=N), 7.27 (d, 2H, J= 6.0 Hz, ArH), 8.59 (d, 2H, J~ 6.0 Hz, ArH). 13C-NMR (CDC13, δ): 53.6, 53.9, 75.8, 79.7, 120.2, 125.3, 125.6, 148.7, 150.5, 155.3, 166.1.

Preparation of Compound 20. Compound 21. Compound 22. Compound 23. Compound 24. Compound 25. Compound 26. Compound 27. Compound 28. Compound 29. Compound 30. Compound 31. Compound 32. Compound 34. Compound 35. Compound 36. Compound 37. Compound 38. Compound 39. Compound 40. Compound 41. Compound 42. Compound 43. Compound 44. Compound 45. Compound 46. Compound 48. Compound 49 and Compound 50.

General method for oxazolines acidic hydrolysis: method E: DI^reo-2-Amino-3-hvdroxy-3-foyri^ dihydrochloride Compound 20.

To a solution of franj-(4,5-dmydro-5-^yridin-3-yl)oxazol-4-yl)(pyrrolidin-l-yl)methanone BLE 04110B (0.932 g, 3.80 mmol) in methanol (10 mL) was added hydrochloric acid 37 % (1.2 mL). After heating (50 °Q the mixture for 2.25 h the reaction mixture was concentrated and the crude product was coevaporated twice with ethyl acetate. After trituration with ethyl acetate, filtration and drying DL-tAreo-2-amino-3-hydroxy-3-(pyridin-3-yl)-l-(pyrrolidin- l-yl)propan-l-one dihydrochloride Compound 20 was obtained as a white solid (1.10 g, 94 % yield).

Compound 20 MW: 308.2; Yield: 94 %; White Solid; Mp (°C): 123.4. Ή-NMR (CD3OD, δ): 1.65-2.00 (m, 4H, 2xCH2), 2.82-3.11 (m, IH, -CH2N), 3.30-3.57 (m, 2H, C¾N), 3.57-3.77 (m, IH, C¾N), 4.54 (d, IH, J= 5.3 Hz, CH- ), 5.38 (d, IH, = 5.3 Hz, CH-O), 8.15 (dd, IH, /= 7.6 Hz, J= 5.0 Hz, ArH), 8.68 (d, IH, J= 7.6 Hz, ArH), 8.89 (d, IH, J= 7.6 Hz, ArH), 8.96 (s, IH, ArH). 13C- MR(CD3OD, δ): 24.9, 26.9, 47.7, 48.2, 58.1, 69.6, 128.7, 141.5, 141.6, 143.1, 146.5, 165.4.

DL-^reo-2-Aimno-3-hvdroxv-3-fovri^ dihydrochloride Compound 21.

Compound 21 was prepared following method E with ira7is'-(4,5-dihydro-5-(pyridm-2-yl)oxazol^yl)(pyrrolidm-l-yl)methanone BLE 04110 B (0.44 g, 1.79 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 2.5 h at 50 °C and work-up DL^i¾reo-2-amino-3-hydroxy-3-(pyridin-2-yl)-l-(pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 21 was obtained as a yellow solid (0.44 g, 84 % yield).

Compound 21 MW: 308.28; Yield: 84%; Yellow Solid. 1H-NMR (CD3OD, 6): 1.75-2.01 (m, 4H, 2χΟ¾), 3.10-3.22 (m, 1H, CH2N), 3.39-3.60 (m, 2H, CH2N), 3.63-3.75 (m, 1H, CH2N), 4.71 (d, 1H, J - 5.0 Hz, C¾N), 5.55 (d, 1H, J= 5.0 Hz, CH-O), 8.05 (t, 1H, J= 6.4 Hz, ArH), 8.13 (d, 1H, J = 8.0 Hz, ArH), 8.61 (t, 1H, = 8.0 Hz, ArH), 8.84 (d, 1H, J = 5.6 Hz, ArH).

D^Areo-2-Aimno-3-hvdroxy-3-(p^ dihydrochloride Compound 22.

Compound 22 was prepared following method E with rranj^S-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(pyrrolidin-l-yl)me±anone Compound 19 (0.750 g, 3.07 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 3.0 h at 50 °C and work-up DI^iAreo-2-ammo-3-hydroxy-3-(pyridin-4-yl)-l-(pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 22 was obtained as a white solid (0.935 g, 99 % yield).

Compound 22 MW: 308.28; Yield: 99 %; White Solid; Mp (°C): 117.0. 1H-NMR (CD3OD, δ): 1.75-2.03 (m, 4H, 2xCH^ 2.93-3.08 (m, IH, CHN), 3.32-3.75 (m, 3H, 2xCH2), 4.54 (d, IH, J= 5.9 Hz, CH-N), 5.40 (d, IH, 5.9 Hz, CH-O), 8.21 (d, 2H, J= 5.8 Hz, ArH), 8.94 (d, 2H, J= 5.8 Hz, ArH).

MS-ESI m/z (% rel. int.): 236.1 ([MH]+ 17), 219 (25), 148 (100).

HPLC: Method A, detection UV 254 nm, Compound 22 RT = 0.8 min, peak area 96.3 %.

DL-^reo-2-Anuno-3-hvdroxy-l-^yrroHdm-l-\iV3-(lMophen-3-^^ one hydrochloride Compound 23.

Compound 23 was prepared following method E with fr n5-(4,5-dihydro-5-(tMophen-3-yl)oxazol-4-yl)(pyrrohdin-l-yl)methanone BLE 04124A (0.486 g, 1.94 mmol), hydrochloric acid 37 % (0.6 mL) and methanol (10 mL). After 3.5 h at 50 °C and work-up D^Areo-2-ammo-3-hydroxy-l-(pyirohdin-l-yl)-3-(thiophen-3-yl)propan-l-one hydrochloride Compound 23 was obtained as a white solid (0.480 g, 89.5 % yield).

Compound 23 MW: 276.7; Yield: 89.5 %; White Solid; Mp (°C): 227.4. 1H-NMR (CD3OD, δ): 1.47-1.88 (m, 4H, 2χΟ¾), 2.31-2.46 (m, IH, CH2N), 3.18-3.46 (m, 3H, CH2N), 4.16 (d, IH, J= 9.0 Hz, CH-N), 4.97 (d, 1H,J= 9.0 Hz, CH-O), 7.14 (dd, IH, J= 4.9 Hz, J= 1.1 Hz, ArH), 7.40-7.50 (m, 2H, ArH). l3C-NMR (CD3OD, δ): 24.9, 26.7, 47.3, 47.6, 592, 70.6, 124.1, 127.1, 127.7, 142.3, 166.3.

D^/Areo-2-Amino-3-hvdroxv- 1 -fpvrrolidin- 1 -vlV3-fthiophen-2-vl propan- 1 -one hydrochloride Compound 24.

Compound 24 was prepared following method E with Compound 24 MW: 276.7; Yield: 84.5 %; White Solid; Mp (°C): 183.2.

^-NMRiCDsOD, δ): 1.49-1.90 (m, 4H, 2xCH2), 2.36-2.48 (m, IH, CH2N), 3.20-3.48 (m, 3H, CH2N), 4.18 (d, IH, J= 9.1 Hz, CH-N), 5.14 (d, IH, J= 9.1 Hz, CH-O), 7.00-7.08 (m, 2H, ArH), 7.45 (dd, IH, 4.9 Hz, J= 1.6 Hz, ArH). 13C-NMR(CD30D, 6): 24.9, 26.8, 47.3, 47.7, 59.6, 70.5, 126.3, 127.0, 128.2, 144.5, 166.1. 77 DL-. ireo-2-amino-3-hvdroxv- 1 -Co vrrolidin- 1 - vlV3 -(thiazol-2-vl>propan- 1 -one dihvdrochloride Compound 25.

Compound 25 was prepared following method E with trans-(4,5-dihydro-5 miazol-2-yl)oxazoM-yl)(pyrrolidin-l-yl)methanone BLE 04124C (0.558 g, 2.22 mmol), hydrochloric acid 37 % (0.6 mL) and methanol (10 mL). After 3.5 h at 50 °C and work-up DL-rAreo-2-amino-3-hydroxy- 1 -(pyrrolidin- l-yl)-3-(thiazol-2-yl)propan-l-one dihydrochloride Compound 25 was obtained as a pale yellow solid (0.532 g, 76.5 % yield).

Compound 25 MW: 276.7; Yield: 76.5 %; Pale Yellow Solid; Mp (°C): 145.8. 1H-NMR(CD3OD, 6): 1.75-2.00 (m, 4H, 2xC¾), 3.05-3.17 (m, IH, -CH2N), 3.36-3.58 (m, 2H, CH2 ), 3.58-3.70 (m, IH, CH2N), 4.67 (d, IH, 5.4 Hz, CH-N), 5.49 (d, IH, J= 5.4 Hz, CH-O), 7.84 (d, IH, J= 3.4 Hz ArH), 7.99 (d, lH, J= 3.4 Hz, ArH). 13C-NMR (CD3OD, δ): 24.9, 27.0, 47.7, 48.0, 57.5, 69.9, 123.6, 142.1, 165.3, 173.3.

DL-f½reo-2-Amfao-3-(3a.7a-dmvdrobe^ fpynroKdin-l-yl'Vpropan-l-one hydrochloride Compound 26.

Compound 26 was prepared following method E with trans-(5-(berizo[£]trnophen-3-yl)-4,5-d ydroo BLE 04124D (1.050 g, 3.49 mmol), hydrochloric acid 37 % (1.2 mL) and 78 methanol (10 mL). After 3.5 h at 50 °C and work-up OL-threo-Z-aamo-S-(3a,7a-dihydrobeiKo[b]tMophen-3-yl)-3-h^ one hydrochloride Compound 26 was obtained as a white solid (0.970 g, 85 % yield).

Compound 26 MW: 326.84; Yield: 85 %; White Solid; Mp (°C): 207.0.

'H-NMR (CD3OD, δ): 0.92-1.09 (m, 2H, 2xCR2), 1.42-1.60 (m, 2H, 2xC¾), 1.83-1.98 (m, 1H, CH2 ), 2.76-2.91 (m, 1H, C¾N), 3.06-3.25 (m, 2H, -CH2 ), 4.30 (d, 1H, 7= 9.5 Hz, CH-N), 5.29 (d, 1H, 9.5 Hz, CH-O), 7.35-7.43 (m, 2H, ArH), 7.78-7.89 (m, 2H, ArH), 7.90-7.97 (m, 1H, ArH). ,3C-NM (CD3OD, δ): 24.5, 26.4, 47.3, 47.4, 59.0, 69.5, 123.1, 124.0, 125.4, 126.1, 126.8, 136.6, 138.3, 141.9, 166.1.

DI^f treo-2-Amino-3-( furan-3-ylV3-hvdroxy- l-fo\rrolidin- 1 -vDpropan- 1-one hydrochloride Compound 27.

Compound 27 was prepared following method E with fr ¾s-(5-(furan-3-yl)-4,5-dmydrooxazol-4-yl)(pyi oUdm-l-yl)methanone BLE 04130B (0.800 g, 3.41 mmol), hydrochloric acid 37 % (0.6 mL) and methanol (10 mL). After 3.5 h at 50 °C and work-up DI^iAreo-2-ammo-3-(furan-3-yl)-3-hydroxy-l-(pyrroUdin-l-yl)propan-l-one hydrochloride Compound 27 was obtained as a white solid (0.738 g, 83 % yield). 79 Compound 27 MW: 260.72; Yield: 83 %; White Solid; Mp (°Q: 218.0. 1H-NMR (CD3OD, δ): 1.62-1.95 (m, 4H, 2xCH2), 2.82-2.95 (m, 1H, CH2N), 3.22-3.38 (m, 1H, CH2N), 3.39-3.55 (m, 2H, CH2N), 4.19 (d, 1H, J= 8.4 Hz, CH-N), 4.90 (d, 1H, J= 8.4 Hz, CH-O), 6.49 (m, 1H, ArH), 7.52-7.57 (m, 2H, ArH). 13C-NMR (CD3OD, δ): 24.9, 26.7, 47.4, 48.0, 58.7, 67.2, 109.8, 125.9, 142.0, 145.2, 166.3. one hydrochloride Compound 28.

Compound 28 was prepared following method E with iranj-(4,5-dihydro-5-(imphthalen-3-yl)oxazol-4-yl)(pyrroUdin-l-yl)methanone BLE 04130C (0.745 g, 2.53 mmol), hydrochloric acid 37 % (0.6 mL) and methanol (10 mL). After 3.5 h at 50 °C and work-up D^iAreo-2-arnino-3-hydroxy-3-(naphthalen-2-yl)-1 -(pynOlidin- 1 -yl)propan- 1 -one hydrochloride Compound 28 was obtained as a white solid (0.706 g, 87 % yield).

Compound 28 MW: 320.81; Yield: 87 %; White Solid; Mp (°C): 173.8. 80 1H-NMR (CD3OD, δ): 0.93-1.10 (m, IH, CH2), 1.20-1.37 (m, IH, CH2), 1.44-1.71 (m, 2H, CH2), 1.99-2.10 (m, IH, C¾ ), 3.11-3.26 (m, 2H, 0¾Ν), 3.31-3.41 (m, IH, CH2N), 4.23 (d, IH, J= 9.1 Hz, CH- ), 5.06 (d, IH, 9.1Hz, CH-O), 7.50-7.63 (m, 3H, ArH), 7.87-7.97 (m, 4H, ArH).

"C- MR (CDjOD, δ): 24.6, 26.3, 47.2, 47.5, 59.4, 74.3, 125.1, 126.9, 127.7, 127.8,128.8, 129.0, 129.4, 134.5, 135.0, 138.0, 166.4.

DL-t »reo-2- Amino-3 -hvdroxv-3-f naphthalan- 1 - vlV 1 -fp\rrohdin- 1 -vDpropan- 1 -one hydrochloride Compound 29.

Compound 29 was prepared following method E with im¾s-(4,5-dihydro-5-(naphthalen-4-yl)oxazol-4-yl)(pyixoKdm-l-yl)methanone BLE 04130D (0.794 g, 2.69 mmol), hydrochloric acid 37 % (0.6 mL) and methanol (10 mL). After 3.5 h at 50 °C and work-up DI^fAreo-2-air-ino-3-hydroxy-3-(naphthalen-l-yl)-1 -(pyrrolidin- 1 -yl)propan- 1 -one hydrochloride Compound 29 was obtained as a white solid (0.768 g, 89 % yield).

Compound 29 MW: 320.81; Yield: 89 %; White Solid; Mp (°C): 177.8.

'H-NMR (CD3OD, δ): 0.71-0.91 (m, 2H, CHz), 1 9-1.51 (m, 3H, CHa), 2.54- 2.67 (m, IH, CH2 ), 2.88-3.02 (m, IH, CH2N), 3.02-3.16 (m, IH, CH2 ), 4.27 (d, IH, J= 9.8 Hz, CH-N), 5.67 (d, IH, 9.8 Hz, CH-O), 7.50-7.61 (m, 3H, ArH), 7.90-7.98 (m, 3H, ArH), 8.08-8.14 (m, IH, ArH).

"C-NMR (CD3OD, δ): 24.4, 26.2, 47.1, 47.3, 59.5, 70.3, 124.0, 126.5 (2xC), 127.2, 127.4, 129.9, 130.4, 132.1, 135.0, 137.1, 166.1. one dihvdrochloride Compound 30.

Compound 30 was prepared following method E with /r nj-(4,5-dihydro-5-(o^nolm-2-yl)oxazoM-yl)(pyiTolidm-l-yl)methanone BLE 04136B (0.923 g, 3.13 mmol), hydrochloric acid 37 % (0.6 mL) and methanol (15 mL). After 3.5 h at 50 °C and work-up DL·ίArβ( 2-amino-3-hydroxy-l-(pyσoUdin-l-yl)-3-(quinolin-2-yl)propan- 1 -one dihydrochloride Compound 30 was obtained as a yellow solid (1.098 g, 98 % yield).

(+/-) Compound 30 MW: 358.26; Yield: 98 %; Yellow Solid; Mp (°C): 131.5. 1H-NMR (CD3OD, 6): 1.69-2.07 (m, 4H, CH2), 3.16-3.34 (m, 3H, CH2), 3.37-3.60 (m, 2H, CH2N), 3.77-3.88 (m, 1H, CH2-M), 5.85 (d, 1H, J= 4.9 Hz, CH-O), 8.03 (t, 1H, J= 7.6 Hz, ArH), 8.17-8.30 (m, 2H, ArH), 8.40 (d, 1H, J= 8.3 Hz, ArH), 8.56 (d, 1H, 7= 8.6 Hz, ArH), 9.25 (d, 1H, 7= 8.6 Hz, ArH), not seen under H20 (d, 1H, CH-MH2). 13C-NMR (CD3OD, 6): 24.9, 27.0, 47.9, 48.2, 57.3, 70.3, 121.5, 122.5, 130.4, 130.5, 131.5, 136.5, 140.2, 148.5, 157.8, 164.8.

DL-t¾reo-2-AiiMo-3-hvdroxv-3-fiso^ one dihvdrochloride Compound 31.

Compound 31 was prepared following method E with /ran-f-(4,5"rdihydro-5-(isoqumol -4-yl)oxazol-4-yl)(pyrroH^ BLE 04136C (0.597 g, 2.02 mmol), hydrochloric acid 37 % (0.4 mL) and methanol (10 mL). After 3.5 h at 50 °C and work-up D^Areo-2-annno-3-hydroxy-3-(i8oquinolin-4-yl)-l-^yrrolidin-l-yl)propan-l-one dihydrochloride Compound 31 was obtained as a off white solid (0.716 g, 99 % yield).

(+/-) Compound 31 MW: 358.27; Yield: 99 %; Off White Solid; Mp (°C): 158.5. 1H-NMR (CD3OD, 6): 1.04-1.32 (m, 2H, CH2), 1.51-1.72 (m, 2H, C¾), 2.05- 2.20 (m, IH, CH2N), 2.68-2.80 (m, IH, CH2N), 3.20-2.47 (m, IH, 0¾Ν), 4.57 (d, IH, J= 8.5 Hz, CH- H2), 5.99 (d, IH, J= 8.5 Hz, CH-OH), 8.09 (t, IH, J= 8.6 Hz, ArH), 8.27 (t, IH, J- 8.6 Hz, ArH), 8.38 (d, IH, J= 8.6 Hz, ArH), 8.45 (d, IH, J= 8.6 Hz, ArH), 8.55 (d, IH, J= 5.6 Hz, ArH), 9.35 (d, IH, J= 5.6 Hz, ArH). 13C-NMR(CD3OD, δ): 24.6, 26.5, 47.5, 48.0, 58.2, 69.1, 122.3, 122.6, 125.9, 127.7, 131.7, 136.7, 138.9, 146.1, 159.4, 165.2.

N-(DL-threo- 1 -hvdroxv-3-oxo-3-fpvrrolidiii- 1 -vlV 1 -Cquinolin-3- vl')propan-2-v ormamide hydrochloride Compound 32.

Compound 32 was prepared following method E with fran5-(4,5-dihydro-5-(qumolm-3-yl)oxazoI-4-yl)(pyrroh Compound 32 MW: 349.81; Yield: 20.0 %; White Solid; Mp (°Q: 203.2. 1HNMR (CD3OD, δ): 1.78-2.09 (m, 4H, CH2), 3.35-3.58 (m, 2 H, CH2N), 3.58- 3.80 (m, 2 H, CH2N), 5.28 (d, IH, J= 4 Hz, CH- ), 5.51 (d, IH, 7= 4 Hz, CH- O), 8.00 (t, 2H, J= 7.1 Hz, ArH) ), 8.18 (t, IH, J= 6.9 Hz, ArH), 8.26 (d, IH, J = 8.6 Hz, ArH) , 8.36 (d, IH, = 8.3 Hz, ArH), 9.18 (s, IH, CHO), 9.26 (s, IH, ArH). 13C-NMR (CD3OD, δ): 25.1, 27.0, 47.5, 48.3, 55.5, 71.2, 121.4, 129.9, 130.6, 131.5, 136.2, 137.3, 138.5, 145.3, 145.8, 163.4, 168.7.

MS-ESI m/z (% rel. Int.): 314 ([MH , 50), 158.1 (100).

HPLC: Method A, detection UV 254nm, Compound 32 RT = 3.36 min, peak area 99.9 %.

D^t¾reo-2-Amino-3-hvdroxv-l-(pmoUdin-l-vlV3-(q iinolm^ one dihvdrochloride Compound 33.

Compound 33 was prepared following method E with trans-(4, 5-dihydro-5-(q^olm-3-yl)oxazol-4-yl)(pyrroHdra-l-yl)methanone BAL 01016 (0.91 g, 3.41mmol), hydrochloric acid 37% (0.6 mL) and methanol (10 mL). After 3 h at 50 °C and work-up DL-iAre( 2-anrino-3-hydroxy- l-(pynolidin- l-yl)-3-(quinolin-3 -yl)pro an- 1 -one dihydrochloride Compound 33 (678 mg, 55 % yield) was obtained as a white solid. 2 HCI (+/") Compound 33 MW: 358.26; Yield: 55 %; White Solid; Mp (°C): 190.9.

,H MR (CD3OD, δ): 1.57-1.80 (m, 2H, C¾), 1.80-1.99 (m, 2H, CH2), 3.01-3.20 (m, IH, CH2 ), 3.35-3.61(m, 2H, CHaN), 3.61-3.82(m, IH, CH2N), 4.70 (d, IH, J= 5.0 Hz, CH-N), 5.58 (d, IH, J= 5.0 Hz, CH-O), 7.96-8.11 (m, IH, ArH), 8.18-8.29 (m, IH, ArH), 8.29-8.38 (m, IH, ArH), 8.38-8.49 (m, IH, ArH), 9.28 (s, IH, ArH), 9.34 (s, IH, ArH). l3C-NMR (CD3OD, δ): 24.9, 26.9, 47.8, 48.3, 58.2, 69.8, 121.8, 130.0, 130.8, 131.9, 135.4, 136.9, 139.3, 145.1, 146.2, 165.6.

MS-ESIm/z (% rel. Int.): 286.2 ([MHf ,100).

HPLC: Method A, detection UV 254 nm, Compound 33 RT = 3.15 rnin, peak area 97.0 %.

DL-f½reo-2-Anuno-3-f2-cnloropvri^ vllpropan-l-one dihvdrochloride Compound 34.

Compound 34 was prepared following method E with trans-(5-(2-cUoropyridm-4-yl)-4,5-dmydrooxazol-4-yl)(2H-pyjiol-l(^ SLA 07158 (0.597 g, 2.02 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 2 h at room temperature and work-up OL-threo-2-ammo-3-(2-chloropyridin-4-yl)-3-hyckoxy-^^ dihydrochloride Compound 34 (0.656 mg, 91 % yield) was obtained as a pale yellow solid. 85 Compound 34 MW: 340.63; Yield: 91 %; Pale Yellow Solid; Mp (°C): 196.2. Ή-NMR (CD3OD, δ): 3.45-3.50 (m, IH, C¾N), 4.04-4.15 (m, IH, 0¾Ν), 4.22-4.36 (m, 3H, CH2N & CHNH2), 5.05 (d, IH, J= 7.1 Hz, -CHO), 5.71 (d, 1H, J= 4.3 Hz, CH=CH), 5.84 (d, IH, J = 4.3 Hz, CH=CH), 7.47 (d, IH, J<= 5.0 Hz, ArH), 7.57 (s, IH, ArH), 8.39 (d, IH, = 5.0 Hz, ArH). ,3C-NMR (CD3OD, δ): 54.3, 54.5, 58.2, 71.7, 122.0, 123.5, 125.7, 126.3, 151.0, 152.8, 154.0, 165.8.

D^^reo-2-Ammo-3-hvdroxy-3-(pyridm-4-vn- 1 -fpiperidin- 1 - vl ropan- 1 -one dihvdrochloride Compound 35.

Compound 35 was prepared following method E with trans~(4,5-d hydio-5-(pyridin-4-yl)oxazol-4-yl) (piperidin- 1 -yl)methanone SLA 07122A (0.33 g, 1.27 nunol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 3 h at 50 °C and work-up DL·ίAreo-2-ammo-3- ydroxy-3-( yridm-4-yl)-l-(piperidin-l-yl)propan-l-one dihydrochloride Compound 35 was obtained as a yellow solid (0.375 g, 91 % yield).

Compound 35 MW: 322.31; Yield: 91 %; Yellow Solid; Mp (°C): 145. 1H-NMR (CD3OD, δ): 1.05-1.17 (m, 1H, C¾) 1.28-1.65 (m, 5H, C¾), 2.75-3.00 (m, 1H, CH2N), 3.10-3.22 (m, 1H, CH2N), 3.23-3.38 (m, 1H, CH2N), 3.53-3.65 (m, 1H, CHjN), 4.68 (d, 1H, J= 5.8 Hz, CHNH2), 5.14 (d, 1H, = 5.8 Hz, CHO), 8.06 (d, 2H, J= 6.0 Hz, ArH), 8.79 (d, 2H, 7= 6.5 Hz, ArH).

DL·¾'^reo-2-Amino-3-hvdro y-3-f yridin-4-yl l-(morph^ dihydrochloride Compound 36.

Compound 36 was prepared following method E with trfl«j-(4,5-dihydro-5-( yridm-4-yl)oxazol-4-yl)(morphohno)methanone SLA 07124A (0.146 g, 0.56 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 3 h at 50 °C and work-up DL-iAreo-2-anmio-3-hy(koxy-3-^yjidin-4-yl)-l-(morpholin-l-yl)propan-l-one dihydrochloride Compound 36 was obtained as a pale yellow solid (0.143 g, 89 % yield).

Compound 36 MW: 287.78; Yield: 89 %; Pale Yellow Solid; Mp (°C): 115.9. 1H- M (CD3OD, δ): 3.32-3.82 (m, 8H, 4xCH2), 5.41 (d, 1H, /= 5.0 Hz, CHO-), 8.28 (d, 2H, J- 5.9 Hz, ArH), 8.97 (d, 2H, J= 5.8 Hz, ArH), CHNH2 not seen.

DL·^reo-2-Anmlo-3-hvdroxy-3-(pyridm-4-yl l- i el^n-l^ trihvdrochloride Compound 37.

Compound 37 was prepared following method E with tra/w-(4,5-dihydro-5-(pyridm-4-yI)oxazol-4-yl)(4-iert-butyloxycarbonyl-piperazin-l-yl)m SLA 07124B (0.31 g, 0.86 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 3 h at 50 °C and work-up b^Areo-2-amino-3-hydroxy-3-^yridin-4-yl)-l-(piperazin-l-yl)propan-l-one trihydrochloride Compound 37 was obtained as a yellow solid (0.303 g, 71 %).

Compound 37 MW: 359.8; Yield: 71 %; Yellow Solid; Mp (°C): 201.4.

Rf. 0.20 (CH2Cl2:MeOH = 90:10), free base. 1H- MR (CD3OD, δ): 3.31-3.48 (m, 4H, 2xCH2), 3.63-3.90 (m, 2H, CH2N), 4.00-4.35 (m, 2H, CH2N), 5.15 (d, IH, J= 4.5 Hz, CHNH2), 5.58 (d, IH, J= 4.5 Hz, CHO), 8.38 (d, 2H, J= 6.4 Hz, ArH), 9.04 (d, 2H, J= 6.5 Hz, ArH).

DL-tArgo-2-arnmo-3-hvdroxv-3- pvridin-4-vlVl-tMomorpholitiopropan-l-one dihydrochloride Compound 38.

Compound 38 was prepared following method E with /r «i-(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(lMomoipholino)methanone SLA 07132 (0.926 g, 3.36 mmol), hydrochloric acid 37 % (1.1 mL) and methanol (10 mL). After 3 h at 50 °C and work-up DL·ίAΓeo-2-arίlmo-3-hydroxy-3-( yridin-4-yl)-l-thiomorpholinopropan-l-one dihydrochloride Compound 38 was obtained as a pale yellow solid (1.1 g, 99 % yield).

Compound 38 MW: 340.35; Yield: 99 %; Pale Yellow Solid; Mp (°C): 200.6. 1H-NMR (CD3OD, δ): 2.42-2.52 (m, IH, CH2), 2.53-2.70 (m, IH, (¾), 2.70-2.90 (m, 2H, CHa), 3.45-3.71 (m, 2H, CH2 ), 3.87-4.00 (m, IH, CH2 ), 4.18-4.28 (m, IH, CH2N), 5.44 (d, IH, J= 5.1 Hz, CHO), 8.34 (d, 2H, J= 5.9 Hz, ArH), 9.03 (d, 2H, J= 5.6 Hz, ArH), -CHNH2 not seen (under H20). 13C- MR (CD3OD, 6): 27.9, 28.7, 46.6, 50.0, 56.0, 71.3, 126.9 (2xC), 143.2 (2xC), 161.3, 165.7.

DL· reo-2-AI)l^ to-3-hvdroxy-3- yridin-4-yΠ- l-(2H-pyrrol- 1 (5H)-yl)propan-1-one dihYdrochloride Compound 39.

Compound 39 was prepared following method E with /ran,s-(4,5-dihydro-5-(pyridm-4-yl)oxazol-4-yl)(2H-pyn:ol-l(5H)-yl)methanone SLA 07180 (0.276 g, 1.14 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 2.5 h at RT and work-up DI^iAreo-2-amino-3-hydroxy-3-( yridm-4-yl)-l-(2H-pyrrol-l(5H)-yl)propan-l-one dihydrochloride Compound 39 was obtained (343 mg, 99 % yield) as a white solid.

Compound 39 MW: 306.27; Yield: 99 %; White Solid; Mp (°C): 186.3. 1H-NMR (CD3OD, 6): 3.91-4.02 (m, IH, CH-NH2), 4.09-4.21(m, IH, CH2), 4.27-4.41 (m, IH, CH2), 4.44-4.59 (m, IH, CH2), 4.55 (d, IH, J = 5.7 Hz, CH2 ), 5.46 (d, IH, J = 5.7 Hz, CHO), 5.80-5.90 (m, 2H, CH=CH), 8.24 (d, IH, J= 6.3 Hz, ArH), 8.93 (d, IH, J= 5.7 Hz, ArH). 13C- MR (CD3OD, δ): 54.6, 54.7, 57.6, 71.0, 125.9, 126.4, 126.8 (2xC), 143.1 (2xC), 161.6, 165.5.

MS-ESI m/z (% rel. Int.): 234.1 (DMH]+, 5), 137.1 (100).

DL-^reo^-Armno-NJV'-die&yl-S-hvdroxy-S-fpyri dihydrochloride Compound 40.

Compound 40 was prepared following method E with trans-N^-dieGiyl-4,5-a hydro-5-(pyridm -yl)oxazole-4-carboxamide diethylamide SLA 07194A (254 mg, 1.03 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 2 h at RT and work-up DL-iAreo^-amino-N^-diethyl-S-hydroxy-S-(pyridin-4-yl)propanamide dihydrochloride Compound 40 was obtained (212 mg, 67 % yield) as a pale yellow solid.

Compound 40 MW: 310.30; Yield: 67 %; Pale Yellow Solid; Mp (°C): 159.6°C.

R/. 0.10 (C¾Cl2:MeOH = 90: 10), free base. Ή-NMR (CD3OD, δ): 1.01-1.12 (m, 6Ή, 2xCH3), 3.01-3.31 (m, 3H, CH2), 3.40-3.52 (m, IH, CH2), 4.64 (d, IH, J= 6.8 Hz, CHN), 5.31 (d, IH, J= 6.8 Hz, CHO), 8.22 (d, IH, 7= 6.4 Hz, ArH), 8.94 (d, IH, J= 6.4 Hz, ArH). 13C-NMR (CD3OD, δ): 12.9, 14.4, 42.1, 43.4, 55.9, 72.1, 126.9 (2xC), 143.3 (2xC), 161.5, 166.1.

MS-ESI m/z (% rel. Int.): 238.1 ([MH]+, 5), 137.1 (100).

DL-fAreo-2-Armno-3-(2-cMoropyridin-4-ylV3-hydroxy-l-(pwohdin-l-vDpropan-l-one dihydrochloride Compound 41. 87 methanol (10 mL). After 3 h at 50 °C and work-up DI^ Areo-2-amino-3-hydroxy-3-(pyri R/. 0.20 (CH2Cl2:MeOH = 90: 10), free base. 1H-N R (CD3OD, δ): 3.31-3.48 (m, 4H, 2xC¾), 3.63-3.90 (m, 2H, CH2N), 4.00-4.35 (m, 2H, CH2N), 5.15 (d, IH, /= 4.5 Hz, CH H2), 5.58 (d, IH, J= 4.5 Hz, CHO), 8.38 (d, 2H, J= 6.4 Hz, ArH), 9.04 (d, 2H, J= 6.5 Hz, ArH).

DIL^f¾reo-2-arnmo-3-hvo oxy-3-(pyri(-m-4-ylVl-tMom dihydrochloride Compound 38.

Compound 38 was prepared following method E with trans-( , 5-dihydro-5-(pyrichn-4-yl)oxazol-4-yl)(thiomoi^holmo)methanone SLA 07132 (0.926 g, 3.36 mmol), hydrochloric acid 37 % (1.1 mL) and methanol (10 mL). After 3 h at 50 °C and work-up DI^iAreo-2-ammo-3-hydroxy-3-(pyridin-4-yl)-l-tWomorpholinopropan-l-one dihydrochloride Compound 38 was obtained as a pale yellow solid (1.1 g, 99 % yield).

Compound 38 88 MW: 340.35; Yield: 99 %; Pale Yellow Solid; Mp (°C): 200.6. 1H- MR (CD3OD, δ): 2.42-2.52 (m, IH, CH2), 2.53-2.70 (m, IH, (¾), 2.70-2.90 (m3 2H, C¾), 3.45-3.71 (m, 2H, CH2N), 3.87-4.00 (m, IH, C¾N), 4.18-4.28 (m, IH, CH2N), 5.44 (d, IH, J= 5.1 Hz, CHO), 8.34 (d, 2H, J= 5.9 Hz, ArH), 9.03 (d, 2H, J= 5.6 Hz, AxH), -CHNH2 not seen (under H20). 13C-NMR (CD3OD, δ): 27.9, 28.7, 46.6, 50.0, 56.0, 71.3, 126.9 (2xC), 143.2 (2xC), 161.3, 165.7.

D^ treo-2-Ammo-3-hvdroxy-3-foyri^ 1-one dihvdrochloride Compound 39.

Compound 39 was prepared following method E with irawj-(4,5-dihydro-5-(pyridm-4-yl)oxazol-4-yl)(2H-pyrrol-l(5i¾-yl)memanone SLA 07180 (0.276 g, 1.14 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 2.5 h at RT and work-up DI^iAreo-2-amino-3-hydroxy-3-(pyridin-4-yl)-l-(2H-pyrrol-l(5H)-yl)propan- 1-one dihydrochloride Compound 39 was obtained (343 mg, 99 % yield) as a white solid.

Compound 39 MW: 306.27; Yield: 99 %; White Solid; Mp (°C): 186.3. 1H-NMR (CD3OD, δ): 3.91-4.02 (m, IH, CH-NH2), 4.09-4.21(m, IH, CH2), 4.27-4.41 (m, IH, C¾), 4.44-4.59 (m, IH, CH2), 4.55 (d, IH, J = 5.7 Hz, CH2N), 5.46 (d, IH, J = 5.7 Hz, CHO), 5.80-5.90 (m, 2H, CH=CH), 8.24 (d, IH, J= 6.3 Hz, ArH), 8.93 (d, IH, J= 5.7 Hz, ArH). 13C-NMR (CD3OD, δ): 54.6, 54.7, 57.6, 71.0, 125.9, 126.4, 126.8 (2xC), 143.1 (2xC), 161.6, 165.5. 89 MS-ESI m/z (% rel. Int.): 234.1 ([MH]+, 5), 137.1 (100).

D^A eo^-A ino-Njy-flemyl-S-h^^ dihvdrochlpr.de Compound 40.

Compoimd 40 was prepared following method E with i^aas-N^V-diethyl-4,5-dihydro-5-(pyridm-4-yl)oxazole^carboxarnide diethylamide SLA 07194A (254 mg, 1.03 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (10 mL). After 2 h at RT and work-up DL-iAreo^-amino-N^-diethyl-S-hydroxy-S-(pyridin-4-yl)propanamide dihydrochloride Compound 40 was obtained (212 mg, 67 % yield) as a pale yellow solid.

Compound 40 MW: 310.30; Yield: 67 %; Pale Yellow Solid; Mp (°C): 159.6°C.

Rf, 0.10 (CH2Cl2:MeOH = 90:10), free base. 1H-NMR (CD3OD, δ): 1.01-1.12 (m, 6Ή, 2xCH3), 3.01-3.31 (m, 3H, CHj), 3.40-3.52 (m, IH, CH2), 4.64 (d, IH, J= 6.8 Hz, CHN), 5.31 (d, IH, J= 6.8 Hz, CHO), 8.22 (d, IH, J= 6.4 Hz, ArH), 8.94 (d, IH, 6.4 Hz, ArH). ,3C-NMR (CD3OD, δ): 12.9, 14.4, 42.1, 43.4, 55.9, 72.1, 126.9 (2xC), 143.3 (2xC), 161.5, 166.1.

MS-ESI m/z (% rel. Int.): 2S8.1 ([MH]+, 5), 137.1 (100). vDpropan-l-one dihydrochloride Compound 41. 90 184725/2 DL-/ ¾rgQ-2-Amino-3-('2-chloropyridin-4-yn-3 -hydroxy- 1 -( pyrrolidin- 1 - yl)propan-l-one dihydrochloride Compound 41.

Compound 41 was prepared following method E with trans-(5-(2- chloropyridin-4-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin- 1 -yl)methanone SLA 07174 (0.179 g, 0.64 mmol), hydrochloric acid 37 % (1.0 mL) and methanol (7 mL). After 2 h at RT and work-up DL-i^reo-2-amino-3-(2-chloropyridin-4-yl)-3 -hydroxy- l-(pyrrolidin-l-yl)propan-l -one dihydrochloride Compound 41 was obtained (142 mg, 65 % yield) as a pale yellow solid.

Compound 41 MW: 342.65; Yield: 65 %; Pale Yellow Solid; Mp (°C): 184.3.

Rf. 0.15 (CH2Cl2:MeOH = 90: 10), free base.

'H-NMR (CD3OD, *): 1.50-1.90 (m, 4H, 2xCH2), 2.50-2.61 (m, 1H, CH2N), 3.25-3.38 (m, 1H, CH2N), 3.40-3.53 (m, 2H, CH2N), 4.26 (d, 1H, J= 7.7 Hz, CHN), 4.99 (d, 1H, J= 7.7 Hz, CHO), 7.45 (d, 1H, J = 4.5 Hz, ArH), 7.53 (s, 1H, ArH), 8.41 (d, 1H, J= 4.9 Hz, ArH). ,3C-NMR (CD3OD, *): 24.9, 26.7, 47.5, 48.0, 58.4, 71.9, 122.0, 123.5, 151.1, 152.7, 154.0, 165.7.

MS-ESI m/z (% rel. Int.): 270.1/272.1 ([MH]+, 40/13), 171.0/172.0 (100/32).

OL-threo-2- Amino-3 -(3 -bromopyridin-4-yl -3 -hydroxy- 1 -(pyrrolidin- 1 -yl propan-l-one dihydrochloride Compound 42.

Compound 42 was prepared following method E with trans-(5-(3-bromopyridin-4-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin- 1 -yl)methanone B AL 01028A (1.141 g, 3.52 mmol), hydrochloric acid 37 % (0.6 mL) and methanol 91 4-yl)-3-hydroxy-l-(pyrroUdin-l-yl)propan-l-one dihydrochloride Compound 42 was obtained as a white solid (667 mg, 49 % yield). (+/-) 2. HCI Compound 42 MW: 387.10; Yield: 49.0 %; White Solid; Mp (°C): 216.3.

¾ NM (CD3OD, δ): 1.73-1.99 (m, 4H, 2xCH2), 3.01-3.05 (m, 1H, CH2 ), 3.44-3.51(m, 2H, CH2N), 3.60-3.73(m, 1H, CH2N), 4.60 (d, 1H, J= 5.5 Hz, CH- ), 5.54 (d, 1H, J= 5.5 Hz, CH-O), 8.26 (d, 1H, 7= 5.7 Hz, ArH) ), 8.86 (d, Hi, J= 5.7 Hz, ArH), 9.10 (s, 1H, ArH). ,3C-NMR (CD3OD, δ): 24.8, 27.1, 56.4, 70.1, 122.7, 127.6, 145.1, 148.4, 156.8, 165.0, 2xC not seen.

MS-ESI m/z (% rel. Int.): 314.1/316.1 ([ΜΗ]+, 35/35), 215.0/217 (50/50).

HPLC: Method A, detection UV 254 nrn, Compound 42 RT = 3.08 min, peak area 92.8 %.

D^fAreo-2-Ammo-3-(3-cMoropyridm yl)propan-l-one dihydrochloride Compound 43.

Compound 43 was prepared following method E with trans-(5-(3-chloropyri(Hn-4-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin-l-y BAL 01028B (0.925 g, 3.31 mmol), hydrochloric acid 37 % (0.6 mL) and methanol (15 mL). After 2 h at 50 °C and work-up DL-iAreo-2-ammo-3-(3-cWo^yridin-4-yl)-3 -hydroxy- 1 -(pyrrolidin- 1 -yl)propan- 1 -one dihydrochloride Compound 43 was obtained as a white solid (599 mg, 53 % yield). 92 184725/2 (+/-) 2. HCI Compound 43 MW: 342.65; Yield: 53 %; White Solid; Mp (°C): 214.0.

•H NMR (CD3OD, *): 1.75-2.02 (m, 4H, 2xCH2), 3.13-3.25 (m, 1H, CH2N), 3.39-3.62(m, 2H, CH2N), 3.65-3.80 (m, 1H, CH2N), 4.66 (d, 1H, J= 4.5 Hz, CH-N), 5.66 (d, 1H, J= 4.6 Hz, CH-O), 8.40 (d, 1H, J= 5.8 Hz, ArH), 8.93 (d, 1H, J= 5.8 Hz, ArH), 9.13 (s, 1H, ArH). 13C-NMR (CD3OD, *): 23.3, 25.6, 46.6, 46.8, 54.6, 66.5, 126.5, 132.4, 141.7, 142.9, 155.6, 163.4.

MS-ESI m/z (% rel. Int.): 270/272 ([MH]+, 33/11), 171/173 (100/32).

HPLC: Method A, detection UV 254 nm, Compound 43 RT = 2.80 min, peak area 97.2 %.

OL-threo-3 -Hydroxy- 1 -oxo-3-( 1 -oxy-pyridin-4-yl - 1 -(pyrrolidin- 1 -yl propan-2-ylcarbamate BAL 01060.

To a solution of OL-threo-3 -hydroxy- l-oxo-3 -(pyridin-4-yl)-l -(pyrrolidin-l-yl) propan-2-ylcarbamate (300 mg, 0.81 mmol, free base obtained from Compound 58 by K2CO3, CH2C12 treatment) in dichloromethane (40 mL) was added Meta-chloroperoxybenzoic acid (MCPBA ,350 mg, 2.03 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was concentrated and the crude product was purified by column chromatography (EtOAc:MeOH = 70:30). OL-threo-3 -Hydroxy- l-oxo-3 -(1 -oxy-pyridin-4-yl)- 1-(pyrrolidin-l-yl)propan-2-ylcarbamate BAL 01060 was obtained as a white solid (292 mg, 94 % yield). 93 BAL 01060 MW: 385.41; Yield: 94 %; White Solid. 1H MR CDC13, δ): 1.71-2.00 (m, 4H, 2xC¾), 3.35-3.53 (m,.3H, CH2N), 3.54-3.68 (m, IH, C¾N), 4.65 (dd, IH, /■= 9.6 Hz, 2.0 Hz, CH-N), 4.90-5.12 (m, 3H, CH20 & OH), 5.20 (d, IH, J= 1.9 Hz, CH-O), 5.83 (d, IH, 7= 9.6 Hz, NH), 7.20-7.40 (m, 7H, ArH), 8.08 (d, 2H, J= 7.1 Hz, ArH).

DL-t¾reo-2-Ainino-3-hvdroxv-3- i-oxv-pvri(Hn-4-vlVl-pvrrolidin-l-vl-propan-l-one hydrochloride Compound 44. [2-Hy-2-amino-3-hydroxy-3-(l -oxy-pyridin-4-yl)- 1 -pyrrolidin- 1 -yl-propan- 1 -one hydrochloride Compound 44 (65 mg, 33. % yield) as a white solid.

Compound 44 94 MW: 287.74; Yield: 33 %; White Solid; Mp (°C): 178.5. 1H NMR (D20, δ): 1.55-1.93 (m, 4H, 2xC¾), 2.65-3.80 (m, 1H, CHzN), 3.22- 3.56 (m, 3H, C¾ ), 4.43 (d, 1H, J= 7.6 Hz, CH-N), 5.19 (d, 1H, J= 7.6 Hz, CH-O), 7.69 (d, 2H, J= 6.1 Hz, ArH), 8.39 (d, 2H, /= 6.9 Hz, ArH). ,3C-NMR (D20, δ): 24.1, 25.8, 47.3, 48.0, 57.4, 70.5, 125.7 (2xC), 139.9 (2xQ, 143.7, 165.1.

MS-ESI m/z (% rel. Int.): 252.1 (Ρ*1Η]+, 18), 120.0 (100).

HPLC: Method A, detection UV 254nm, Compound 44 RT= 0.8 min, peak area 99.9 %.

D^/>rep-2-(PimethvlaminoV3-hv&^ vOpropan-l-one dihvdrochloride Compound 45.

DL-tAreo-2- Amino-3 -hydroxy-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1 - yl)propan-l-one dihydrochloride Compound 22 (0.50 g, 1.62 rmnol) and para ' formaldehyde (0.245 g, 8.11 mmol) were stirred in methanol (25 mL) for 10 rnin. Sodium cyanoborohydride (0.612 g, 9.73 mmol) was added. The solution was stirred 19 h at 50 °C and then concentrated. The residue was partitioned between dichloromethane and water. The aqueous layer was basified with IN sodium hydroxyde (pH = 10). The organic layer was combined with additional dichloromethane extracts, washed with aqueous sodium chloride and dried with MgSC>4. The crude product was purified by column chromatography on silica (CH2Cl2:MeOH = 95:05). D^Areo-2-(dimemylanimo)-3-hydroxy-3-(pyridiji- 4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one SLA 07140 was obtained (187 mg, 44 %) as a yellow oil. To a stirred solution of DI_-iAreo-2-(dimemylamino)-3-hydroxy- 3-(pyridm-4-yl)-l-(pyrrolidin-l-yl)propan-l-one SLA 07140 (0.142 g, 0.54 mmol) in ethyl acetate (5 mL) was added dropwise via syringe 4 mL of a solution of HCl in Et20 (0.3 M). The reaction mixture was stirred at 0 °C for 0.5 95 h. The precipitate was filtered, washed with El^O and dried. OL-threo-2-(Pimethylarnmo)-3-hydroxy-3-( yridm-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one dihydrochloride Compound 45 was obtained (0.077 g, 43 % yield) as a white solid.

Compound 45 MW: 336.34; Yield: 43 %; White Solid; Mp (°C): 201.0. 1H-NMR(CD3OD, δ: 1.48-1.64 (m, 2H, C¾)f 1.65-1.83 (m, 2H, CH2), 2.60-2.72 (m, 1H, CHz ), 3.15-3.33 (m, 1H, CH2), 3.30-3.52 (m, 2H, C¾), 4.60 (d, 1H, J= 8.4 Hz, CHNHz), 5. 41 (d, 1H, J= 8.4 Hz, CHO), 8.10 (d, 2H, J= 6.6 Hz, ArH), 8.84 (d, 2H, J= 6.7 Hz, ArH).

D^Areo-2-Arnmo-l-^yridm-4-ylV3-fpmoli Compound 46 MW: 221.30; Yield: 12 %; Pale Yellow Solid.

Rf. 0.35 (CH2Cl2:MeOH:NH3 = 90:08:02). 1H-NMR (CD3OD, δ): 1.60-1.80 (m, 4H, 2XCH2), 2.30-2.80 (m, 6Ή, 3xCH2N), 3.14-3.19 (m, 1H, CHN¾)> 4.68 (d, 1H, /= 3.0 Hz, CHO), 7.30 (d, 2H, J= 6.0 Hz, ArH), 8.55 (d, 2H,J- 6.0 Hz, ArH). l3C-NMR (CD3OD, δ): 23.5 (2xC), 54.1, 54.7 (2xC), 60.1, 74.5, 121.4 (2xC), 149.5 (2xQ, 152.1.

MS-ESI m/z (rel. int): 222.1 (|MH]+, 100), 205.0 (80), 189.0 (45), 151.0 (70), 134.0 (42), 121.9 (100), 107.9 (40).

D^/zreo-2-Ammo-3-hvdroxv-3-(2-m yDpropan-l-one dilivdrochloride Compound 48. 7Va/w-(4,5-Dmydro-5-(2-mera yl)methanone BAL 01014 (0.465 g, 1.69 mmol) was dissolved in methanol (6 mL). The solution of hydrochloric acid (37 %, 0.3 mL) was added via a syringe at RT. The mixture was stirred for 3 h at RT. The residue was concentrated, dissolved in the minimum of MeOH, precipitated with EtOAc and filtered to obtain a white solid D^rAreo-2-amino-3-hydroxy-3-(2-methoxypyridin-3-yl)-l-(pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 48 (103 mg, 18.0 % yield). 97 Compound 48 MW: 338.23; Yield: 18.0 %; White Solid; Mp (°C): 171.5.

¾ NMR (CD3OD, 6): 1.85-2.10 (m, 4H, CH2), 3.30-3.82 (m, 4 H, CH2N), 4.26 (s, 3H, OCH3), 4.60 (d, 1H, J= 3.7 Hz, CH-N), 5.45 (d, 1H, /= 3.7 Hz, CH-O), 7.39 (dd, 1H, J= 5.6 Hz, J= 7.3, ArH), 8.32 (dd, 1H, J= 5.6 Hz, J= 7.3 Hz, ArH). 13C-NMR (CD3OD, δ): 24.9, 27.1, 47.8, 47.9, 56.4, 56.7, 66.0, 119.2, 125.6, 141.5, 143.9, 160.6, 166.1.

MS-ESI m/z (% rel. Int.): 266.2 ([MH]+, 30), 248.2.0 (100).

HPLC: Method A, detection UV 254nm, Compound 48 RT = 3.31 min, peak area 97.9 %. 3-roil^r½reo-2-Ammo-l-hvdroxv-3-oxo^ 2-one hydrochloride Compound 49. 7Va/w-(4,5-Dihydro-5-(2-methoxyp^ yl)methanone BAL 01014 (0.684 g, 2.487 mmol) was dissolved in methanol (10 mL). A solution of hydrochloric acid (37 %, 0.6 mL) was added via syringe at RT. The mixture was stirred for 22 h at reflux. The residue was concentrated, triturated with EtOAc and filtered to obtain a yellow pale solid 3-(DL-i/ireo-2-ainino-l-hyckoxy-3-oxo-3-pyrroUdin-l-yl-propyl)-lH-pyridin-2-one hydrochloride Compound 49 (136 mg, 19.0 % yield).

HCl 98 184725/2 (+/-) Compound 49 MW: 287.74; Yield: 19.0 %; Yellow Pale Solid; Mp (°C): 180. Ή NMR (CD3OD, *): 1.82-2.09 (m, 4H, 2xCH2), 3.35-3.80 (m, 4 H, 2xCH2N), 4.63 (s, 1H, CH-N), 5.17 (s, 1H, CH-O), 6.56 (t, lH, ArH) ), 7.5 (d, 1H, J= 6.1 Hz, ArH), 7.86 (d, 1H, J= 6.5 Hz, ArH).

I3C-NMR (CD3OD, *): 24.2, 26.0, 46.6, 46.6, 75.8, 79.7, 127.3, 127.5, 127.9, 129.4, 130.0, 132.3, 133.2, 148.1, 148.4, 155.3, 166.2.

MS-ESI m/z (% rel. Int.): 252.1 ([MH]+, 18), 163.0 (100).

HPLC: Method A, detection UV 254nm, Compound 49 RT = 1.13 min, peak area 84.0 %.

Preparation of Compound 51, Compound 52, Compound 53, Compound 54 Compound 55, Compound 56 and Compound 57.

General procedures: Method F: To a suspension of DL-i/zreo-2-amino-3-hydroxy-3-(pyridin-4-yl)-l-(pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 22 (0.150 g, 0.44 mmol) in CH2C12 (4 mL) was added Triethylamine (TEA ,0.185 mL, 1.32 mmol) and the reaction mixture was stirred for 10 min and cooled in an ice bath with continuous stirring. The acyl chloride (0.484 mmol) was dissolved in CH2C12 (1 mL) and added dropwise to the reaction mixture. The reaction mixture was allowed to reach room temperature, stirred for 16 h and partitioned with H20 (3 x 4 mL), washed with brine (3 x 4 mL), NaOH (0.5 M, 3 x 4 mL) and the organic layer was evaporated, adsorbed on silica gel (0.3 g) with EtOAc. The desired product was isolated by column chromatography using a gradient 0 to 8 99 % [v/v] MeOH in EtOAc. The solid obtained was dissolved in ethanol (1 mL) and a solution of HC1 (0.8 M, 1 mL) in EtOH was added. Evaporation of the volatiles led to the corresponding hydrochloride salt iV-(T)L-t/zreo-l -Hvdroxv-3 -oxo- 1 -fp\ridm-4-vlV 3-(pvnoUdin- 1 - vDpropan-2-yl)hexanamide hydrochloride Compound 51.

The compound was prepared according to method F with hexanoyl chloride (59 mg, 0.484 mmol) and D^Areo-2-animo-3-hydroxy-3-(pyridin-4-yl)-l-^yrroMdm-l-yl)propan-l-one dihydrochloride Compound 22. N-(DL-iAreo-l-Hydroxy-3-oxo-l-(pyridm-4-yl)-3-(pyri lidm yl)hexanamide hydrochloride Compound 51 was obtained as an off white solid. (56 mg, 34 % yield).

Compound 51 MW: 369.89; Yield: 34 %; Off White Solid; Mp (°C): 182.0.

!H-NMR (CD3OD, δ): 0.84 (t, 3H, /= 6.7, CH3), 1.10-1.32 (m, 4H, C¾), 1.35- 1.50 (m, 2H, CH2), 1.80-2.00 (m, 4H, CH2), 2.05-2.30 (m, 2H, C¾), 3.35-3.45 (m, 2H, C¾), 3.50-3.65 (m, 2H, CH2), 5.09 (d, 1H, 7= 3.7 Hz, N-CH), 5.38 (d, 1H, J= 3.7 Hz, O-CH), 8.14 (d, 2H, J= 6.3 Hz, ArH), 8.80 (d, 2H, J= 6.3 Hz, ArH).

MS-ESI m/z (% rel. int.): 334.2 ([MH]+, 10).

HPLC: Method A, detection UV 214 nm, Compound 51 RT « 3.90 min, peak area 99.0 %. r 100 N-toL-r½reo-l-Hvdroxy-3-oxo-l-^ ylYheptanamide hydrochloride Compound 52.

The compound was prepared according to method F with heptanoyl chloride (72 mg, 0.484 mmol) and Dl iAreo-2-an-mo-3-hydroxy-3-(pYridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one dihydrochloride Compound 22. αν-CDL· fAreo-l-Hydroxy-3-oxo-l-(pyridm-4-yl)-3-(p^ yl)heptanarnide hydrochloride Compound 52 was obtained as an off white solid. (192 mg, 66 % yield).

Compound 52 MW: 383.91; Yield: 66 %; Off White Solid; Mp (°Q: 187.1. 1H-NMR (CD3OD, δ): 0.88 (t, 3H, .7=3.7 Hz, CH3), 1.15-1.37 (m, 6Ή, CH2), 1.37 (m, 2H, CH2), 1.85-2.02 (m, 4H, CH2), 1.18-2.27 (m, 2H, CH2), 3.37-3.50 ( m, 2H, N-CH2), 3.55-3.70 (m, 2H, NCHj), 5.14 (d, IH, N-CH), 5.42 (d, IH, O- CH), 8.19 (d, 2H, 6.3 Hz, ArH), 8.83 (d, 2H, J - 6.3 Hz, ArH).

I3C-NM (CD3OD, 6): 14.4, 23.6, 25.0, 26.7, 27.0, 29.9, 32.6, 36.4, 47.5, ,56.7, 72.6, 126.6, 142.0, 164.5, 169.2, 175.9.

MS-ESI m/z (% rel. Int.): 348.2 ([MH]+, 10).

HPLC: Method A, detection UV 254 nm, Compound 52 RT = 4.10 min, peak area 99.0 %.

N-CDL-threo- 1 -Hydroxv-3-oxo- 1 -fpvridin-4-vlV3-(pvrrolidin- 1 -vl>propan-2-yDoctanamide hydrochloride Compound 53. 101 The compound was prepared according to method F with octanoyl chloride (78 mg, 0.484 mmol) and DL-i/ireo-2-amino-3-hydroxy-3-(pyridin-4-yi 1 -(pyrrolidin- 1 -yl)propan- 1 -one dihydrochloride Compound 22. JV-(DL-iAreo-l-Hydroxy-3-oxo-l-(pyridm-4-yl)-3-(pyrro yl)octanamide hydrochloride Compound 53 was obtained as an off white solid. (131 mg, 75 % yield).

Compound 53 MW: 397.94; Yield: 75 %; OffWhite Solid; Mp (°C): 185.9.

'H-NMR (CD3OD, δ): 0.91 (t, 3H,/= 6.4 Hz, C¾), 1.12-1.37 (m, 8H, CH2), 1.40-1.52 (m, 2H, CH2), 1.81 (m, 4H, CH2), 2.12-2.25 (m, 2H, CH2), 3.40-3.52 (m, 2H, N-CHj), 3.55-3.65 (m, 2H, N-CH2), 5.14 (d, 1H, 7= 3.7 Hz, -CH), 5.43 (d, 1H, 3.7 Hz, OCH), 8.19 (d, 2H, J= 6.3 Hz, ArH), 8.84 (d, 2H, /= 6.3 Hz, ArH).

"C- MR (CD3OD, δ): 14.4, 23.7, 24.9, 25.0, 25.5, 26.8, 27.0, 30.1, 30.2, 32.8, 34.3, 36.5, 47.5, 56.8, 71.6, 72.6, 126.7, 126.9, 142.1, 143.7, 164.5, 169.2, 176.0.

MS-ESI m/z (% rel. Int.): 362.2 ([MH]+, 10).

HPLC: Method A, detection UV 254 nm, Compound 53 RT =» 4.37 rrrin, peak area 99.9 %.

N-(OL-threo~ 1 -Hvdroxv-3 -oxo- 1 -fpvridin-4- vlV3-(pvrrolidin- 1 -vl propan-2-yl^alnntamide hydrochloride Compound 54. 102 Hie compound was prepared according to method F with palmitoyl chloride (133 mg, 0.484 mmol) and D eo-2-amino-3-hydroxy-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one dihydrochloride Compound 22. iV-(DL-iAreo-l-Hydroxy-3-oxo-l-(pyridin-4-yl)-3-^yrroUdin-l-yl)propan-2-yl)palrmtamide hydrochloride Compound 54 was obtained as an off white solid. (105 mg, 47 % yield).

Compound 54 MW: 510.15; Yield: 47 %; White Solid; Mp (°C): 185.9. Ή- MR (CD3OD, δ): 0.92 (t, 3H, CH3), 1.18 -1.42 (m, 24H, CH2), 1.42-1.58 (m, 2H, CH2), 1.85 (m, 4H, CH2), 2.15 (m, 2H, CH2), 3.41-3.50 (m, 2H, CH2), 3.50-3.68 (m, 2H, CH2), 5.14 (d, 1H, = 3.5 Hz, N-CH), 5.42 (d, 1H, /= 3.5 Hz, O-CH), 8.18 (d, 2H, /= 6.0 Hz, ArH), 8.82 (d, 2H, = 5.7 Hz, ArH). 13C- MR (CD3OD, δ): 14.4, 23.7, 25.0, 26.8, 27.0, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 33.1, 36.4, 47.5, 56.8, 72.6, 126.6, 142.1, 164.5, 169.2, 175.9.

MS-ESI m/z (% rel. Int): 474.2 (pVfflf , 40).

HPLC: Method A, detection UV 254 nm, Compound 54 RT = 6.36 min, peak area 97.0%.

N- DL-threo- 1 -Hvdroxv-3-oxo- 1 -rr>vridjn-4-vD-3- pvrrolidin- 1 -vDpropaB-2-yl^benza ide hydrochloride Compound 55.

The compound was prepared according to method F with benzoyl chloride (141 mg, 0.484 mmol) and DL-/¾reo-2-amino-3-hydroxy-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1-one dihydrochloride Compound 22. N-(DL- 103 fAreo- l-Hy&oxy-3-oxo-l-(pyri^ yl)benzamide hydrochloride Compound 55 was obtained as an off white solid. (67 mg, 34 % yield).

Compound 55 MW: 375.85; Yield: 34 %; Off White Solid; Mp (°C): 212. Ή-NMR (CD3OD, 6): 1.69-1.91 (m, 4H, CH2), 3.25-3.40 (m, 2H, N-CH2), 3.40-3.58 (m, 2H, N-C¾), 5.22 (d, IH, J = 3.7 Hz, N-CH), 5.43 (d, IH, J= 3.5 Hz, O-CH), 7.32 (t, 2H, J= 7.8 Hz, ArH), 7.40 (t, IH, J= 6.9 Hz, ArH), 7.63 (d, 2H, J = 7.1 Hz, ArH), 8.08 (d, 2H, J = 6.6 Hz, ArH), 8.66 (d, 2H, J = 6.1 Hz, ArH). 13C-NMR (CD3OD, δ): 25.0, 27.1, 47.6, 57.6, 72.7, 126.6, 128.4, 129.7, 133.3, 134.4, 142.1, 164.5, 169.0, 169.7.

S-ESI m/z (% rel. Int.): 340.2 ([MH]+, 5).

HPLC: Method A, detection UV 254 nm, Compound 55 RT = 3.66 min, peak area 99.0 %.

N-^L-f¾reo-l-Hvdroxy-3-oxo-l-fpyridm-4-ylV3-(pynOlidin-l-^^^ \l) -4-methoxv-b enzamide hydrochloride Compound 56.

The compound was prepared according to method F with 4-methoxybenzoyl chloride (82 mg, 0.484 mmol) and DI^tAreo-2-amino-3-hydroxy-3-(pyridin-4-yl)-l-(pynolidin-l-yl)propan-l-one dihydrochloride Compound 22. iV-(DL· iAreo-l-Hydroxy-3-oxo-l-(pyridm-4-yl 3-(pyrrolidm-l-yl)prop 104 methoxy-benzamide hydrochloride Compound 56 was obtained as an off white solid. (105 mg, 58 % yield).

Compound 56 MW: 405.87; Yield: 58 %; Off White Solid; Mp(°C): 205.3 (dec). 1H-NMR (CD3OD, δ): 1.82-2.08 (m, 4H, C¾), 3.45-3.55 (m, 2H, CH2- ), 3.60-3.70 (m, 2H, NCHj), 3.86 (s, 3H, O-CH3), 5.35 (d, 1H, J= 3.7 Hz, N-CH), 5.56 (d, 1H, J= 3.6 Hz, O-CH), 6.99 (dd, 2H, J= 6.9 Hz, J= 1.9 Hz), 7.76 (dd, 2H, J= 6.9 Hz, J = 1.9 Hz, ArH), 8.21 (d, 2H, = 6.6 Hz, ArH), 8.79 (d, 2H, J = 6.6 Hz, ArH).

I3C-NMR (CD3OD, 6): 25.0, 27.1, 47.6, 56.0, 57.5, 72.7, 114.9, 115.2, 126.3, 126.6, 130.4, 133.7, 142.1, 164.4, 164.5, 169.1.

MS-ESI m/z (% rel. Int.): 370.2 (fMH , 10).

HPLC: Method A, detection UV 254 ran, Compound 56 RT = 3.76 rnin, peak area 99 %. yl¾?ropan-2-yr)benzamide Compound 57.

The compound was prepared according to method F with 3,4-dichlorobenzoyl chloride (101 mg, 0.484 mmol) and D^iAreo-2-amino-3-hydroxy-3-(pyridm-4-yl)-l-(pyixoU Compound 22.3,4-Dichloro-N-(DL-*Areo-l-hydrox^ 105 (pyrroUdm-l-yl)propan-2-yl)benzainide Compound 57 was obtained white solid. (92 mg, 55 % yield).

Compound 57 MW: 444.74; Yield: 55 %; Off White Solid; Mp (°C): 319.5 (dec). 1H-NMR (CD3OD, δ): 1.82-2.05 (m, 4H, CH2), 3.40-3.70 (m, 4H, N-CH2), 5.33 (d, IH, J= 3.9 Hz, N-CH), 5.55 (d, IH, J= 4.0 Hz, O-CH), 7.61-7.75 (m, 2H, ArH), 7.96 (d, IH, J= 1.5 Hz, ArH), 8.22 (d, 2H, 7= 6.4 Hz, ArH), 8.81 (d, 2H, J= 6.0 Hz, ArH). 13C-NMR (CD3OD, δ): 25.0, 27.0, 57.8, 72.6, 126.6, 128.3, 130.7, 131.9, 133.8, 134.7, 137.2, 142.2, 164.3, 167.2, 168.8.

MS-ESI m z (% rel. Int): 408.0, ([MH]+, 10) HPLC: Method A, detection UV 254 nm, Compound 57 RT - 4.28 min, peak area 99.9 %.

Preparation of Compound 58. Compound 59. Compound 60. Compound 61. Compound 62. Compound 63. Compound 64. Compound 65. Compound 66. Compound 67. Compound 68. Compound 69.

General procedures: Method G (in CH2C12): 106 To a stirred solution of DI^tireo-2-araino-3-hydroxy-3-(pyridin-4-yl)- 1 -(pyiTolidm-l-yl)propan-l-one dihydrochloride Compound 22 (0.15 g, 0.49 mmol) in 10 mL of CH2C12 at +4 °C were added triemylarnine (200 μΐ, 1.45 mmol) and very slowly acid chloride in 3 mL of CH2C12. The mixture was stirred overnight at RT under nitrogen and then partitioned between CH2CI2 and 1 N aqueous sodium carbonate. The organic layer was evaporated and the obtained residue purified by column chromatography on silica (EtOAc:MeOH = 95:5). The hydrochloride salt was obtained in MeOH at 0 °C with 0.3 M HCl in diethylether to give after evaporation of solvents and drying the acylated compound.

Method H (in MeOH): To a stirred solution of DL·ίAreo-2-ar mo-3-hydΓoxy-3- pyridin-4-yl>·l-(pyrrolidin- 1 -yl)propan- 1 -one dihydrochloride Compound 22 (0.20 g, 0.65 mmol) in 3 mL of MeOH were added trielhylamine (180 μΐ, 1.30 mmol) and aldehyde (or ketone). The rnixture was stirred overnight at RT under nitrogen and then was added AcOH (200 μί, 3.2 mmol) and NaBH3CN. After 5 h at 20 °C, MeOH was evaporated and the residue was partitioned between CH2CI2 and 1 N aqueous sodium carbonate. The organic layer was evaporated and the obtained residue was purified by column chromatography on silica (EtOAc:MeOH or C¾Cl2:MeOH). The hydrochloride salt was obtained in MeOH at 0 °C with 0.3 M HCl in diethylether to give after evaporation of solvents and drying the alkylated compound.

Benzyl DL-f¾reo-3-hvdroxy-l^xo-3-(pyridfa-^ 2-ylcarbarnate hydrochloride Compound 58.

The compound was prepared according to method G with benzyl chloroformate (91 mg, 0.53 mmol). After work-up benzyl D^Are0-3-hydroxy- 107 Compound 58 was obtained as a white solid (90 mg, 46 % yield).

Compound 58 MW: 405.9; Yield: 46.0 %; White Solid; Mp (°C): 185.3.

R : 0.38 (MeOHrEtOAc = 10:90) free base. 1H-NMR (CD3OD, δ): 1.87-2.03 (m, 4H, 2χΟ¾), 3.40-3.48 (m, 2H, CH2N), 3.56-3.62 (m, 2H, CH2 ), 4.85-5.04 (m, 3H, CH20, CHO), 5.39 (d, 1H, 2.8 Hz, NH), 7.26-7.36 (m, 5H, ArH), 8.12 (d, 2H, J= 6.0 Hz, ArH), 8.69 (d, 2H, J = 6.0 Hz, ArH). ,3C-NMR(CD3OD, δ): 25.0, 27.0, 47.5, 48.0, 58.8, 67.9, 72.7, 126.6 (2xQ, 129.1, 129.2, 129.5, 138.1, 141.9 (2xQ, 158.1, 164.4, 169.2.

MS-ESI m/z (% rel. Int.): 370.1 ([MH]+, 15), 219.0 (100).

HPLC: Method A, detection UV 254 nm, Compound 58 T = 4.10 min, peak area 99.8 %.

N-(TD31^t treo-3-hvdroxv- 1-οχο-3- νπάΐη-4-ν1")- 1 -Cpvrrolidin- 1 -vnpropan-2-vDdecanamide hydrochloride Compound 59.

The compound was prepared according to method G with decanoyl chloride (111 μί, 0.53 mtnol). After work-up -V-(D^Areo3-hyxy- l-oxo-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan-2-yl)decanamide hydrochloride Compound 59 was obtained as a white solid (115 mg, 55 % yield).

PC jS2006/002S57 108 Compound 59 MW: 425.99; Yield: 55 %; White Solid; Mp (°C): 184.8.

Ry: 022 (MeOH:EtOAc » 5:95) free base. 1H- MR (CD3OD, δ): 0.90 (t, 3H, J= 7.0 Hz, C¾), 1.26-1.34 (m, 12H, 6XCH2), 1.42-1.50 (m, 2H, C¾), 1.86-1.98 (m, 4H, 2χΟ¾, 2.13-2.20 (m, 2H, C¾CO), 3.41-3.46 (m, 2H, CH¾ )> 3.52-3.61 (m, 2H, C¾N), 5.12 (d, 1Η,/= 3.8 Hz, CH), 5.40 (d, 1H, /= 3.7 ίίζ, CH), 8.16 (d, 2H, = 6.5 Hz, ArH), 8.97 (d, 2H, J= 6.7 Hz, ArH). 13C-N (CD3OD, δ): 14.4, 23.7, 25.0, 26.8, 27.0, 30.3, 30.4, 30.6, 33.0, 36.5, 47.5, 56.8, 72.6, 126.6 (2xQ, 142.1 (2xQ, 164.4, 169.2, 175.9.

MS-ESI m/z (% rel. Int.): 390.1 ([MH]+, 20), 219.1 (100).

HPLC: Method A, detection UV 254 nm, Compound 59 RT = 4.9 min, peak area 99.5 %.

D^^reo-2-fflenzylan inoV3-hvdroxy-3-(pyridm-4-ylVl-vDpropan-l-one dihydrochloride Compound 60.

The compound was prepared according to method H with benzaldehyde (78 mg, 0.72 mmol). After column chromatography (EtOAc:MeOH = 95:5) and HC1 treatment D^Areo-2-(beiizylammo)^ (pyiTolidin-l-yl)propan-l-one dihydrochloride Compound 60 was obtained as a white solid (114 mg, 46 % yield). 109 Compound 60 MW: 398.33; Yield: 46 ; White Solid; Mp (°C): 131.5.

R/.- 0.60 (MeOH:EtOAc = 10:90) free base. Ή-NMR (CD3OD, δ): 1.35-1.72 (m, 4H, 2xCH2)i 2.10-2.18 (m, IH, CH2 ), 2.78-2.86 (m, IH, CH2N), 3.18-3.24 (m, 2H, CH2 ), 4.22 (d, IH, J= 8.5 Hz, CH), 4.26-4.36 (m, 2H, CH2N), 5.18 (d, IH, 8.5 Hz, CH), 7.43-7.51 (m, 5H, BzH), 7.86 (d, 2H, J= 6.6 Hz, ArH), 8.69 (d, 2H, J= 6.6 Hz, ArH). 13C-NM (CD3OD, δ): 24.7, 26.3, 47.3, 47.9, 51.4, 63.9, 72.4, 126.2, 130.3, 131.0, 131.4, 131.5, 148.9, 156.1, 163.9.

MS-ESI m/z (% rel. Int.): 326.1 ([MH]+, 100), 227.0 (80).

HPLC: Method A, detection UV 254 nm, Compound 60 RT = 4.30 min, peak area 98.2 %.

OLrthreo-3-HYdroxy-2-(meihylmBnoY3-(p^ yl)propan-l-one dihvdrochloride Compound 61.

The compound was prepared according to method H with paraformaldehyde (21 mg, 0.65 mmol). After colummn chromatography (EtOAc:MeOH = 7:3) and HC1 treatment Dl iAreo-3-hydroxy-2-(methylamino)-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one dihydrochloride Compound 61 was obtained as a pale yellow solid (28 mg, 13 % yield). 110 Compound 61 MW: 322.23; Yield: 13 %; Pale Yellow Solid. : 0.20 (MeOH:EtOAc - 30:70) free base.

'H-NMR (CD3OD, δ): 1.60-1.80 (m, 4H, 2xC¾), 2.61 (s, IH, CH3), 2.68-2.76 (m, IH, C¾N), 3.24-3.57 (m, 3H, CH2N), 4.53 (d, IH, J= 6.8 Hz, CH), 5.26 (d, IH, J= 7.0 Hz, CH), 8.11 (d, 2H, = 5.8 Hz, ArH), 8.85 (d, 2H, J= 5.6 Hz, ArH).

"C-NMR (CDjOD, 6): 24.8, 26.7, 32.8, 47.7, 48.3, 65.4, 71.7, 126.7 (2xC), 143.4 (2xC), 161.1, 163.9.

MS-ESI m/z (% rel. Int.): 251.1 ([MH]+, 10), 151.0 (100).

HPLC: Method A, detection UV 254 nm, Compound 61 RT = 0.70 min, peak area 97.5 %.

D^ trgo-3-Hvdroxy-2-(pentylaTTifa^ vDpropan-l-one dihydrochloride Compound 62.

The compound was prepared according to method H with valeraldehyde (60 mg, 0.68 mmol). After column chromatography (EtOAc:MeOH = 95:5) and HC1 treatment DI^iAreo-3-hydroxy-2-^entylarmno)-3-(pyridin-4-yl)-l-(pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 62 was obtained as a white solid (107 mg, 44 % yield). 111 Compound 62 MW: 378.34; Yield: 44 %; White Solid; Mp (°C): 86.6. fi 0.30 (MeOH:EtOAc - 20:80) free base. 1H-NMR (CD3OD, δ): 0.95 (t, 3H, J= 6.4 Hz, CH3), 1.32-1.40 (m, 6H, 3xCH2), 1.70-1.87 (m, 4H, 2xC¾), 2.70-2.75 (m, IH, CH2 ), 2.90-3.00 (m, IH, CH2 ), 3.10-3.39 (m, 3H, C¾N), 3.46-3.60 (m, IH, C¾N), 4.61 (d, IH, J= 7.5 Hz, CH), 5.39 (d, IH, 7= 7.5 Hz, CH), 8.22 (d, 2H, J= 6.2 Hz, ArH), 8,97 (d, 2H, J = 6.2 Hz, ArH). ,3C-NMR (CD3OD, δ): 9.3, 14.1, 23.2, 24.8, 26.7, 26.8, 29.7, 47.6, 47.9, 64.5, 72.1, 126.8 (2xC), 143.3 (2xC), 161.1, 164.1.

MS-ESI m/z (% reL Int.): 306.3 ([MH]+, 15), 207.1 (100).

HPLC: Method A, detection UV 254 nm, Compound 62 RT = 3.60 nrin, peak area 98.5 %.

DL-f¾reo-3-Hvdroxy-2-(hexylammoV3-fpyri(¾n-4-ylVl^\Troli yllpropan-l-one dihydrochloride Compound 63.

The compound was prepared according to method H with hexanal (71 mg, 0.68 mmol). After column chromatography (EtOAc:MeOH = 95:5) and HC1 treatment DL·/ΛΓeo-3-hydro y-2- hexylammo)-3- yridin-4-yl)-l-(pyrrolidin- 1 -yl)propan- 1 -one dihydrochloride Compound 63 was obtained as a beige solid (112 mg, 45 % yield).

(+/-) Compound 63 MW: 392.36; Yield: 45 %; Beige Solid; Mp (°C): 108.2. 112 R -: 0.35 (MeOH:EtOAc = 20:80) free base. Ή-NMR (CD3OD, δ): 0.94 (t, 3H,y= 7.2 Hz, CH3), 1.30-1.42 (m, 6Η, 3xC¾), 1.66-1.90 (m, 6H, 3xC¾), 2.68-2.74 (m, IH, CH2N), 2.90-2.99 (m, IH, C¾N), 3.09-3.16 (m, IH, CH2 ), 3.32-3.39 (m, IH, CH2N), 3.47-3.60 (m, 2H, CH2N), 4.60 (d, IH, J= 7.7 Hz, CH), 5.38 (d, IH, J= 7.7 Hz, CH), 8.24 (s, 2H, ArH), 8.97 (s, 2H, ArH).

"C-NMR (CD3OD, δ): 14.3, 23.4, 24.8, 26.7, 27.1, 27.2, 32.4, 47.6, 64.4, 72.1, 126.9 (2xQ, 143.2 (2xQ, 161.3, 164.1.

MS-ESI m z (% rel. Int.): 320.1 ([MH]+, 30), 221.1 (100).

HPLC: Method A, detection UV 254 nm, Compound 63 RT = 3.80 min, peak area 97.8 %.

DL·^go-3-Hvdroxy-2-fll tylammo 3-fpyridm-4-yl l-(pyrro yl)propan-l-one dihydrochloride Compound 64.

The compound was prepared according to method H with heptaldehyde (82 mg, 0.68 mmol). After column chromatography with EtOAciMeOH = 95:5 and HC1 treatment DL-tAreo-3-hydroxy-2-(heptylamino)-3-(pyriciin-4-yl)-l-(pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 64 was obtained as a white solid (121 mg, 47 % yield).

Compound 64 MW: 406.39; Yield: 47 %; White Solid; Mp (°C): 242.4.

Ry: 0.40 (MeOH:EtOAc = 20:80) free base. 113 1H-NMR (CD3OD, δ): 0.92 (t, 3H, /= 7.0 Hz, CH3), 1.32-1.40 (m, 8H, 4χΟ¾), 1.65-1.90 (m, 6H, 3xCH2), 2.71-2.76 (m, IH, CH2 ), 2.90-2.99 (m, IH, CH2 ), 3.09-3.38 (m, IH, α¾Ν), 3.47-3.62 (m, 2H, CH2N), 4.61 (d, IH, 7= 7.5 Hz, CH), 5.39 (d, IH, J= 7.5 Hz, CH), 8.24 (d, 2H, J= 6.0 Hz, ArH), 8.97 (d, 2H, J = 5.9 Hz, ArH). 13C-NMR (CD3OD, 6): 14.4, 23.6, 24.8, 26.7, 27.1, 27.5, 29.9, 32.7, 47.7, 64.4, 72.1, 126.9 (2xC), 143.2 (2xQ, 161.4, 164.1.

MS-ESI m/z (% rel. Int.): 334.1 ([MH]+, 45), 235.1 (100).

HPLC: Method A, detection UV 254 run, Compound 64 RT - 4.00 min, peak area 97.5 %.

DI^r¾reo-2-f4-Me1hvlben-rvlarninoV3-hvdroxv-3-(pvricU^ l-yl)propan-l-one Compourld 65.

The compound was prepared according to method H with 4-methylbenzaldehyde (86 mg, 0.70 mmol). After column chromatography (EtOAc:MeOH = 95:5) and HC1 treatment D^iAreo-2-(4-memylbenzylamino 3-hydroxy-3 -(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one Compound 65 was obtained as a white solid (137 mg, 51 % yield).

Compound 65 MW: 412.35; Yield: 51 %; White Solid; Mp (°Q: 87.5. fy: 0.20 (MeOH:EtOAc = 5:95) free base. 114 1H-NMR (CD3OD, δ): 1.49-2.12 (m, 4H, 2χΟ¾), 2.30-2.40 (m, IH, C¾ ), 2.35. (s, 3H, CH3), 2.75-2.95 (m, IH, CH2 ), 3.18-3.25 (m, 2H, CH2 ), 4.12-4.32 (m, 3H, C¾N, CH), 5.30 (d, IH, 7.9 Hz, CH), 7.24-7.39 (m, 4H, BzH),.8.11 (d, 2H, J= 6.7 Hz, ArH), 8.89 (d, 2H, J= 6.6 Hz, ArH). 13C-NMR (CD3OD, δ): 21.2, 24.7, 26.3, 26.4, 47.4, 47.9, 51.2, 63.4, 72.4, 126.1, 126.6 (2xQ, 128.2, 130.9, 131.4, 131.5, 141.4, 143.5 (2xC), 148.9, 156.1; 160.5, 163.8.

MS-ESI m/z (% rel. Int.): 340.1 ([MH]+, 10), 104.9 (100).

HPLC: Method A, detection UV 254 nm, Compound 65 RT = 3.70 min, peak area 97.3 %.

DL-^reo-2-f4-C)MorobenzylammoV3-hvdroxy-3-fpyridm yl^propan-l-one Compound 66.

The compound was prepared according to method H with 4-chlorobenzaldehyde (98 mg, 0.70 rmnol). After column chromatography (EtOAc:MeOH = 95:5) and HCl treatment D^i trec^2-(4-chloroberizylamino 3-hydroxy-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one Compound 66 was obtained as a white solid (126 mg, 45 % yield).

Compound 66 MW: 432.77; Yield: 45 %; White Solid; Mp (°C): 122.7.

R : 0.20 (MeOH: EtOAc = 5:95) free base. 115 1H-NMR (CD3OD, ό): 1.54-1.75 (m, 4H, 2X.CR 2.41-2.49 (m, IH, CH2 ), 3.08-3.15 (m, IH, CH2 ), 3.19-3.27 (m, 2H, CH2N), 4.25-4.47 (m, 3H, CH2N, CH), 5.34 (d, IH, J= 7.9 Hz, CH), 7.46-7.55 (m, 4H, BzH), 8.15 (d, 2H, /= 6.0 Hz, ArH), 8.92 (d, 2H, J= 5.7 Hz, ArH).

I3C-NMR (CD3OD, δ): 24.7, 26.5, 47.5, 47.8, 50.8, 63.8, 72.3, 126.7 (2xQ, 130.3, 133.4, 137.1, 143.5 (2xQ, 149.0, 160.6, 163.8.

MS-ESI m z (% rel. Int.): 360.1/362.1 ([ΜΒΤ , 20), 124.9 (100).

HPLC: Method A, detection UV 254 nm, Compound 66 RT = 3.70 min, peak area 97.0 %.

D^/½rgo-2-(4-MemoxybenzylanMnoV3-h^ 1-vDpropan-l-one one Compound 67.

The compound was prepared according to method H with 4-methoxybenzaldehyde (95 rag, 0.70 mmol). After column chromatography (EtOAc:MeOH = 95:5) and HC1 treatment DL-threo-2-(4-methoxybenzylainino)-3-hydroxy-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one one Compound 67 was obtained as a white solid (123 mg, 44 % yield).

Compound 67 MW: 428.35; Yield: 44 %; White Solid; Mp (°C): 193.2. 116 R/: 0.20 (MeOH:EtOAc = 5:95) free base.

'H- MR CCDaOD, δ): 1.51-1.72 (m, 4H, 2xC¾), 2.38-2.41 (m, 1H, CH2N), 2.94-3.01 (m, 1H, CH2 ), 3.18-328 (m, 2H, C¾ ), 3.81 (s, 3H, CH30), 4.18-4.34 (m, 3H, CH2N, CH), 5.31 (d, 1H, J= 7.3 Hz, CH), 6.97 (d, 2H„/= 8.5 Hz, ArH), 7.42 (d, 2H, J= 8.5 Hz, ArH), 8.13 (d, 2H,J= 6.5 Hz, ArH), 8.91 (d, 2H, J= 6.3 Hz, ArH). l3C-NMR (CD3OD, δ): 24.7, 26.5, 47.5, 47.9, 51.1, 55.9, 63.2, 72.3, 115.5, 122.9, 126.8 (2xQ, 133.1, 143.3 (2xC), 160.9, 162.4, 163.8.

MS-ESI m z (% rel. Int): 356.1 ([MH]+, 10), 120.9 (100).

HPLC: Method A, detection UV 254 run, Compound 67 RT = 3.50 rnin, peak area 98.6 %.

DL-fΛreo-2-(3.4-ΓMchlorobenzylammo)-3-hvdro y-3- yrid^ (pyrrolidin-l-yl propan-l-one dihvdrochloride Compound 68.

The compound was prepared according to method H with 3,4-dichlorobenzaldehyde (122 mg, 0.70 mrnol). After column chromatography (EtOAc:MeOH = 95:5) and HC1 treatment DL-rtreo-2-(3,4-dicWorobenzylarmno)-3 -hyciroxy-3 -(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one diliydrochloride Compound 68 was obtained as a white solid (153 mg, 50 % yield).

Compound 68 117 MW: 467.22; Yield: 50 %; White Solid; Mp (°C): 190.3.

I : 0.20 (MeOH:EtOAc = 5:95) free base. lH-NMR (CD3OD, δ): 1.58-1.76 (m, 4H, 2xC¾), 2.48-2.55 (m, IH, C1¾N), 2.85-3.00 (m, IH, CHjN), 3.18-3.26 (m, 2H, CH2N), 4.23-4.41 (m, 2H, CH2 ), 4.54 (d, IH, 7= 7.7 Hz, CH), 5.34 (d, IH, J= 7.2 Hz, CH), 7.48 (d, IH, 7= 8.3 Hz, ArH), 7.63 (dd, IH, /= 8.2 Hz, .7=1.4 Hz, ArH), 7.75 (s, IH, ArH), 8.16 (d, 2H, J= 5.4 Hz, ArH), 8.92 (d, 2H, J= 5.3 Hz, ArH). 13C-NMR (CD3OD, δ): 23.2, 25.0, 46.0, 46.4, 48.9, 62.5, 70.7, 125.3, 130.2, 130.6, 130.7, 132.3, 133.6, 141.9, 159.2, 162.3.

MS-ESI m/z (% rel. Int): 394.1/396.1 ([MH]+, 40), 110.0 (100).

HPLC: Method A, detection UV 254 mn, Compound 68 RT = 3.90 min, peak area 99.0 %.

D^¾reo-2-(4-Me1hoxybenzylaiT»inn)-3-hYQ oxy-3-fpy^ l-yl)propan-l-one Compound 69.

The compound was prepared according to method H with cyclohexanone (75 uL, 0.70 mmol). After column chromatography (EtOAc:MeOH = 95:5) and HC1 treatment DL- f Areo-2-(4-methoxyb enzylamino)- 3 -hydroxy-3 - (pyridin-4-yl)- l-(pyrrolidin-l -yl)propan-l-one Compound 69 as a white solid (154 mg, 61 % yield).

Compound 69 MW: 390.35; Yield: 61 %; White Solid; Mp (°C): 144.1.

R/: 0.25 (MeOH: EtOAc = 5:95) free base.

O 2006/081273 118 Ή- MR (CD3OD, 6): 1.16-2.15 (m, 15H, 7xCH2> CH), 2.65-2.72 (m, 1H, CH2 ), 3.07-3.15 (m, 1H, CH2N), 3.43-3.65 (m, 2H, CH2N), 4.61 (d, 1H, /= 7.8 Hz, CH- ), 5.35 (d, 1H, J= 7.8 Hz, CH-O), 8.21 (d, 2H, 6.3 Hz, ArH), 8.95 (d, 2H, 7= 6.1 Hz, ArH). ,3C- MR (CD3OD, δ): 23.2, 24.0, 24.2, 24.4, 25.2, 28.2, 29.3, 46.1, 57.4, 60.5, 71.0, 125.4 (2xC), 141.8 (2xC), 159.5, 162.6.

MS-ESI m z (% rel. Int.): 318.2 ([MH]+, 40; 219.1, 100).

HPLC: Method A, detection UV 254 run, Compound 69 RT = 3.40 min, peak area 99.7 %.

Preparation of ^ ^Γβο-Σ-αηιΐηο -ΓίυτΜ-Σ-νΐ Β-ίνάΓθχν-Ι- ρνΓΓθΙίάίη-Ι-yppropan-l-one hydrochloride Compound 201. frgflj-5-(Furan-2-yl .5-dfovd^^ BLE 04136D.

BLE 04136D was prepared in accordance with method D using 2-furaldehyde (0.449 mL, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-l-(pynOhdin-l-yl)ethanone BLE 04098 (0.75 g, 5.42 mmol). After work-up the residue was purified by column chromatography (Si02, cyclohexane:EtOAc ·» 100:0 to 0:100) to led, after evaporation, to trans-. 5-(furan-2-yl)-4,5-d¾ydrooxa2»l-4-yl)(pyrrolidm-l-yl)meuianone BLE 04138D (0.742 g, 58.5 % yield) as a pale yellow oil.

BLE 04136D 119 MW: 234.25; Yield: 58.5 %; Pale Yellow Oil. 1H-NMR (CDC13,6): 1.80-2.10 (m, 4H, CH2), 3.47-3.60 (m, 3H, CH2N), 3.93-4.03 (m, IH, CH2N), 4.94 (dd, IH, 7= 7.4 Hz, 2.2 Hz, CH-N), 6.14 (d, IH, 7.4 Hz, CH-O), 6.37 (dd, IH, J= 3.3 Hz, = 1.8 Hz, CH=C), 6.47 (d, IH, J - 3.3 Hz, CH=0, 6.92 (d, IH, 2.2 Hz, 0-CH=N), 7.44 (t, IH, J « 1.6 Hz, OCH=C). (,.fcV^reo-2-Aimno-3 -(ίίΐΓΒη-2-ν1)-3 -hydroxy- 1 -fpvrrolidin- 1 - vDpropan- 1 -one hydrochloride Compound 201.

Compound 201 was prepared following method E with fr ¾s-(5-(furan-2-yl)-4,5-dmydrooxazol-4-yl)(pyn:oUdm-l-yl)rnethanone BLE 04136D (0.30 g, 1.28 mmol), hydrochloric acid 37 % (0.3 mL) and methanol (10 mL). After overnight at RT and work-up (±)-/Areo-2-amino-3 -(furan-2-yl)-3-hydroxy- 1 -^yrrolidin-l-yl)propan-l-one hydrochloride (0.22 g, 66 % yield) was obtained as a pale brown solid.

Compound 201 MW: 260.72; Yield: 66 %; Pale Brown Solid; Mp (°Q: 159.8 1H-NMR (CD3OD,6): 1.62-1.95 (m, 4H, 2xCH2), 2.72-2.85 (m, IH, CH2N), 3.22-3.35 (m, IH, CH2N), 3.38-3.55 (m, 2H, C¾N), 4.35 (d, IH, 8.5 Hz, CH-N), 4.91 (d, IH, J= 8.5 Hz, CH-O), 6.45 (m, 2H, ArH), 7.52-7.57 (m, IH, ArH). ,3C-NMR (CD3OD,6): 24.9, 26.9, 47.4, 47.6, 57.4, 67.8, 109.9, 111.9, 144.4, 153.0, 166.0. 120 MS-ESI m/z (% rel. Int.): 225.1 ([ΜΗ]+, 18), 207.1 (100).

HPLC: Method A, detection UV 254 nm, Compound 201 RT » 2.87 min, peak area 92.0 %.

Preparation of Γ-Vf 2R.3S1-2-amincH3-hvdroxv-3 -favridin-4- vlV 1 -( pvrrolidin- 1 -vDpropan- 1-one dihydrochloride Compound 203 and (+Vf2iSl.3.RV2-arnino-3-hvdroxy-3-foyridwi-4-ylM-foyro^ Compound 204.

Extraction of the free base of Compound 22: (±)-iAreo-2-Amino-3-hydroxy-3-(pyridin-4-yl)-l-(pyr^ 1-one dihydrochloride Compound 22 (350 mg, 1.14 mmol) was dissolved in 20 mL of a K2CO3 (10 %) solution and the aqueous mixture was then saturated with NaCl. The aqueous phase was extracted by a mixture CH2CI2:2-PrOH = 9: 1 (6x15 mL). The organic phase was dried over MgSC<4 and evaporated to afford 226 mg (85 % yield) of the free base of Compound 22.

Analytical chiral separation: 20 uL of a 1 mg/mL solution of Compound 22 were injected on Chiralpak AD: flow-rate = 1 mL/min, temperature = 25 °C, mobile phase: hexane:ethanol = 1:1, detection by UV at 220 nm and by polarimeter, Rt (-) = 8.20 min, Rt (+) = 10.61 min, k (-) = 1.72, k (+) = 2.51, a = 1.47 and resolution Rs = 3.08.

Semi-preparative chiral separation: A solution of 100 mg/mL was prepared and 10 uL of this solution were injected every 4.5 min on Chiralpak AD, flow-rate = 1 rriiymin, mobile phase hexane:ethanol = 4:6, detection by UV at 254 ran. 135 successive injections were done. The two main fractions were identified by UV and collected in two 121 different flasks. The solvent was removed in vacuo at 30 °C. The resulting solid was dissolved in 50 mL of CH2C12 and then filtered on a 0.45 μηι millipore membrane. After evaporation of CH2C12, the solid was dissolved in 50 mL of methanol and men filtered. The salts were regenerated according to the procedure reported above.

Regeneration of the salt After the chiral separation, about 63 mg of each enantiomer of the free base were dissolved in 100 mL of ethanol and 6.7 mL of HQ (0.2 N, 5 eq) were added. The solvent was evaporated, then 50 mL of ethanol were added and then removed in vacuo and the products were dried over P2O5 under vacuum overnight. The enantiomeric purity of the products was checked by analytical injection of the regenerated salts: f-V(2 3S)-2-Amino-3-hydioxv-3-fo one dihvdrochloride Compound 203.

Compound 203 MW: 308.20; 83 mg obtained; Yield: 23.5 %; White Solid; Mp (°C): 183.5 Enantiomeric excess = 99.3 % aaD = - 22.7 (MeOH, c = 0.51).

(+V(25 .R -2-Aii.mo-3-hvd^ one dihvdrochloride Compound 204. 122 Compound 204 MW: 308.20; 82 mg obtained; Yield: 23.5 %; White Solid; Mp (°C): 176.9 Enantiomeric excess - 98.5 % a25D = + 23.1 (MeOH, c = l).

Preparation of f+ irgo-2-aTTiirio-3-hvdroxv- 1 -(pvirolidin- l-vlVS-ftl^phen-S-yDpropan-l-one hydrochloride Compound 205 and f- ½reo-2-amino-3-hvdroxy-l-(pmolidm-l^V3-(tMoph^ Compound 206.

Extraction of the free base: (±)-fArea-2-ammo -hydroxy^ yl)propan-l-one hydrochloride Compound 23 (243 mg, 0.88 mmol) was dissolved in 10 mL of a Na2C03 (10 %) solution and the aqueous mixture was then saturated with NaCl. The aqueous phase was extracted by 5 x 15 mL of a mixture CH2Cl2:2-PrOH = 9:1. The organic phase was dried over MgS04 and evaporated to afford 190 mg (90 %) of the free base of Compound 23.

Analytical chiral separation: 20 uL of a 1 mg/mL solution of Compound 23 were injected on an analytical Chiralpak AD: flow-rate = 1 mL/min, temperature = 25 °C, mobile phase: ethanol, detection by UV at 220 nm and by polarimeter, Rt (+) = 4.98 min, Rt (-) = 6.23 min, k (+) = 0.55, k (-) = 0.93, a = 1.17 and resolution Rs = 3.34. 123 Regeneration of the salt: After the chiral separation, about 70 mg of each enantiomer of the free base were dissolved in 100 mL of ethanol and 3.6 mL of HC1 (0.2 N, 2.5 eq) were added. The solvent was evaporated then 50 mL of ethanol were added and then removed in vacuo. The product was dissolved in 2 mL of methanol and 3 mL of ethyl acetate were added. The solvents were removed to give a white solid and then, the solids were dried over P2O5 under vacuum overnight.

Semi-preparative chiral separation: A 175 mg/mL solution of the free base was prepared and 6 xL of this solution were injected every 3 min on an analytical Chiralpak AD, flow-rate = 1 mL/min, mobile phase ethanol, detection by UV at 254 nm. 150 successive injections were done. The two main fractions were identified by UV and collected in two different flasks. The solvent was removed in vacuo at 30 °C. The resulting solid was dissolved in 50 mL of CH2C12 and then filtered on a 0.45 urn millipore membrane. After evaporation of CH2C12, the solid was dissolved in 50 mL of methanol and then filtered. The salt was regenerated according to the procedure reported above.

The enantiomeric purity of the products was checked by analytical injection of the regenerated salts: (+Vf¾reo-2-Arnino-3-hvdroxy- l-fpvrrolidin- l-vlV3-(thiophen-3-vnpro an- 1-one hydrochloride Compound 205. 124 MW: 276.78; 83 mg obtained; Yield: 34 %; White Solid; Mp (°C): too hygroscopic.

Enantiomeric excess = 99.5 % αΜη = + 20.4 (MeOH, c = 0.5). - >reo-2-Amino-3 -hydroxy- l-fyvrroUc^ one hydrochloride Compound 206.

HCI {-yth o Compound 206 MW: 276.78; 77 mg obtained; Yield: 32 %; White Solid; Mp (°Q: too hygroscopic.

Enantiomeric excess = 99.0 % o D = - 20.0 (MeOH, c = 0.52).

Preparation of (-) -threo-2-a o-3 -hydroxv-3 - ipvri din-3 - vl 1 -f pvrrolidin- 1 -vDpropan-l-one dihydrochloride Compound 207 and (+Vf¾reo-2-amino-3-hvdroxy-3 -fpyri din-3 -yll- 1 - ρνττοΐίάίη- 1 -yPpropan- 1 -one dihvdrochloride Compound 208.

Semi-preparative separation was performed on C!hiralpak AD (250x10 mm): The semi-preparative chiral separation needed three steps : First step A: A 80 mg mL solution of (±)-i tre(>-2-amino-3-hydroxy-3-(pyridin-3-yl)- l-(pyrrolidin- 1 -yl)propan- 1 -one Compound 20 free base (220 mg) racemate was prepared and 200 uL of this solution were injected every 8 125 rain on Qiiralpak AD, flow-rate = 4 mlVmin, mobile phase: ethanol, detection by UV at 290 nm. Two main fractions were collected after 13 successive injections: • 1 A containing about 61 mg of (-) enantiomer Compound 207 free base with ee > 97 %. • 2A containing about 135 mg of mixture +/- enantiomers in a 74/26 ratio.

Second step B: A 30 mg/mL solution of fraction 2A was prepared and 100 uL of mis solution were injected every 6 min on Chiralpak AD, flow-rate = 4 mUmin, mobile phase: ethanol, detection by UV at 290 nm. Two main fractions were collected after 45 successive injections: • IB containing about 27 mg of (-) enantiomer Compound 207 free base with ee > 97 %. • 2B containing about 105 mg of mixture (+)/(-) in a 93 7 ratio.

Third step C: A 15 mg/mL solution of fraction 2B was prepared and 250 uL of this solution were injected every 6 min on Chiralpak AD, flow-rate = 4 mlJmin, mobile phase: ethanol, detection by UV at 254 nm. Two main fractions were collected after 28 successive injections: • 1C containing about 7 mg of (-) enantiomer Compound 207 free base with ee > 97 %. • 2C containing about 89 mg of (+) enantiomer with ee > 97 %.

Fractions 1A, IB and 1C of (-) enantiomer Compound 207 free base were mixed together. Fraction 2C of (+) enantiomer Compound 208 free base was taken alone. For the both enantiomers, the solvent was removed in vacuo at 30 °C. The resulting solid was dissolved in 50 mL of CH2CI2 and then filtered on a 0.45 μιη millipore membrane. After evaporation of CH2CI2, the solid was dissolved in 50 mL of methanol and then filtered. The salt was regenerated 126 according to the procedure reported below. The intermediate fraction collected contains 25 mg of a mixture of the both enantiomers in 50/50 (+)/(-) ratio and some impurities.

Regeneration of the salt (dihydrochloride): After the chiral separation, about 90-95 mg of each enantiomers of the free base were dissolved in 100 mL of ethanol and 10 mL of HCI (0.2 N, 5 eq) were added. The solvent was evaporated and 50 mL of ethanol were added and then removed in vacuo. The product was dissolved in 1 mL of methanol and 5 mL of ethyl acetate were added to precipitate the salt. The solvents were removed to give a white solid and then, the solids were dried over P2O5 under vacuum overnight The enantiomeric purity of the products was checked by analytical HPLC injection of the regenerated dihydrochloride salts: ( -Vt^reo-2- Aj-i o-B-hvdroxv-S- vridin-S-vl 1 -(pvrrolidin- 1 -yPpropan- 1 -one dihydrochloride Compound 207.

Compound 207 MW: 308.20; 124 mg obtained; Yield: 43 %; White Solid; Mp (°C): 120.4 Enantiomeric excess = 97.8 % measured by HPLC at 220 nm (C!hiralpak AD) RT = 6.24 min, eluent ethanol, flow 1 mL/min. a25D = - 15.9 (MeOH, c = l). f+ /treo-2-Amino-3-hydroxv-3-(pvri dihydrochloride Compound 208.

Compound 208 MW: 308.20; 117 mg obtained; Yield: 40.5 %; White Solid; Mp (°C): 120.1 Enantiomeric excess = 98.0 % measured by HPLC at 220 nm (Chiralpak AD) RT = 7.39 min, eluent ethanol, flow 1 mlJmin. a25D = + 15.8 (MeOH, c = l).

Preparation of (±V^rgo-2-ammo-3-hvdroxy-3-(2-iodophenylVl-(pyrrolidin-l-vDpropan-l-one hydrochloride Compound 209.

VIB 01090A.

VIB 01090A was prepared in accordance with method D using 2-isocyano- 1 -(pyrrolidin- 1 -yl)ethanone SLA 09100 (327.9 mg, 2.155 mmol), potassium hydroxide (121 mg, 2.155 mmol) in methanol (2.2 mL) and 2-iodo-benzaldehyde (500 mg, 2.155 mmol). The solution was stirred for 3 h at 0 °C. After work-up the crude product was purified by column chromatography (florisil, EtOAcrMeOH = 9:1) to obtain after evaporation tra/w-(4, 5-dihydro-5-(2-iodophenyl)oxaz»l-4-yl)(pyrroUdin-l-yl)methanone VIB 01090A as a yellow oil (364 mg, 44 % yield). 128 VIB 01090A MW: 384.22; Yield: 44 %; Yellow Oil.

Rfi 0.51 (EtOAcrMeOH = 9:1). 1H-NMR (CDC13, δ): 1.85-2.07 (m, 4H, 2xCH2), 3.50-3.62 (m, 3H, CH2), 3.78-3.90 (m, IH, CHz), 4.57 (dd, IH, J= 5.6 Hz, J= 1.9 Hz, CH-N), 6.19 (d, IH, J - 5.6 Hz, CH-O), 7.05 (dt, IH, /= 7.7 Hz, J= 1.6 Hz, ArH), 7.15 (d, IH, J=> 1.9 Hz, HON), 7.27 (dd, IH, J= 7.9 Hz, 7-1.6 Hz, ArH), 739 (t, IH, /= 7.3 Hz, ArH), 7.87 (d, IH, J= 7.8 Hz, ArH). 13C-NMR (CDCI3, 6): 24.3, 26.0, 46.3, 46.6, 74.8, 84.4, 95.0, 126.5, 128.4, 129.9, 139.8, 142.2, 155.7, 167.1.

(± Areo-2-Armno-3-hydroxy-3^ one hydrochloride Compound 209.

Compound 209 was prepared following method E with ira^-(4,5-dfty(lro-5-(2-iodophenyl)oxazol-4-yl)^ VIB 01090A (0.345 g, 0.89 mmol), HCl 37 % (0.22 mL) and methanol (4 mL). After heating at 50 °C for 3 h and work-up, a trituration with EtOAc followed by filtration and drying afforded to (±)-iAreo-2-amino-3-hydroxy-3-(2-iodophenyl)-l-(pyrrolidin- 1 -yl)propan- 1 -one hydrochloride Compound 209 as a white solid (287 mg, 74 % yield).

Compound 209 MW: 396.65; Yield: 74 %; White Solid; Mp (°C): 164.0 1H-NMR (CD3OD, δ): 1.47-1.90 (m, 4H, 2xC¾), 1.95-2.10 (m, IH, C¾), 3.25-3.55 (m, 3H, 0¾), 4.23 (d, IH, J= 9.0 Hz, CH"N), 5.20 (d, IH, /= 9.0 129 Hz, CH-O), 7.11 (t, IH, /== 7.4 Hz, ArH), 7.50 (t, IH, J= 7.5 Hz, ArH), 7.78 (d, 2H, J= 7.9 Hz, ArH), 7.88 (d, 2H, 7= 7.7 Hz, ArH). 13C-NMR (CD3OD, δ): 24.8, 26.8, 47.8, 48.1, 58.6, 75.8, 98.3, 130.1, 130.8, 131.8, 141.1, 143.8, 165.6.

MS-ESI m/z (% rel. Int.): 360.9 ([MH]+, 100), 342.9 (40).

HPLC: Method A, detection UV 254 nm, Compound 209 RT = 3.88 nrin, peak area 97.8 %.

Preparation of f±Vf¾reo-2-ammo-3-hvdroxy-3-hvdroxy-3-f4-iodophenylVl-( p vrrolidin- 1 -vl½:opan- 1 -one dihvdrochloride Compound 210. fr¾.ws-(4.5-Dihvdro-5-(4-iodophen^ VIB 01090B.

VTB 01090B was prepared in accordance with method D using 2-isocyano-l-(pyrroUdin-l-yl)ethanone SLA 09100 (327.9 mg, 2.155 mmol), potassium hydroxide (121 mg, 2.155 mmol) in methanol (2.2 mL) and 4-iodobenzaldehyde (500 mg, 2.155 mmol). The solution was stirred for 3 h at 0 °C. After work-up, the crude product was washed in a minimum amount of MeOH and filtered to obtain after drying iranj-(4,5-dihydro-5-(4-iodophenyl)oxa∞l-4-yl)(pyrroUdin-l-yl)methanone VIB 01090B as a white solid (0.377 g, 52 % yield). (±yttans VIB 01090B MW: 384.22; Yield: 52 %; White Solid; Mp (°Q: 115.1 130 Ή-NMR (CDCI3, δ): 1.75-2.10 (m, 4H, 2xCH2), 3.35-3.60 (m, 3H, C¾), 3.88-4.02 (m, 1H, CH2), 4.53 (dd, 1H, J= 7.7 Hz, J= 1.9 Hz, CH- ), 6.09 (d, 1H, J = 7.7 Hz, CH-O), 6.92-7.11 (m, 3H, 2xArH & CH=N), 7.69-7.70 (dd, 2H, /= 8.4 Hz, J= 1.7 Hz, ArH). ,3C- MR (CDC13, δ): 24.1, 26.0, 46.2, 46.4, 75.7, 80.8, 94.0, 127.6 (2xC), 137.9 (2xC), 139.4, 155.2, 166.4. vDpropan-l-one dihvdrochloride Compound 210.

Compound 210 was prepared following method E with trans-(4,5-dmydro-5-(4-iodophenyl)oxazol-4-yl)(p^ VIB 01090B (0.345 g, 0.89 mmol), hydrochloric acid 37 % (0.24 mL) and methanol (4.4 mL). After heating at 50 °C for 3 h and work-up, a trituration with EtOAc followed by filtration and drying afforded to (±)-tAreo-2-amino-3 -hydroxy-3 -(4-iodophenyl)-l-(pyirolidin-l-yl)propan-l-one hydrochloride Compound 210 as a white solid (247.5 mg, 64 % yield).

Compound 210 MW: 396.65; Yield: 64 %; White Sohd; Mp (°C): 184.4 1H-NMR (CD3OD, δ): 1.35-1.9 (m, 4H, 2xCH2), 2.20-2.33 (m, 1H, CH2), 3.18-3.40 (m, 3H, CH2), 4.11 (d, 1H, 8.9 Hz, CH'N), 4.82 (d, 1H, = 8.9 Hz, CH-O), 7.22 (d, 2H, J= 8.2 Hz, ArH), 7.76 (d, 2H, J= 8.2 Hz, ArH).

"C-NMR (CD3OD, δ): 24.8, 26.6, 47.3, 47.7, 59.2, 73.6, 95.1, 129.8 (2xC), 138.9 (2xQ, 140.6, 166.1. 131 MS-ESI m/z (% rel. Int.): 360.9 (|MH]+, 100), 342.9 (85).

HPLC: Method A, detection UV 254 nm, Compound 210 RT = 4.08 mm, peak area 96.8%.

Preparation of f±V/¾reo-2-amino-3-hvdroxv-3-('3-iodophenvlV 1 -rpvrrolidin- 1 -vDpropan-l-one hydrochloride Compound 211. fra¾. 4.5-dmvdro-5-f3-iodophenyl)ox SLA 09104.

To a stirred and cooled (0 °C) solution of KOH (0.144 g, 2.57 mmol) in methanol (10 mL) was added 3-iodobenzaldehyde (0.500 mg, 2.15 mmol) and 1 -i8ocyano-3-(pyiTolidin- 1 -yl)propan-2-one (0.295 g, 2.13 mmol). The solution was stirred 24 h with continued cooling and then concentrated. Water (50 mL) was added and the solution was extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine (50 mL), dried over MgSC«4, filtered and evaporated. frans-(4,5-Dmydro-5-(3-iodophenyty^ yl)methanone SLA 09104 was obtained (0.63 g, 80 % yield) as a pale yellow solid.

SLA 09104 MW: 370.19; Yield: 80 %; Pale Yellow Solid. Ή-NMR (CDCI3, δ): 1.80-2.08 (m, 4H, 2xC¾), 3.42-3.58 (m, 3H, 1.5xC¾), 3.90-3.96 (m, IH, 0.5χΟ¾), 4.56 (dd, IH, /= 7.7 Hz, J= 2.2 Hz, CH-N), 6.10 132 (d, 1H, J° 7.7 Hz, CH-O), 7.01 (d, 1H, J= 2.2 Hz, CH=N), 7.11 (t, 1H, J= 6.8 Hz, ArH), 7.29 (m, 1H, ArH), 7.66 (m, 2H, ArH).

"C-NMR (CDa3, δ): 24.2, 26.0, 46.5, 46.6, 75.8, 80.4, 94.7, 125.0, 130.6, 134.6, 137.5, 142.0, 155.2, 166.3. one hydrochloride Compound 211. /ra/is-(4,5-D ydro-5-(3-iodophenyl)^ yl)methanone SLA 09104 (0.620 g, 1.67 mmol) was dissolved in methanol (5 mL). The solution was stirred at room temperature and a solution of HCl (37 %, 1 mL) was added via syringe and the mixture was stirred at 50 °C for 6 h. The mixture was concentrated and triturated with EtOAc. After filtration and drying (±)-tAre< 2-aniino-3-hydroxy-3-(3-iodophra^ hydrochloride Compound 211 was obtained (586 mg, 88 % yield) as a white solid.

Compound 211 MW: 396.65; Yield: 88 %; White Solid; Mp (°C): 183.7 1H-NMR (CD3OD, δ): 1.35-1.50 (m, 1H, 0.5xC¾), 1.58-1.82 (m, 3H, 1.5xCH2), 2.08-2.18 (m, 1H, 0.5xCH2), 3.21-3.45 (m, 4H, 2χΟ¾), 4.09 (d, 1H, J= 9.1 Hz, CH-N), 4.80 (d, 1H, 7= 9.2 Hz, CH-O), 7.19 (t, 1H, J= 7.1 Hz, ArH), 7.49 (d, 1H, J= 7.6 Hz, ArH), 7.74 (m, 2H, ArH).

MS-ESI m/z (% rel. Int.): 360.9 (PVTH]+, 100), 342.9 (40).

HPLC: Method A, detection UV 254 nm, Compound 211 RT = 4.07 min, peak area 93.4 %. 133 Preparation of (±yf¾rgrt-2-aTniiio-3-hvdroxy-l-i4-m ( vn'rii-n- -vPpropan- 1 -one trihvdrochloride Compound 212. 2-Isocvano- 1 -f4-methvl-piperazin- 1 -vlVethanone VIB 01128.

Prepared in accordance with Method B with methyl isocyanoacetate (1.0 g, 10.09 mmol) and JNT-methylpiperazine (1.37 mL, 15.14 mmol). The reaction mixture was stirred overnight at RT and then concentrated. The residue was dissolved in dichloromethane (50 mL) and evaporated. The residue was coevaporated three times with a mixture of CEbCfocyclohexane = 50:50 (3x10 mL). After drying 2 socyano-l-(4-methyl-piperazin-l-yl)-ethanone VIB 01128 was obtained as yellow solid (1.67 g, 99 % yield).

VIB 01128 MW: 167.21; Yield: 99 %; Yellow Solid; Mp (°C) = 106.0 Ή NMR (CDCI3, δ): 2.32 (m, 3H, Me) 2.38-2.50 (m, 4H, 2xCH2), 3.42 (t, 2H, J = 4.7 Hz, CHa), 3.66 (t, 2H, J= 4.7 Hz, C¾), 4.30 (s, 2H, (¾). 13C-NMR(CDC13, δ): 42.4, 44.4, 45.5, 46.0, 54.3, 54.5, 160.8, 161.2. vnmethanone VIB 01130.

To a stirred and cooled (0 °C) solution of KOH (0.335 g, 5.98 mmol) in 7 mL MeOH were added successively pyridine-4-carbaldehyde (0.705 g, 6.58 mmol) and 2-isocyano- 1 -(4-methyl-piperazin- l-yl)-ethanone VIB 01128 (1.00 134 g, 6.58 mmol). The mixture was stirred at 0 °C until precipitation and concentrated. The mixture was partitioned between EtOAc (20 mL) and H20 (10 mL). The aqueous layer was extracted twice with EtOAc (60 mL). The EtOAc fractions were combined, washed twice with brine (2x10 mL), dried over MgS04 and filtered. After evaporation and drying /ra i1s'-(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(4-methylpiperazin- 1 -yl)methanone VIB 01130 was obtained (1.282 g, 78 % yield) as a yellow oil.

VIB 01130 MW: 274.32; Yield: 78 %; Yellow Oil. 1H N R (CDC13, δ): 2.32 (m, 3H, Me) 2.35-2.58 (m, 4H, 2xC¾), 3.50-3.70 (m, 2H, C¾-N), 3.80-4.00 (m, 2H, CH2-N), 4.59 (dd, IH, J= 7.8 Hz, J= 2.2 Hz, CH-N), 6.27 (d, IH, J= 7.8 Hz, O-CH), 7.02 (d, IH, J= 2.2 Hz, OCH=N), 7.23 (d, 2H, J= 4.7 Hz, ArH) , 8.62 (dd, 2H, J= 4.5 Hz, J= 1.6 Hz, ArH). 13C-NMR (CDCI3, δ): 42.6, 45.7, 46.0, 54.6, 55.1, 74.7, 79.6, 120.0 (2xQ, 148.6, 150.3 (2xC), 154.8, 166.0.

MS-ESI m/z (% rel. Int.): 275.2 ([MHf, 40), 190.1 (35), 147.0 (40), 127.0 (100).

HPLC: Method A, detection UV 254 nm, VTB 01130 RT = 0.70 mm, peak area 99.9 %. (■fcV^reQ-2-Arnmo-3-hvdroxy-l-f4-memylpiDerazm-l-ylV3-fpyrio^ yPpropan-l-one trihvdrochloride Compound 212.

To a solution of rrfl/ts-(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(4-methylpiperazin-l-yl)methanone VIB 01130 (1.235 g, 4.50 mmol) in MeOH 135 (15 mL) was added HC137 % (1.6 mL). After heating (50 °C) the mixture for 3.5 h a white solid precipitated and the reaction mixture was concentrated and the crude product was coevaporated twice with ethyl acetate. After trituration with ethyl acetate, filtration and drying, (±)-fAreo-2-ammo-3-hydroxy-l-(4-methylpiperazan-l-yl)-3-(pyrid^ Compound 212 (1.62 g, 96 % yield) was obtained as a white solid.

Compound 212 MW: 373.71; Yield: 96 %; White Solid; Mp (°C): 203.1 ^-NMR (CD3OD, 5): 2.95 (s, 3H, Me), 3.10-3.40 (m, 4H, 2xQ¾), 3.48-3.80 (m, 2H, CH2), 4.19-4.49 (m, 1H, 0.5χΟ½), 4.51-4.79 (m, 1H, O.SxCHa), 5.06 (d, 1H, J = 4.3 Hz, CH-NH2), 5.35-5.63 (m, 1H, CH-O), 8.30 (s broad, 2H, ArH), 8.95 (d, 2H, J= 6.7 Hz, ArH).

MS-ESI m/z (% rel. Int): 265.1 ([MH , 5), 248.1 (20), 156.1 (20), 148.0 (100). HPLC: Method A, detection UV 254 nm, Compound 212 RT - 0.68 min, peak area 99.9 %.

Preparation of ^ t^rgcH2-arnino- l- J-difluoronvrrolidin- l-vlV3-hvdroxv-3-^yridin^-ynpropan-l-one dihvdrochloride Compound 213. l-fSJ-Difluoropyn-ohdm-l-v^-isocvanoethanone VIB 01158.

To stirred and cooled (0 °C) methyl isocyanoacetate (96 % technical grade, 345 mg, 3.48 mmol) was slowly added 3,3-diiluoropyrrolidine hydrochloride (500 mg, 3.48 mmol), trietiiylamine (487 |iL, 3.48 mmol) and 136 MeOH (1 mL). The mixture was stirred for 15 h at RT and then concentrated. The resulting oil was coevaporated twice from EtOAc. l-(3,3- Diiluoropyirolidin-l-yl)-2-isocyanoethanone VIB 01158 was obtained as a yellow oil (305 mg, 60 % yield) and used in the next step without purification.

VIB 01158 MW: 174.17; Yield: 60 %; Yellow Oil. 1H NMR (CDC13> 5): 2.30-2.62 (m, 2H, CH2) 3.65-3.90 (m, 4H, C¾), 4 5 (d, 2H,J= 17.5 Hz, CH2). frg/Ly-G^-DifluoropyrroKdm-l-yl^ vnmethanone VIB 01160.

To a stirred and cooled (0 °C) solution of KOH (0.098 g, 1.75 mmol) in MeOH (2 mL) were added successively pyridine-4-carbaldehyde (0.206 g 1.92 mmol) and l-(3,3-difluoTopyrrolid^-l-yl)-2-isocyanoethanone VEB 01158 (0.305 g, 1.75 mmol). The mixture was stirred at 0 °C for 3 h. After evaporation of MeOH, the rnixture was partitioned between EtOAc (50 mL) and ¾0 (40 mL). The aqueous layer was extracted with EtOAc (4x50 mL). The fractions were combined, washed twice with brine (2x20 mL), dried over MgS04 and filtered. After evaporation and drying /roni-(3,3-difluorc^yTolidin-l-yl)(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)methanone VIB 01160 (0.33 g, 67 % yield) was obtained as a yellow oil.

VIB 01160 137 MW: 281.26; Yield: 67 %; Yellow Oil. Ή NMR (CDCI3, 5): 2.30-2.60 (m, 2H, CH2) 3.67-3.99 (m, 3H, l.SxCHj), 4.22- 4.59 (m, 2H, CH-N & 0.5xC¾), 6.17 (d, IH, J= 7.8 Hz, CH-O), 7.04 (dd, IH, J= 3.2 Hz, J= 2.5 Hz, HC=N), 7.20-7.38 (m, 2H, ArH), 8.55-8.70 (m, 2H, ArH). yl)propan-l-one dihydrochloride Compound 213.

To a solution of ira»s-(3,3-diiluoropyiTolia¼-l-yl)(4,5-diliydro-5- (pyridin-4-yl)oxazol-4-yl)methanone VLB 01160 (0.305 g, 1.08 mmol) in methanol (4 mL) was added hydrochloric acid 37 % (395 μΐ,). After heating (50°C) the mixture for 3.5 h the reaction mixture was concentrated and the crude product was coevaporated twice with EtOAc. After trituration with EtOAc, filtration and drying, (±)-iAreo-2-armno-l-(3,3-difluoropyrroUdin-l-yl 3-hydroxy-3-(pyridin-4-yl)propan-l-one dihydrochloride Compound 213 (269 mg, 44 % yield) was ohtained as a beige solid. 2HCI (±) Compound 213 MW: 344.19; Yield: 44 %; Beige Solid; Mp (°Q: 182.2 1H-NMR (CD3OD, δ): 2.25-2.62 (m, 2H, CH2), 3.30-4.20 (m, 4H, CH2), 4.55 (d, IH, J= 5.5 Hz , 0.35xCH-N), 4.66 (d, IH, J= 5.5 Hz , 0.65xCH"N), 5.42 (m, IH, CH-O), 8.23 (d, 2H, J= 4.8 Hz, ArH), 8.94 (d, 2H, 7= 5.9 Hz, ArH).

MS-ESI m/z (% rel. Int.): 272.2 ([MH]+, 15), 254.1 (15), 178.1 (20), 148.1 (100), 137.1 (95). 138 HPLC: gradient of solvent B:solvent A = 5:95 to 100% solvent B in 7 min. Solvent A was H20 with 0.1 % Et3N and solvent B was CH3CN with 0.1 % Et3N; detection UV 254 nm, Compound 213 RT = 4.70 min, peak area 98.1 %.

Preparation of(2S3R)- & (2R.3iS^-2-arrimo-l- riy)-3-fluoropyrroli(nn-l-ylV3- hvdroxy-3-(pyrifln-4-yr)propan-l-one dihvdrochlorides Compounds 214. l-( -SV3-Fluoropwolidm-l-ylV2-isocvanoethanone VIB 01166.

To stirred and cooled (0 °C) methyl isocyanoacetate (96 % technical grade, 1,18 g, 11.9 rnmol) was slowly added (iS)-(+ 3-fluorc^yiroUdine hydrochloride (97%, 1.5 g, 11.9 mmol), trie ylarnine (1.67 mL, 11.9 mmol) and MeOH (3 mL). The mixture was stirred for 15 h at RT and concentrated. The mixture was stirred for 15 h at RT and concentrated. Water was added (50 mL) and the mixture was extracted with EtOAc (3x50 mL), dried over MgSO-i, filtered and evaporated to obtained crude l-((iS)-3-fluoropyrrolidin-l-yl)-2-isocyanoethanone VEB 01166 (1.47 g, 79 % yield) as a brown oil which was used in the next step without purification.

MW: 156.152; Yield: 79 %; Brown Oil. lHNMR (CDCl3, δ): 1.85-2.50 (m, 2H, C¾), 3.40-4.35 (m, 6H, 3xCH2), 5.17-5.47 (m, 1H, CHF).

MS-ESI m/z (% rel. Int.): 171.1 ([MH+ -Na], 100), 157.1 (p GHf , 82), 130.1 (95). 139 trans-((S)-3-nuoTap\no]i0 )((4SSK)- & 4ig.5,SV4.5-dmvdro-5-(p\ridin-4- vDoxazol-4-yr)methanones VEB 01168, To a stirred and cooled (0 °C) solution of KOH (0.526 g, 9.39 mmol) in MeOH (10 mL) were added successively pyridine-4-carbaldehyde (1.10 g, 10.33 mmol) and l-((5)-3-fluoropyrroHoin-l-yl)-2-isocyanoe11ianone VIB 01166 (1.47 g, 9.39 mmol). The mixture was stirred at 0 °C to RT for 24 h. After evaporation of MeOH, the mixture was partitioned between EtOAc (40 mL) and ¾0 (20 mL). The aqueous layer was extracted with EtOAc (6x40 mL). The EtOAc fractions were combined, washed twice with brine (2x10 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography (florisil, EtOAc:MeOH = 9: 1). After evaporation and drying ^c^-((i¾-3-fluoropyrroUdin-l-yl)((45,5i?)- & 4R,55)-4,5-dihydro-5- fcyridm-4-yl)oxazol-4-yl)methanones VIB 01168 (590 mg, diastereoisomeric mixture in ratio 1 : 1, 24 % yield) were obtained as a yellow oil.

VIB 01168 MW: 26327; Yield: 24 %; Yellow Oil. 1HNMR(CDC13, δ): 1.89-2.46 (m, 2H, CH2) 3.5-4.45 (m, 4H, CH2), 4.46-4.60 (m, IH, CH-N), 5.16-5.45 (m, IH, CH-F), 6.12-625 (m, IH, CH-O), 6.95-7.18 (m, IH, CH=N), 7.20-7.40 (m, 2H, ArH), 8.50-8.70 (m, 2H, ArH). (2S.3K)- & (2R ^-2-Amino-l-ff^-3-fluorop\aroH(hn-l-ylV3-hvdroxy-3-(pyridin-4-yl)propgn-l-one dihydrochlorides Compounds 214.

To a solution of ((^-S-fluoropyrrolidin-l-y ^S ?)- & 4R,55)-4»5-dmydro-5-( yridin-4-yl)oxazol-4-yl)methanones VIB 01168 (0.590 g, 2.24 140 mmol) in methanol (8 mL) was added hydrochloric acid 37 % (686 uL). After heating (50 °C) the mixture for 3.5 h the reaction mixture was concentrated and the crude product was coevaporated twice with EtOAc. After trituration with EtOAc, filtration and cJrying (2S,3R)- & (2/,,35 2-arnino-l-((iS)-3- fluoropynolia¾-l-yl)-3-hydroxy-3-(pyri(hn-4-yl)propan-l-one dihydrochlorides Compounds 214 (474 mg, diastereoisomeric mixture in ratio 1 : 1, 68 % yield) were obtained as a pale yellow solid. threo threo Compounds 214 MW: 326.2; Yield: 68 %; Pale Yellow Solid; Mp (°C): 173.1. 1H-NMR (CD3OD, 6): 1.82-2.38 (m, 2H, C¾), 2.80-4.15 (m, 4HS 2xCH2), 4.35-4.68 (m, 1H, CH"N), 5.00-5.50 (m, 2H, CH-0 & CH-F), 8.11-8.32 (m, 2H, ArH), 8.82-9.00 (m, 2H, ArH).

MS-ESI m/z (% rel. Int.): 254.2 ([MH]+, 15), 237.1 (20), 148.1(100), 137.1 (70).

HPLC: gradient of solvent B:solvent A = 5:95 to 100% solvent B in 7 min. Solvent A was HzO with 0.1 % Et3N and solvent B was CH3CN with 0.1 % Et3N; detection UV 254 nm, Compounds 214 RT = 4.35 rnin, peak area 99.0 %.

Preparation of (2S.3RY & r2ig.3^-2-ammo-l-ffflV3-fluoroDmolidin-l-ylV3-hydroxy-3-(pyridin-4-yl)propan-l-one dihydrochlorides Compounds 215. l-frRV3-Fluoropmolidin-l-ylV2-isocvanoethanone BLE 04170, 141 To stirred and cooled (0 °C) methyl isocyanoacetate (96 % technical grade, 0.79 g, 7.96 mmol) was slowly added (i?)-(-)-3-fluoropyrrolidine hydrochloride (1.0 g, 7.96 mmol), triethylamine (1.11 mL, 7.96 mmol) and MeOH (2.5 mL). The mixture was stirred for 15 h at RT and concentrated. Water was added (50 mL) and the mixture was extracted with EtOAc (3x50 mL), dried over MgS04, filtered and evaporated to obtained crude 1-((Λ)-3- fluoropyrrolidin-l-yl)-2-isocyanoethanone BLE 04170 as a brown oil (0.96 g, 77 % yield) which was used in the next step without further purification.

MW: 156.152; Yield: 77 %; Brown Oil. 1H MR (CDCI3, δ): 1.85-2.50 (m, 2H, CH2), 3.40-4.35 (m, 6H, 3xCH2), 5.17- 5.47 (m, 1H, CHF). trans-((R)-3-muoTov o]i0mA )((4S.5R\- & 4^.5^-4.5-(iihvdro-5-(pyridin-4-vDoxazol-4-vnmethanones BLE 04172.

To a stirred and cooled (0 °C) solution of KOH (0.34 g, 6.06 mmol) in MeOH (4.5 mL) were added successively pyridine-4-carbaldehyde (0.71 g, 6.66 mmol) and a solution of BLE 04170 (0.95 g, 6.06 mmol) in MeOH (2.5 mL). The mixture was stirred at 0 °C to RT for 15 h. After evaporation of MeOH, the mixture was partitioned between EtOAc (40 mL) and H20 (20 mL). The aqueous layer was extracted with EtOAc (3x40 mL). The EtOAc fractions were combined, washed withbrine (50 mL), dried over MgS0 , filtered and evaporated. The crude product was purified by column chromatography (florisil, EtOAc:MeOH = 9:1). After evaporation and drying trans-((R)-3-fluoropyrrohdin-l-ylX^SjSR)- & 4i?,5jS)-4,5-dmydro-5-^yridin-4-yl)oxazol-4- 142 yl)methanones BLE 04172 (653 mg, diastereoisomeric mixture in ratio 1:1, 41 % yield) were obtained as a colorless oil. trans trans BLE 04172 MW: 263.27; Yield: 41 %; Colorless Oil.

!H NMR (CDC13, δ): 1.89-2.46 (m, 2H, C¾) 3.5-4.45 (m, 4H, 2xC¾), 4.46- 4.60 (m, IH, CH-N), 5.16-5.45 (m, IH, CH-F), 6.12-6.25 (m, IH, CH-O), 6.95-7.18 (m, IH, CH=N), 7.20-7.40 (m, 2H, ArH), 8.50-8.70 (m, 2H, ArH). (2S.3R)- & (2R.3iS 2-Amino-l-rf^V3-fluoropmoHdm-l-ylV3-hvdroxy-3-foyridm-4-yl)propan-l-one dihydrochlorides Compounds 215.

To a solution of franj-^-S-fluOTo yrrolidm-l-yl)^^^)- & 4R,5S)-4,5-dmydro-5-( yridm-4-yl)oxazol-4-yl)methanones BLE 04172 (0.65 g, 2.47 mmol) in methanol (8 mL) was added hydrochloric acid 37 % (757 uL). After heating (50 °C) the mixture for 3.5 h the reaction mixture was concentrated and the crude product was coevaporated twice with EtOAc. After trituration with EtOAc, filtration and drying {2S,3R)- & (^S -a ino-l-K-XyS-fluoropyrroh^-l-yl)-3-hydroxy-3-(py^ dihydrochlorides Compounds 215 (544 mg, diastereoisomeric mixture in ratio 1 : 1, 68 % yield) were obtained as a pale yellow solid. threo threo Compounds 215 143 MW: 326.2; Yield: 68 %; Pale Yellow Solid; Mp (°C): 134.5 'H- MR^CDjOD, 5): 1.82-2.38 (m, 2H, C¾), 2.80-4.15 (m, 4H, C¾), 4.35- 4.68 (m, 1H, CH- ), 5.00-5.50 (m, 2H, CH-0 & CHF), 8.11-8.32 (m, 2H, ArH), 8.82-9.00 (m, 2H, ArH).

Preparation ofN-(i-fcVfAreo-l-hydroxy-3-oxo-l-(py^ yl)propan-2-yl formainide hydrochloride Compound 216. anj-(4,5-D ydro-5-(pyrio¾^-yl)oxa∞^ yl)methanone Compound 19 (0.200 g, 0.81 mmol) was dissolved in methanol (5 mL). Dowex 50WX8-200 (0.5 mL, washed beforehand by a 0.5 M solution of HCI then water) was added at RT. The mixture was stirred for 1 h at 50 °C and after cooling was filtered off. MeOH was evaporated and the residue was dried to give 150 mg of a pasty product (150 mg, 61.0 % yield). The free base form was dissolved in a rninimum of a mixture of EtOAc:MeOH = 95:5 and a 0.4 M solution of HCI in ether (1.3 mL, 0.52 mmol) Was added at + 4 °C. After evaporation of solvents, the product was precipitated with diethyl ether, filtered and dried to obtamN-((±)-iArei l-hydroxy-3-oxo-l-^yridin-4-yl)-3-(pyiTolidm-l-yl)propan-2-yl)formamide hydrochloride Compound 216 as a beige solid (100 mg, 41 ,0 % yield).

HCI (±) Compound 216 MW: 299.75; Yield: 41.0 %; Beige Solid; Mp (°C): 203.1 R . 0.35 (C¾Cl2:MeOH = 90:10) free base. 144 1H-NMR (CD3OD, δ): 1.87-2.00 (m, 4H, 2xC¾), 3.41-3.46 (m, 2H, C¾-N), 3.62-3.66 (m, 2H, C¾-N), 5.18 (d, IH, J= 3.6 Hz, CH-N), 5.40 (d, IH, J= 3.8 Hz, CH-O), 7.99 (s, IH, CHO), 8.16 (d, 2H, J= 5.8 Hz, ArH), 8.81 (d, 2H, J= 5.5 Hz, ArH). 13C-NMR (CD30D, δ): 25.0, 27.0, 47.5, 48.3, 55.6, 72.4, 126.6 (2xC), 142.1 (2xQ, 163.4, 164.1, 168.5.

MS-ESI m z (% rel. Int): 264.1 ([MH]+, 10), 148.0 (100).

HPLC: Method A, detection UV 254 nm, Compound 216 RT = 1.30 min, peak area 98.0 %.

Preparation of N-( (± /;reo-2-acetoxy-2-pyridm-4-yl- l-foyrrolidine- 1 - carbonylVethylVformamide hydrochloride Compound 217.

N-((±)- re0-l-hydroxy-3-oxo-l-te^ 2-yl)formarnide hydrochloride Compound 216 (0.220 g, 0.80 mmol) was dissolved in CH2C12 (10 mL) with triemylamine (280 uL, 2 mmol) at 0 °C. Then acetic anhydride (160 uL, 1.6 mmol) was added slowly and the mixture was stirred for 72 h at RT. The solvent was evaporated and the residue was dried under vacuum. After column chromatography (Si02, EtOAc:MeOH = 90: 10) to give a pasty product (100 mg, 41% yield). The product obtained was dissolved in MeOH (10 mL) and a solution of HC1 (0.4 M, 1 mL) in Et20 was added at 0 °C. Evaporation of the volatiles led to acetic acid N-((±)-iAreo-2-acetoxy-2-pyridm-4-yl-l-(pyn h"dme-l-car^^ Compound 217 was obtained as a white solid (110 mg, 40 % yield). 145 Compound 217 MW: 341.79; Yield: 40.0 %; White Solid; Mp (°C): 173.9.

R/: 0.25 (EtOAc:MeOH = 90: 10, free base). 1H-NMR (CD3OD,6): 1.80-2.00 (m, 4H, 2xC¾), 2.19 (s, 3H, CH3) 3.29-3.64 (m, 4H, 2xC¾-N), 5.34 (s, IH, N-CH), 6.44 (s, IH, O-CH), 8.01 (s, IH, CHO), 8.16 (s, 2H, ArH), 8.85 (s, 2H, ArH). l3C- M (CD3OD, δ): 20.5, 25.0, 27.0, 47.6, 47.7, 53.9, 73.4, 126.7 (2xC), 142.8 (2xC), 144.3, 163.3, 166.9, 170.9.

MS-ESI m/z (% rel. Int.): 306.1 ([MH]+, 10), 261.1 (100).

HPLC: Method A, detection UV 254 nrn, Compound 217 RT = 0.90 min, peak area 97.0 %.

Preparation of fe -butyl ^- Vf¾reo-l-hv0^oxy-3-oxo-l-(p\ddin-4-ylV3-^yrroHdin-l-yl propan-2-ylcarbarnate hydrochloride Compound 218. (±)-iAreo-2-Armno-3-hydroxy-3-(pyridm-4-yl)-l-^yn 1-one dihydrochloride Compound 22 (2.90 g, 9.3 mmol) was dissolved in CH2C12 (250 mL) with Et3N (4.3 mL, 30.7 mmol) at 0 °C. Di-teri-butyl dicarbonate (2.45 g, 11.2 mmol) in CH2C12 (50 mL) was added slowly and the mixture was stirred for 15 h at RT. Brine (50 mL) was added and the product was extracted with CH2C12. After drying over M S0 and filtration, CH2C12 was evaporated and the residue was dried in vacuum. After column chromatography (Si02, EtOAc.-MeOH = 90:10), terf-butyl (±)-/Areo-l-hydroxy-3-oxo-l-(pyridm-4-yl)-3-(pynOH^ TTA 08100 was 146 obtained as a beige solid (2.00 g, 64 % yield). A Sample of TTA 08100 (55 mg) was dissolved in CH2CI2 (1 mL) and Et20 (30 mL) and a solution of HCl (0.1 M, 2 mL) in El^O was added at 0 °C. Evaporation of the volatiles led to ferf-butyl (±)-i¾reo-l-hydroxy-3-oxo-l-(pyridm-4-yl)-3-(pyrrolidin-l- yl)propan-2-ylcarbamate hydrochloride Compound 218 (50 mg, 52% yield) as a white solid.

Compound 218 MW; 371.86; Yield: 52.0 %; White Solid; Mp (°C): 141.2. fy: 0.30 (EtOAc:MeOH = 90:10, free base). 1H-NMR (CD3OD, 6): 1.33 (s, 9H, 3xC¾) 1.91-2.00 (m, 4H, 2xCH2), 3.44- 3.49 (m, 2H, Ciy, 3.60-3.64 (m, 2H, 0¾-Ν), 4.78 (s, IH, N-CH), 5.38 (s, IH, O-CH), 8.16 (s, 2H, ArH), 8.83 (s, 2H, ArH). 13C-NMR (CD3OD, δ): 25.0, 27.1, 28.5 (3xC), 47.5, 48.0, 58.3, 72.8, 81.0, 126.7 (2xC), 142.0 (2xC), 157.3, 164.6, 169.5.

MS-ESI m z (% rel. Int.): 336.1 ([MH]+, 20), 219.1 (100).

HPLC: Method A, detection UV 254 nm, Compound 218 RT - 3.8 min, peak area 98.0 %. yl)propan-l-one dihvdrochloride Compound 219. fe -Butyl f±V^reo-l-hvdroxy-3-oxo-l-^yridin-4-ylV3-fpyrrolidin-l-vnpropan-2-ylcarbamate VIB 01080, 147 To a solution of (±)-^reo-2-armno-3-hydroxy-3-(pyridin-4-yl)-l- (pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 22 (3.25 g, 10.54 mmol) in CH2G2 (250 mL) in a 500 mL round bottom flask equipped with a magnetic stirrer and under nitrogen atmosphere was added via syringe at 0 °C triethylarnine (4.69 mL, 33.73 mmol). A solution of di-tert-butyldicarbonate (2.76 g, 12.65 mmol) in CH2C12 (75 mL) was added at 0 °C dropwise via a dropping funnel. The reaction mixture was abandoned at 0° C for 2 h then at RT overnight. A solution of brine (130 mL) was added and the solution was extracted with CH2C12 (3 x 75 mL), dried over MgS04, filtered and evaporated. The crude product was purified by column chromatography (Si02, EtOAc:MeOH = 90:10). After evaporation to dryness of the combined fractions, ferf-butyl (±)-threo- l-hydroxy-3-oxo- l-(pyridm^yl)-3-(pyirolidin- 1- yl)propan-2-ylcarbamate VIB 01080 (2.79 g, 79 % yield) was obtained as a yellow solid.

MW: 335.4; Yield: 79 %; Yellow Solid; Mp (°C): 160.5 : 0.31 (EtOAc:MeOH = 90:10).

'H-NMR (CDCI3, δ: 1.26 (s, 9H, 3xCH3), 1.71-2.00 (m, 4H, 2xCH2), 3.25-3.60 (m, 4H, 2xCH2N), 4.61 (dd, IH, J= 9.8 Hz, J= 2.6 Hz, N-CH), 4.96 (s, IH, OH), 5.08 (d, IH, J= 2.6 Hz, NH), 5.47 (d, IH, J= 9.8 Hz, O-CH), 7.35 (d, 2H, J= 5.7 Hz, ArH), 8.58 (d, 2H, J- 5.4 Hz, ArH). 13C-NMR (CDC13, δ): 24.0 (2xC), 25.9 (2xC), 28.1 (3xC), 46.1, 46.7, 56.1, 60.4, 72.8, 80.2, 121.4 (2xC), 148.7, 149.5 (2xC), 155.6, 169.4. 148 MS-ESIm/z (% rel. Int.): 336.1 ([MH]+, 45), 280 (18), 219 (100); 148 (38). fert-Butyl (±)-1.3-dioxo-3-(pyridin-4-yl)-l-(pyrroKdin-l-yl')propan--2- ylcarbamate TTA 08120.

To a solution of ter/-butyl (±)-/Areo-l-hydroxy-3-oxo-l-(pyridin-4-yl)-3- (pyrrolidin-l-yl)propan-2-ylcaTbarnate VIB 01080 (3.92 g, 11.70 mmol) in CH2C-2 (320 mL) in a 500 mL round bottom flask equipped with a magnetic stirrer and under nitrogen atmosphere was added slowly Dess-Martin periodinane (4.96 g, 11.70 mmol) at RT. The reaction mixture was stirred at RT for 0.5 h and CH2CI2, washed with a mixture of saturated sodium bicarbonate (100 mL), 1 M sodium thiosulfate (50 mL), brine (50 mL) and dried over MgSC>4, filtered and evaporated. Diethyl ether (250 mL) was added and the precipitate was filtered off. After evaporation of the filtrate, the crude product was purified by column chromatography (Si02, CEkCfe.'EtOAc - 4:6). After evaporation to dryness of the combined fractions tert-butyl (±)-l,3-dioxo-3- (pyri(nn-4-yl)-l-(pyrrolidm -yl)propan-2-ylcarbarm TTA 08120 (3.0 g, 77 % yield) was obtained as a white solid.

TTA 08120 MW: 333.38; Yield: 77 %; White Solid; Mp (°C): 125.4 /: 0.25 (CH2Cl2:EtOAc = 4:6).

'H-NMR (CDC13) δ): 1.36 (s, 9H, 3xCH3), 1.86-2.00 (m, 4H, 2xC¾), 3.47-3.71 (m, 4H, 2xC¾N), 5.62 (d, 1H, J= 7.4 Hz, N-CH), 6.07 (d, 1H, J= 7.4 Hz, NH), 7.80 (dd, 2H, J= 4.6 Hz, J= 1.3 Hz, ArH), 8.80 (dd, 2H, J= 4.5 Hz, J= 1.5 Hz, ArH). 149 ,3C-NMR (CDC13, δ): 24.0, 26.0, 28.1 (3xC), 46.8, 47.0, 1.0, 80.9, 121.5 (2xC), 141.4, 150.8 (2xC), 155.1, 163.8, 194.3.

MS-ESI m/z (% rel. Int.): 334.1 ([MH]+, 10), 173.1 (30), 129.1 (100). fert-Butyl f= Veryf¾ro-3-hvdroxy-l-oxo-3- p>ddin^-yl -l- pmoHdin-l- vDpropan-2-ylcarbamate TTA 08124P.

To a solution of tert-butyl (±)-l,3-dioxo-3-(pyridm^yl)-l-(pyiTolidin-l- yl)propan-2-ylcarbamate TTA 08120 (2.28 g, 6.80 mmol) in MeOH (50 mL) in a 250 mL round bottom flask equipped with a magnetic stirrer and under nitrogen atmosphere was added slowly sodium borohydride (285 mg, 7.50 mmol) at RT. The reaction mixture was stirred at RT for 0.5 h and was cooled at 4 °C. A solution of 2 M NaOH (10 mL) was added and MeOH was evaporated at 30 °C. EtOAc (300 mL) was added and the organic phase was washed with brine (20 mL), dried over MgS04, filtered and evaporated to give a crude compound (ratio erythr ithreo - 80:20 estimated by 1H NMR 300 MHz) TTA 08124 (2.1 g, 92 % yield). The crude product was recrystallized in EtOAc and after filtration and drying terf-butyl (±)-er ^Aro-3-hydroxy-l-oxo-3-(pyjidin-4-yl)-l-(pyrrolidin-l-yl)propan-2-ylcarbamate TTA 08124P (1.30 g, ratio er thro threo = 96:4 estimated by 1H NMR 300 MHz analysis, 57 % yield) was obtained as a white solid. (±)-etythto TTA 08124P MW: 335.40; Yield: 57 %; White Solid; Mp (°C): 170.3 150 Rf 0.45 (EtOAc : MeOH = 85:15).

'H-NMR CCDCk, δ): 1.43 (s, 9H, 3xCH3), 1.64-1.83 (m, 4H, 2xC¾), 2.88-2.96 (m, 1H, C¾N), 3.23-3.29 (m, 1H, CH2N), 3.34-3.43 (m, 1H, C¾N), 3,56-3.63 (m, 1H, CH2N), 4.66 (dd, 1H, J= 8.9 Hz, J= 3.7 Hz, N-CH), 4.91 (dd, 1H, J= 8.4 Hz, J= 3.4 Hz, O-CH), 5.42 (d, 1H, J= 8.8 Hz, OH), 5.75 (d, 1H, J= 8.8 Hz, NH), 7.30 (d, 2H, J= 5.9 Hz, ArH), 8.57 (d, 2H, J= 5.8 Hz, ArH). Ratio erythro'.threo = 96:4. 13C-NMR (CDC13, 6): 24.0, 25.7, 28.1 (3xC), 45.7, 46.8, 55.2, 74.5, 80.5, 120.9 (2xC), 149.6, 149.8 (2xC), 155.4, 168.8.

MS-ESI m/z (% rel. Int.): 336.1 ([MH]+, 10), 280.1 (20), 110.0 (100). f±Ven^¾ro-2-Amino-3-hvdroxy-3-(pyridin-4-yl)-l- one dihvdrochloride Compound 219.

To a solution of teri-butyl (±)-i?r ^Aro-3- ydroxy-l-oxo-3-(pyridin-4-yl)- l-(pyrroHdin-l-yl)propan-2-ylcarbarnate TTA 08124P (1.15 g, 3.40 mmol) in MeOH (30 rnL) in a 250 mL round bottom flask equipped with a magnetic stirrer was added HQ 37 % (3 mL, 35 mmol) at RT. The reaction mixture was stirred at RT for 0.4 h at 45 °C and MeOH was evaporated at 45 °C to give after drying, a white solid TTA 08136 (ratio erythro'.threo - 96:4 estimated by 1H NMR 300 MHz analysis). Amberlite IRA-400 (CO (10 g) was washed successively with water (2x10 mL), 0.5 N NaOH (3x20 mL), water (2x10 mL) and MeOH (3x10 mL). A solution of TTA 08136 in MeOH (30 mL) was stirred with washed Amberlite IRA-400 for 5 min at RT. After filtration, the MeOH was evaporated and the free base form was purified by column chromatography (Si02, CHCl3:EtOH 95° = 86:14) to give TTA 08136A (445 mg, 55 % yield) as a beige solid (no threo isomer detected by 1H NMR 300 MHz and HPLC). TTA 08136A (193 mg) was stirred at RT in ethyl acetate (5 mL) with a solution of 151 0.1 N HCl in isopropanol (17 mL). Solvents were evaporated at 33 °C, MeOH (0.5 mL) was added and the salt was precipitated by addition of EtOAc (20 mL) to give nearly quantitatively after filtration and drying (±)-e/yiAro-2-amino-3- hydroxy-3-(pyridm-4-yl)-l-(py^^ Compound 219 as a white solid (no threo isomer detected by 1H NMR 300 MHz and HPLC). 2.HCI (t erythro Compound 219 MW: 308.20; Yield: 55 %; White Solid; Mp (°C): 154.1. fy: 0.18 (CHCl3:EtOH 95° = 86:14, free base). 1H-NM (CD3OD, δ): 1.94-2.04 (m, 4H, 2xCH2), 3.45-3.56 (m, 2H, CH2N), 3.66-3.78 (m, 2H, CH2 ), 4.71 (d, 1H, J= 5.2 HzN-CH), 5.50 (d, 1H, J= 5.1 Hz, O-CH), 8.12 (d, 2H, J= 5.6 Hz, ArH), 8.92 (d, 2H, J= 5.4 Hz, ArH). 13C-NM (CD3OD, δ): 25.0, 27.0, 47.8, 58.4, 70.0, 127.2 (2xC), 143.1 (2xQ, 159.8, 164.8.

MS-ESI m/z (% rel. Int.): 236.1 ([MHf, 10), 219.1 (55), 110.0 (100).

Preparation of (-)-(2R,3R)-2-ammo-3-hy(koxy-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1-yl)propan-l-one dihydrocliloride Compound 220 and (+Vr2S -^-2-arnino-3-hydroxy-3-(pyridm-4-yl)-l-(p^^ Compound 221.

Analytical chiral separation: 20 μL of a 1 mg/mL solution of Compound 219 were injected on Chiralpak AD: flow-rate = 1 rnL/min, temperature = 25 °C, mobile phase: 152 hexane:ethanol = 8:2, detection UV at 220 nm and by polarimeter, Rt (-) = 16.26 min, Rt (+) = 19.02 min, k(-) = 4.38, k(+) = 5.30, a = 1.21 and resolution Rs = 1.90.

Semi-preparative separation was performed nn nhiralpak AS C250xl0 mm) : A 40 mg/mL solution of (.t)-e^Aro-2-amino-3-hydroxy-3-^y idin-4-yl)- 1 -(pyrroh* din- 1 -yl)propan- 1 -one Compound 219 racemate was prepared and 100 |jL of this solution were injected every 4 min on Chiralpak AS, flow-rate = 5 mL/min, mobile phase hexane:ethanol = 1:1, UV detection at 254 nm 56 successive injections were done. The two main fractions were identified on UV and collected in two different flasks. The solvent was removed in vacuo at 30 °C. The resulting solid was dissolved in 50 mL of CH2CI2 and then filtered on a 0.45 urn millipore membrane. After evaporation of CH2CI2, the solid was dissolved in 50 mL of methanol and then filtered. The salt was regenerated according to the procedure reported for Compound 203 and Compound 204.

The enantiomeric purity of the compounds was checked by analytical injection on Chiralpak AD of the regenerated salts: -(,2J?.3i-V2-anTmo-3-hvdroxy-3-rpyridk-4-ylVl- pm one dihvdrochloride Compound 220.

Compound 220 MW: 308.20; 133 mg obtained; White Solid; Mp (°Q: too hygroscopic.

R,: 0.18 (CHCl3:EtOH 95° = 86: 14, free base). 153 Enantiomeric excess = 99.1 % measured by HPLC at 220 nm (Chiralpak AD) a25D = - 6.4 (MeOH, c = l) 1H-NMR (CD3OD, δ): 1.94-2.03 (m, 4H, 2xCH2), 3.45-3.55 (m, 2H, CH2-N), 3.63-3.76 (m, 2H, CH2-N), 4.68 (d, IH, J= 5.1 Hz, N-CH), 5.48 (d, IH, /= 5.5 Hz, O-CH), 8.08 (d, 2H, J= 6.4 Hz, ArH), 8.90 (d, 2H, J= 6.6 Hz, ArH). ,3C-NMR (CD3OD, 5): 23.4, 25.4, 46.2, 56.7, 68.4, 125.7 (2xC), 141.3 (2xC), 158.5, 163.2. (+)-( 2£3iSV2-ammo-3-hvdroxy-3-(n yridin-4-ylV 1 -C yrrolidin- 1 -yl)pf opan- 1 - one d-hvdrochloride Compound 221. 2.HCI (+ erythro Compound 221 MW: 308.20; 140 mg obtained; White Solid; Mp (°C): too hygroscopic.

Ry: 0.18 (CHCl3:EtOH 95° = 86: 14, free base).

Enantiomeric excess = 99.1 % measured by HPLC at 220 nm (Chiralpak AD) a2SD = + 6.3 (MeOH, c = l).

'H-NMR (CD3OD, δ): 1.94-2.02 (m, 4H, 2xCH2), 3.44-3.52 (m, 2H, CH2-N), 3.64-3.74 (m, 2H, C¾-N), 4.68 (d, IH, J= 5.2 Hz, N-CH), 5.48 (d, IH, J= 4.3 Hz, O-CH), 8.09 (d, 2H, J= 6.4 Hz, ArH), 8.90 (d, 2H, J= 6.1 Hz, ArH). ,3C-NMR (CD3OD, δ): 23.4, 25.4, 46.2, 56.8, 68.4, 125.7 (2xC), 141.3 (2xQ, 158.5, 163.2.

Preparation of (±V^rgo-3-hvdroxy-2-fisopropylarnmo)-3-fpyridin-4-yl)-l-fpyrroUdin-l-vDnropan-l-one dihydrochloride Compound 223. 154 To a stirred solution of (±)-i ireo-2-a-riino-3-hyciroxy-3-(pyridin-4-y (pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 22 (0.20 g, 0.65 mmol) in 3 mL of MeOH were added triethylarnine (180 μΐ, 1.30 mmol) and acetone (75 μΐ,, 1.00 mmol). The mixture was stirred overnight at RT under nitrogen and then was added AcOH (200 μΐ,, 3.2 mmol) and NaB¾CN (85 mg, 1.3 mmol). After 5 h at 20 °C, MeOH was evaporated and the residue was partitioned between CHjCLj and 1 N aqueous sodium carbonate. The organic layer was evaporated and the obtained residue was purified by column chromatography (Si02, EtOAc:MeOH = 9:1). HC1 treatment in MeOH gave (±)- Areo-3-hydroxy-2-(isopropylarmno)-3-^ yl)propan-l-one dihydrochloride Compound 223 (56 mg, 25 % yield) as a white solid. 2.HCI (±ythmo Compound 223 MW: 350.28; Yield: 25 %; White Solid; Mp (°Q: 189.8.

Rf : 0.20 (EtOAc:MeOH= 9:1, free base). Ή-NMR (CD3OD, δ): 1.32 (d, 3H, J= 6.5 Hz, CH3), 1.40 (d, 3H, J = 6.5 Hz, CH3), 1.55-1.84 (m, 4H, 2xCRJ, 2.66-2.74 (m, IH, CH), 3.27-3.54 (m, 4H, CHj-N), 4.60 (d, IH, J= 7.9 Hz, N-CH), 5.38 (d, IH, J= 7.8 Hz, O-CH), 8.24 (d, 2H, J = 6.3 Hz, ArH), 8.98 (d, 2H, /= 6.3 Hz, ArH). 13C-NMR (CD3OD, 6): 18.7, 20.1, 24.7, 26.7, 47.7, 48.5, 52.2, 62.4, 72.5, 127.0 (2xC), 143.2 (2xC), 161.1, 164.1.

MS-ESI m z (% rel. Int.): 278.1 ([ΜΗ]+, 25), 179.1 (100). 155 HPLC: Method A, detection UV 254 nm, Compound 223 RT = 1.30 rnin, peak area 99.0 %.

Preparatiori of f±V2-arn o-3-(Tiydroxy.^ vDpropan-l-one dihvdrochloride Compound 224.

±V2-ter^Butyloxycarbonylarnmo-3-flivdroxyirnmoV3-(Dyri fpyrrolidin-l-yl opan-l-one TTA 08160.

To a stirred solution of terf-butyl (±)-l,3-dioxo-3-(pyridin-4-yl)-l- (pyrroUdin-l-yl)propan-2-ylcarbamate TTA 08120 (0.20 g, 0.60 mmol) in 10 mL of dioxane were added Et3N (125 μΐ, 0.90 mmol) andhydroxylarnine hydrochloride (65 mg, 0.90 mmol). The mixture was stirred 2 h at 110 °C in a sealed tube then dioxane was evaporated. The obtained residue was purified by column chromatography (Si02, CH2Cl2:MeOH = 9: 1 to 97:3) to give (±)-2-tert-butyloxycarbonylanimo-3-(¾y0^ yI)propan-l-one TTA 08160 (100 mg, 48 % yield) as an oil.

TTA 08160 MW: 348.40; Yield: 48 %; Oil. fy: 0.30 (CH2Cl2:MeOH = 97:3). 1H-NMR(CDCl3j δ): 1.39 (s, 9H, 3xCH3), 1.81-1.98 (m, 4H, 2xCH2), 3.37-3.62 (m, 4H, 2xCH2-N), 5.44 (d, 1H,J= 8.1 Hz, N-CH), 5.97 (d, 1H,J= 8.1 Hz, H), 7.37 (d, 2H, J- 5.6 Hz, ArH), 8.65 (d, 2H, J- 6.0 Hz, ArH). 156 "C- MR (CDCI3, δ): 24.0, 26.0, 28.2 (3xC), 46.5, 46.7, 55.8, 80.3, 123.1 (2xC), 139.7, 149.4 (2xC), 155.1, 166.4.

MS-ESI m/z (% rel. Int.): 349.2 (| H]+, 85), 293.2 (100).

HPLC: Method A, detection UV 254 nm, TTA 08160 RT = 3.90 min, peak area 97.0 %. fcV2-Am¾o-3-flivdroxyimino ^^^ one dihvdrochloride Compound 224. (±)-2-ier/-Butyloxycarbonylanimo-3-(hydroxyirrimo)- (pyrrolidin-l-yl)propan-l-one TTA 08160 (100 mg, 0.29 mmol) was dissolved in MeOH (2 mL) and a solution of 1 M HC1 in MeOH (1 mL, 3.00 mmol) was added and the mixture was heated for 10 min at 45 °C. MeOH was evaporated and the residue was dried to give crude (±)-2-ammo-3-(hydroxyimino)-3- (pyridm-4-yl)-l-(pyrrohdin-l-yl)propan-l-one TTA 08164. Amberlite IRA-400 (CT) (1 mL, 1.4 mmol) was washed successively with water (2x10 mL), NaOH 0.5 N (3x20 mL), water (2x10 mL) and MeOH (3x10 mL). A solution of TTA 08164 in MeOH (30 mL) was stirred with washed Amberlite IRA-400 for 5 min at RT. After filtration, the MeOH was evaporated and the free base form was purified by column chromatography (Si02, CH2Cl2:MeOH = 9:1). HC1 Treatment in MeOH gave (. )-2-ammo-3-(hydroxyirrmo)-3-(pyridin-4-yl)-l-(pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 224 (29 mg, 31 % yield) as a beige solid.

(±) Compound 224 MW: 321.20; Yield: 31 %; Beige Solid; Mp (°C): 225.2 157 Rfi 0.30 (EtOAc:MeOH= 9: 1, free base). Ή-NMR (CD3OD, δ): 1.85-2.04 (m, 4H, 2χα¾), 3.23-3.73 (m, 4H, α¾-Ν), 5.58 (d, 1H, J= 4.4 Hz, CH), 8.23 (d, 2H, J= 5.0 Hz, ArH), 9.03 (d, 2H, J= 5.0 Hz, ArH).

"C-NMR (CD3OD, 5): 24.9,26.9, 47.9, 48.0, 55.6, 128.7 (2xC), 143.8 (2xQ, 145.5, 148.8, 163.8.

MS-ESI m/z (% rel. Int): 249.2 ([MH]+, 10), 115.0 (100).

HPLC: Method A, detection UV 254 nm, Compound 224 RT = 0.60 min, peak area 99.0 %.

Preparation of 6b ¾reo-2-(4-iodobeiizy.ammoV3-hy^ (pyrroHdin-l-ynpropan-l-one hydrochloride Compound 225.

To a stirred solution of (±)-/Areo-2-animo-3-hydroxy-3-(pyridm-4-yl)-l- (pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 22 (500 mg, 1.62 mmol) in 7.5 mL of MeOH at RT under nitrogen was added dropwise Memylamine (495 μί, 3.56 mmol) and 4-iodobenzaldehyde (413 mg, 1.73 mmol). The mixture was stirred for 5 h at RT under nitrogen. Acetic acid (463 uL, 8.1 mmol) and NaBH3CN (356 mg, 5.67 mmol) were added. The mixture was stirred for another 15 h at RT. The mixture was partitioned between EtOAc (750 mL) and an 10 % aqueous solution of potassium carbonate. The organic layer was washed with brine (2 x 20 mL), dried over MgS0 and filtered. After evaporation, the crude product was purified by column chromatography (Si(½, EtOAc:MeOH = 85:15) to give (±)-iAreo-2-(4-iodobenzylanmio)-3-hydroxy-3-(pyridin-4-yl)-l-(pyrrolidin-l-yl)propan-l-one VIB 01096 as a yellow solid (380 mg, 52 % yield). To a solution of (±)-iAreo-2-(4-iodobenzylarnino)-3-hychoxy-3-(pyridm-4-yl)-l-(pyiTolidin-l-yl)propan-l-one VIB 01096 (380 mg, 8.43 mmol) in methanol (10 mL) was added a solution of 0.5 M aqueous 158 hydrochloric acid (7 mL). After stirring the mixture at RT for 0.5 h the reaction mixture was concentrated and the crude product was coevaporated twice with EtOAc. After trituration with EtOAc, filtration and drying, (±)-threo-2-(4~ iodobenzylarn½o)-3-hydroxy-3^yri hydrochloride Compound 225 (373 mg, 44 % yield) was obtained as a pale yellow solid.

Compound 225 MW: 524.37; Yield 44 %; Pale Yellow Solid Mp (°C): 194.7 1H-NMR(CD3OD, δ): 1.42-1.80 (m, 4H, 2xCH2), 2.32-2.50 (m, 1H, CH2), 2.96-3.12 (m, 1H, CH2), 3.12-3.25 (m, 2H, C¾), 4.27 (q, 2H, J= 13.3 Hz, CH2), 4.42 (d, 1H, J= 7.8 Hz, HC-N), 5.31 (d, 2H, J= 7.7 Hz, HC-O), 7.29 (d, 2H, J- 8.1 Hz, ArH), 7.80 (dd, 2H, J= 2.9 Hz, J = 8.1 Hz, ArH), 8.15 (d, 2H, J= 5.5 Hz, ArH), 8.91 (d, 2H, J= 5.5 Hz, ArH). 13C-NMR (CD3OD, δ): 24.7, 26.5, 47.5, 48.4, 51.1, 63.7, 72.3, 96.9, 126.9 (2xC), 131.0, 133.6 (2xC), 139.5 (2xC), 143.2 (2xC), 161.1, 163.8.

MS-ESI m/z (% rel. Int.): 451.9 ((MH]+, 100), 363.8 (45), 342.9 (70), 216.9 (75), 148.0 (30).

HPLC: Method A, detection UV 254 nm, Compound 225 RT= 3.83 min, peak area 98.7 %. (p-yrrolidin- 1 -vD-propan- 1 -one dihydrochloride Compound 226. 159 To a stirred solution of (±)-/Areo-2-amino-3-hyo^oxy-3-pyridin-4-yl-l- pyrrolidin- 1 -yl-propan- 1 -one Compound 22 (500 mg, 1.62 rnmol) in 10 ml methanol was added successively Et3N (496 uL, 3.57 mmol) and 2-iodo- benzaldehyde (414 mg, 1.78 mmol) in 1 ml methanol. The mixture was stirred 6 h at RT under nitrogen and acetic acid (464 JJL, 8.11 mmol) and sodium cyanoborohydride (356 mg, 5.57 mmol) were added. The mixture was stirred overnight at 20°C and evaporated to give a residue which was partitioned between CH2CI2 and 1 N aqueous potassium hydroxyde. The organic layer was washed with brine and dried over MgS04, filtered and evaporated. The crude product was purified by column chromatography (S1O2, EtOAcMeOH = 9:1). After evaporation and drying a white solid (±)-/Areo-2-(2-iodobenzylarnino)-3- hydroxy-3-(pyriom-4-yl)-l-(pyrroUdm-l-yl)-propan-l-one was obtained (419.6 mg, 57 % yield). The product was dissolved in methanol (10 mL). The solution was stirred at room temperature and a solution of HCl (1 M, 7.4 mL) was added via syringe at RT for 10 rnin. The mixture was concentrated and triturated with EtOAc. After filtration and drying, (-fc)-i treo-2-(2-iodobenzylarriino)-3-hydroxy-3-(pyridm-4-yl)-l-(pyrroli^ Compound 226 was obtained (195 mg, 25 % yield) as a white solid.

Compound 226 MW: 524.22; Yield: 25 %; White Solid; Mp (°Q: 148.0 fy: 0.50 (MeOH:EtOAc = 20:80, free base). 1H-NMR (CD3OD, δ): 1.33-1.80 (m, 4H, 2xC¾), 2.12-2.25 (m, 1H, C¾), 2.75-2.88 (m, 1H, CH2), 3.14-3.25 (m, lH, CH2), 3.25-3.31 (m, 1H, 0½), 4.14 160 (d, IH, J= 8.4 Hz, NH-CH), 4.37-4.52 (m, 2H, NH-CH2) 5.10 (d, IH, J= 8.3 Hz, CH-O), 7.18 (t, IH, J= 7.6 Hz, ArH), 7.49 (d, IH, J= 7.5 Hz, ArH), 7.61 (d, IH, J= 7.7 Hz, ArH), 7.68 (d, 2H, J= 5.2 Hz, ArH), 7.97 (d, J= 7.9 Hz, IH, ArH), 8.66 (d, J= 4.9 Hz, 2H, ArH). 13C-NMR (CD3OD, δ): 24.7, 26.5, 47.6, 47.8, 55.3, 64.3, 72.7, 101.8, 124.4 (2xC), 130.3, 132.0, 132.5, 135.1, 141.7 (2xC), 148.2, 154.0, 164.2.

MS-ESI m/z (% rel. Int.): 451.9 ([MH]+, 100), 352.9 (55), 342.9 (30).

HPLC: Method A, detection UV 254 nm, Compound 226 RT = 3.72 min, peak area 98.95 %.

Preparation of (±Vf¾reo-2-(3-iodobenzylammoV3-hv0^oxy-3-fpyridm-4-ylVl- Cp vrrolidin- 1 -vlV-propan- 1 -one dihydrochloride Compound 227.

To a stirred solution of (±)-/Areo-2-amko-3-hydroxy-3-pyridin-4-yl-l- pyrrolidin-l-yl-propan-l-one Compound 22 (500 mg, 1.62 mmol) in 10 ml methanol was added successively Et3N (496 uL, 3.55 mmol) and 3-iodo-benzaldehyde ( 14 mg, 1.78 mmol) in 1 ml methanol. The mixture was stirred 6 h at RT under nitrogen and acetic acid (464 uL, 8.11 mmol) and sodium cyanoborohydride (356 mg, 5.57 mmol) were added. The mixture was stirred overnight at 20 °C then evaporated and the residue was partitioned between CH2C12 and 1 N aqueous potassium hydroxyde. The organic layer was washed with brine and dried. The organic layer was evaporated. The crude product was purified by column chromatography (Si02, CH2Cl2:MeOH = 95:5). After evaporation and drying a white solid (±)-/ tre H2-(3-iodoben2ylamino)-3-hyoroxy-3-(pyridin-4-yl)-l-( yn:oHdm-l-yl)-propan-l-one (437 mg; 60 % yield). This product was dissolved in methanol (10 mL). The solution was stirred at RT and a solution of HC1 (1 M, 7.7 mL) was added at room temperature for 10 min. The mixture was concentrated and triturated with 161 diethyl ether. After filtration and drying, (±)-iAreo-2-(3-iodobenzylarnino)-3- hydroxy-3-(pyridin -yl)-l-(pyrroHdin-l-yl)-propan-l-one dihydrochloride Compound 227 was obtained (205 mg, 26 % yield) as a white solid.

Compound 227 MW: 524.22; Yield: 26 %; White Solid; Mp (°C): 142.8 R/: 0.30 (MeOH:CH2Cl2 = 5:95, free base).

^J-N R (CD3OD, δ): 1.25-1.80 (m, 4H, 2xC¾), 2.03-2.12 (m, 1H, CH2), 2.80-2.92 (m, 1H, CH2), 3.11-3.25 (m, 2H, CH2), 4.06-4.30 (m, 3H, CH-N & N- CH2), 5.04 (d, 1H, J= 8.8 Hz, CH-OH), 7.23 (t, 1H, J= 7.8 Hz, ArH), 7.51 (d, 1H, 7= 7.5 Hz, ArH), 7.67 (d, 2H, J= 5.8 Hz, ArH), 7.80 (d, 1H, J= 5.2 Hz, ArH), 7.87 (s, 1H, ArH), 8.66 (d, J= 5.2 Hz, 2H, ArH).

"C-NMR (CD3OD, δ): 24.7, 26.5, 47.3, 47.7, 50.5, 64.3, 72.8, 95.3, 124.5 (2xC), 130.9, 132.0, 133.9, 140.1, 140.5, 148.3, 153.7, 164.2.

S-ESI m/z (% rel. Int.): 451.9 ([MHT, 100), 352.9 (40), 342.9 (50).

HPLC: Method A, detection UV 254 nm, Compound 227 RT = 3.80 min, peak area 98.7 %.

Preparation of (+ -(2 .3i?V2- -iodoben2^1ammoV3-hv&oxy-3-^yridm^-ylV l- pyrrolidin-l-yl -propan-l-one dihydrochloride Compound 228.

To a stirred solution of (+)-(2.S',3^)-2-ariimo-3-hydroxy-3-(pyridin-4-yl)-l-(pyrroHdin-l-yl)propan-l-one dihydrochloride Compound 204 (204 mg, 0.67 mmol) in MeOH (6 mL) was added Et3N (202 uL, 1.46 mmol) and, via syringe, 162 a solution of 3-iodobenzaldehyde (169 mg, 0.73 mmol) in methanol (1 mL). The mixture was stirred 5 h at RT under nitrogen. CH3COOH (190 uL, 3.30 mmol) and sodium cyanoborohydride (146 mg, 2.32 mmol) were added and the reaction mixture was stirred overnight at RT. MeOH was evaporated and the residue was partitioned between CH2CI2 and a solution of 1 N aqueous potassium carbonate. The organic layer was washed with brine, dried over MgS04, filtered and evaporated. The crude product was purified by column chromatography (S1O2, CH2C.2:MeOH - 95:5). After evaporation and drying (2£,3i.)-2-(3-iodoben2ylannno)-3-hy^ propan-l-one (246 mg) was obtained as a white solid. The product was dissolved in methanol (5 mL) and a solution of HC1 in MeOH (1 M, 2.5 mL) was added via syringe and the solution was stirred at RT for 0.6 h. The mixture was concentrated and the resulting solid triturated with Et20. After filtration and drying (+)-(2£,32e)-2-(3-iodobe^larimio)-^ (pyrrolidin-l-yl)-propan-l-one dihydrochloride Compound 228 (280 mg, 80 % yield) was obtained as a white solid.

Compound 228 MW: 524.22; Yield: 80 %; White Solid; Mp (°C): 107.4 Ό = + 101.9 (MeOH, c = 1.02).

R 0.30 (MeOH:C¾Cl2 = 5:95, free base). Ή-NMR (CD3OD, δ): 1.52-1.82 (m, 4H, 2xCH2), 2.38-2.45 (m, 1H, C¾), 3.01-3.09 (m, 1H, C¾), 3.18-3.32 (m, 2H, CH2), 4.20-4.29 (dd, 2H, J= 28.1 163 Hz, J = 13.4 Hz, ΝΗ-0¾), 4.40 (d, 1H, J= 7.9 Hz, N-CH), 5.30 (d, J= 7.9 Hz, 1H, CH-O), 7.25 (t, 1H,J= 5.4 Hz, ArH), 7.54 (d, 1H,J= 7.1 Hz, ArH), 7.81 (d, 1H, J= 7.2 Hz, ArH), 7.89 (d, 1H, J= 1.3 Hz, ArH), 8.13 (d, J= 5.5 Hz, 2H, ArH), 8.90 (d, J= 5.3 Hz, 2H, ArH).

MS-ESI m/z (% rel. Int): 452.1 ([MH]+, 100), 353.0 (65), 343.1 (80). HPLC: Method A, detection UV 254 nm, Compound 228 RT = 3.87 min, peak area 97.0 %.

Preparation of (2jg.3^-2- 3-iodoben2^1ammoV3-hvdroxy-3-fo\ddin-4-v -l- ^yrrolidin-l-ylVpropan-l-one dihydrochloride Compound 229.

Similar to Compound 228 with (-)-(2/^3iS)-2-arnmo-3-hydroxy-3- (pyridin-4-yl)- 1 -(pyrrolidui- 1 -yl)propan- 1 -one dihydrochloride Compound 203 (77 mg, 0.25 mmol) in 2.3 ml of MeOH, Et3N (76 uL, 0.79 mmol), 3- iodobenzaldehyde (64 mg, 0.275 mmol), CH3COOH (78.6 uL, 1.37 mmol) and NaB¾CN (60.5 mg, 0.96 mmol). (2i?,3-^-2-(3-iodobenzylarmno)-3-hydroxy-3-(pyridin-4-yl)-l^ l-yl)-propan-l-one dihydrochloride Compound 229 (70 mg, 53.5 % yield) was obtained as a pale yellow solid.

Compound 229 MW: 524.22; Yield: 53.5 %; Pale Yellow Solid; Mp (°C): 179.7 R 0.30 (MeOH:CH2Cl2 = 5:95, free base).

'H-NMR (CD3OD, δ): idem to Compound 228. 164 MS-ESI m/z (% rel. Int.): 452.1 ([MH]+, 100), 353.0 (70), 343.1 (60). HPLC: Method A, detection UV 254 ran, Compound 228 RT » 3.78 min, peak area 99.0 %.

Preparation of fc f Areo2-anrino-3-hvdroxy- 1 -morpholino-3-(thiophen-3- vDpropan-l-one hydrochloride Compound 230. ranj-f4.5-Dihydro-5-ftm^phen-3-yfl^ SLA 09052A.

SLA 09052A was prepared in accordance with method D using thiophene-3-carbaldehyde (0.768 mL, 5.35 mmol), KOH (0.273 mg, 4.86 mmol) in methanol (5 mL) and 2-isocyano-l-morpholinoethanone SLA 07118 (0.75 g, 4.86 mmol). The solution was stirred for 2 h at 0 °C. After work-up the residue was purified by column chromatography (florisil, EtOAc). After evaporation and drying, tra/i-?-(4,5-dihydro-5-( biophen-3-yl)oxazol-4-yl)(morpholino)methanone SLA 09052A (0.327 g, 25 % yield) was obtained as a yellow oil.

SLA 09052A MW: 266.32; Yield: 25 %; Yellow Oil. 1H-NMR (CDC13, δ): 3.40-4.00 (m, 8H, 4xCH2), 4.67 (dd, 1H, J= 7.3 Hz, J= 2.2 Hz, CH- ), 6.29 (d, 1H, J= 7.3 Hz, CH-O), 6.97 (d, 1H, J= 2.2 Hz, CH=N), 7.01 (dd, 1H, J= 5.0 Hz, J= 1.3 Hz, CH=C), 7.28-7.40 (m, 2H, CH=Q. 165 f:_.)-.7trep-2-Ammo-3-hvdroxy-l-m hydrochloride Compound 230.

To a solution of Z7-an,y-(4,5-dihydro-5-(thiophen-3-yl)oxazol-4- yl)(morpholino)methanone SLA 09052A (0.327 g, 1.12 mmol) in MeOH (5 mL) was added HCl 37 % (2 mL). After heating (50 °C) the mixture for 24 h the reaction mixture was concentrated and the crude product was coevaporated twice with EtOAc. After trituration with EtOAc, filtration and drying (±)-threo- 2-arnmo-3-hydroxy-l-mo oImo-3-(1hiophen-3-yl)propan-l· Compound 230 (276 mg, 77 % yield) was obtained as a pale yellow solid.

(±) Compound 230 MW: 292.78; Yield: 77 %; Pale Yellow Solid; Mp (°C): 209.1 1H-NMR (CD3OD, δ): 2.77-2.92 (m, 2H, CH2), 3.20-3.60 (m, 6H, 3xCH2), 4.49 (d, 1H, J= 8.7 Hz, CH-N), 4.95 (d, 1H, J= 8.8 Hz, CH ), 7.18 (d, 1H, J= 4.5 Hz, CH=C), 7.44 (d, 1H, J= 1.7 Hz CH=C), 7.44 (dd, 1H, J= 4.5 Hz, J= 1.7 Hz CH=C).

Preparation of f--: f¾Γgo-2-ammo-3-hvάΓo y-l- iperidm-l-yl 3- m^ yl propan-l-one hydrochloride Compbund 231. frgn -f4.5-Dmvdro-5-ftMophen-3-yl^oxazol-4-yl piperidm-l-yl mem SLA 09052B.

SLA 09052B was prepared in accordance with method D using thiophene-3-carbaldehyde (0.778 mL, 5.43 mmol), KOH (0.273 mg, 4.94 166 mmol) in methanol (5 mL) and 2-isocyano- l-(piperidin-l -yl)ethanone SLA 07Π6Β (0.75 g, 4.94 mmol). The solution was stirred for 2 h at 0 °C. After work-up (without any further purification) and drying irfl/u-(4,5-dihydro-5- (tHophen-3-yl)oxazol-4-yl)(piperidin-l-yl)methanone SLA 09052B was obtained as a yellow oil (1.29 g, 99 % yield).

SLA 09052B MW: 264.34; Yield: 99 %; Yellow Oil. 1H-NMR (CDC13, δ): 1.47-1.75 (m, 6H, 3xCH2), 3.42-3.82 (m, 4H, 2xC¾), 4.72 (dd, IH, J= 7.2 Hz, J= 2.2 Hz, CH-N), 6.28 (d, IH, J= 7.2 Hz, CH-O), 6.96 (d, IH, J= 2.2 Hz, CH=N , 7.01 (dd, IH, J= 5.0 Hz, J= 1.2 Hz, CH=C), 7.30-7.35 (m, 2H, CH=C). 13C-NMR (CDCl3s δ): 24.5, 25.5, 26.5, 43.7, 46.8, 73.4, 78.0, 122.6, 125.1, 127.2, 140.5, 155.0, 166.3. hydrochloride Compound 231.

To a solution of /ranj-(4,5-dihydro-5-(thiophen-3-yl)oxazol-4-yl)(piperidin-l-yl)methanone SLA 09052B (1.29 g, 4.88 mmol) in methanol (5 mL) was added hydrochloric acid 37 % (5 mL). After heating (50 °C) the mixture for 24 h the reaction mixture was concentrated and the crude product was coevaporated twice with EtOAc. After trituration with EtOAc, filtration and drying (±)-rAreo-2-amino-3-hydroxy- 1 -morpholino-3-(thiophen-3-yl)propan- 1 - 167 one hydrochloride Compound 231 was obtained as a pale yellow solid (1.07 g, 75 % yield).

Compound 231 MW: 290.81; Yield: 75 %; Pale Yellow Solid; Mp (°C): 210.6 1H-NMR (CD3OD, δ): .82-0.97 (m, 1H, 0.5χΟ¾), 1.30-1.70 (m, 5H, 2.5xCH2), 2.75-2.91 (m, 1H, C¾), 3.12-3.55 (m, 3H, 1.5χΟ½), 4.51 (d, 1H, J = 8.4 Hz, CH-N), 4.94 (d, 1H, J= 8.5 Hz, CH ), 7.16 (d, 1H, J= 4.9 Hz, CH=C), 7.44 (d, 1H, J= 2.5, Hz CH=C), 7.44 (dd, 1H, /= 4.5 Hz, J= 3.2 Hz CH=C). yl)propan-l-one dihvdrochloride Compound 232. fran.?-i4,5-Di vo o-5-foyrirt^ 09050A.

SLA 09050A was prepared in accordance with method D using pyridine-3-carbaldehyde (0.65 mL, 4.86 mmol), KOH (0.273 mg, 4.86 mmol) in methanol (10 mL) and 2-isocyano-l-moipholinoethanone SLA 07118 (0.75 g, 4.86 mmol). The solution was stirred for 20 h at 0 °C. After work-up (without any further purification), evaporation and drying /ra iJ-(4,5-dihydro-5-(pyridin-3-yl)oxazol-4-yl)(morpholino)methanone SLA 09050A was obtained as a yellow solid (0.92 g, 72.5 % yield). 168 SLA 09050A MW: 261.28; Yield: 72.5 %; Yellow Solid. Ή-NMR (CDC13, δ): 3.42-4.00 (m, 8H, 4xCH2), 4.63 (dd, 1¾J= 7.7 Hz, J= 2.3 Hz, CH-N), 6.29 (d, 1H, J= 7.7 Hz, CH-O), 7.02 (d, 1H, J= 2.2 Hz, CH=N), 7.33 (m, 1H, ArH), 7.60-7.66 (m, 1H, ArH), 8.57-8.62 (m, 2H, ArH). 13C-NMR (CDC13, δ): 43.0, 46.3, 66.7, 66.8, 74.6, 79.2, 123.5, 133.4, 135.1, 147.5, 150.0, 155.0, 166.3.

MS-ESI m/z (% rel. Int): 262.1 ([MH , 55), 108.0 (100). dihvdrochloride Compound 232.

To a solution of i *a«j-(4,5-dmydro-5-(pyridin-3-yl)oxazol-4-yl) moφholino)methanone SLA 09050A (0.911 g, 3.48 mmol) in methanol (10 mL) was added hydrochloric acid 37 % (5 mL). After heating (50°Q the mixture for 2.25 h the reaction mixture was concentrated and the crude product was coevaporated twice with EtOAc and the crude product was dissolved in a 1 N solution of K2CO3 which was extracted with a mixture CH2Cl2:iPrOH = 9: 1 (6 x 100 mL). The combined organic layer was dried over MgSC , filtered and evaporated to led to a crude product which was purified by column chromatography (S1O2, EtOAC:MeOH = 70:30). After evaporation the product was dissolved in a solution of HC1 in MeOH (0.5M, 29 mL) and stirred at T for 1.5 h. The product was co-evaporated twice with EtOAc. After trituration with EtOAc, filtration and drying, (±)-/¾reo-2-ammo-3-hydroxy-l-morpholino- 169 3-(pyridin-3-yl)propan-l-one dihydrochloride Compound 232 (270 mg, 24 % yield) was obtained as a yellow solid.

(±) Compound 232 MW: 324.2; Yield: 24 %; Yellow Solid. Ή- MR (CD3OD, δ): 3.20-3.78 (m, 8H, 4xCH2), 4.87 (d, IH, J= 5.5 Hz, ΟΓ N), 5.40 (d, IH, J= 5.4 Hz, CH ), 8.20 (m, IH, ArH), 8.77 (d, IH, J= 8.3 Hz, ArH), 8.93 (d, IH, J= 5.5 Hz, ArH), 9.03 (s, IH, ArH).

Preparation of f±Vt½reo-2-ainmo-3-hvdro^ vDpropan-l-one dihydrochloride Compound 233. frgws-f4.5-Dihvdro-5-f pyridm-S-vDoxazol^ylVpiperidintoiethanone SLA 09050B.

SLA 09050B was prepared in accordance with method D using pyridine-3-carbaldehyde (0.512 mL, 5.42 mmol), KOH (0.277 mg, 4.93 mmol) in methanol (10 mL) and 2-isocyano-l-piperidinethanone SLA 07116B (0.75 g, 4.93 mmol). The solution was stirred for 20 h at 0 °C. After work-up (without any further purification), evaporation and drying, frfl/w-(4,5-dihydro-5-(pyridin-3-yl)oxazol-4-yl)(piperidin)methanone SLA 09050B (0.917 g, 72 % yield) was obtained as a yellow solid. 170 SLA 09050B MW: 259.30; Yield: 72 %; Yellow Solid. Ή-NMR (CDC13, δ): 1.59-1.73 (m, 6H, 3xCH2), 3.44-3.83 (m, 4H, 2χΟ¾), 4.68 (dd, IH, J= 7.6 Hz,J= 2.3 Hz, CH-N), 6.30 (d, IH, J= 7.6 Hz, CH-O), 7.02 (d, IH, J= 2.2 Hz, CH=N), 7.32 (m, IH, ArH), 7.60-7.66 (m, IH, ArH), 8.57-8.62 (m, 2H, ArH). 13C- MR (CDC13, δ): 24.4, 25.5, 26.4, 43.8, 46.9, 74.6, 79.5, 123.6, 133.5, 135.4, 147.5, 149.9, 154.8, 165.9. dihydrochloride Compound 233.

To a solution of ir /ij-(4,5-dmydro-5-(pyridin-3-yl)oxazol-4-yl)(piperidin)methanone SLA 09050B (0.917 g, 3.54 mmol) in methanol (10 mL) was added hydrochloric acid 37 % (5 mL). After heating at 50 °C the mixture for 2.25 h the reaction mixture was concentrated and the crude product was coevaporated twice with EtOAc. After trituration with EtOAc, filtration and drying, the crude product was dissolved in a 1 N solution of K2CO3 and the product was extracted CH2Cl2:iPrOH - 9: 1 (6 x 100 mL). The crude product was purified by column chromatography (EtOAc:MeOH == 7:3) (±)-threo-2-arnko-3-hydroxy-l-pipOTdm-3-(p^ was obtained pale yellow solid (223.5 mg). The product was dissolved in a solution of HC1 in MeOH (0.5 M, 18 mL) and stirred at RT for 1.5 h. After trituration with EtOAc, filtration and drying, (±)-f¾reo-2-aimno-3-hydroxy- 1 -piperidm-3-(pyridin-3-yl)propan-l-one dihydrochloride Compound 233 (208 mg, 18 % yield) was obtained as a yellow solid. 171 Compound 233 MW: 322.2; Yield: 18 %; Yellow Solid.

'H-NMR (CD3OD, δ): 1.15-1.80 (m, 6H, 4xC¾), 3.10-3.80 (m, 4H, 2xCHa), 4.88 (d, IH, J= 5.6 Hz, CH'N), 5.33 (d, IH, 7» 5.6 Hz, CHO), 8.19 (t, lH„/= 7.1 Hz, ArH), 8.74 (d, IH, 7.9 Hz, ArH), 8.93 (d, IH, /= 5.6 Hz, ArH), 9.01 (s, IH, ArH).

Preparation of (2Jg 5 2-ffi?V2-hvdroxy-l-phenyleihylaminoY-3-hvdroxy-3-( pvridin-4-vlV 1 -(pvrrolidin- 1 - v propan- 1 -one dihvdrochloride Compound 234. fi?V5-Phenylmorpholin-2-one EBE 06134.

To a solution of phenylbromoacetate (18.58 g, 86 mmol) in CH3CN under nitrogen was added a solution of (i?)-phenylglycinol (10.17 g, 74 mmol) and di-isopropylemylarnine (34 mL, 195 mmol) in CH3CN. The volatiles were removed under reduced pressure keeping the bath temperature below 25 °C to obtain an oil that was treated with EtOAc (120 mL) and stirred for 15 min. The resulting white precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and the desired product was isolated using column chromatography (Si02) with a step gradient of 10 % to 50 % [v/v] EtOAc in cyclohexane to give after evaporation (J?)-5-phenylmorpholin-2-one EBE 06134 (3.17 g, 24 % yield) as a white solid. 172 EBE 06134 MW: 177.2; Yield: 24 %; White Solid; Mp (°C): 50.3 Kf i 0.30 (EtOAc:cyclohexane = 50:50). 1H-NMR (CDa3, δ): 1.99 (s, 1H, NH), 3.89 (q, 2H, 17.8 Hz, N-CH2), 4.18 (dd, 1H, J= 3.7 Hz, J= 10.3 Hz, O-CH), 4.29 (t, lH, 10.5 Hz, N-CH), 4.40 (dd, 1H, J= 3.7 Hz, ./-= 10.5 Hz, O-CH), 7.30-7.45 (m, 5H, ArH).

I3C-NMR (CDC13, δ): 46.8, 54.8, 72.8, 125.3 (2xC), 127.0, 127.3 (2xC), 135.9, 166.0. [ ]ηΌ » + 30.3 0 (c = 1.00, MeOH). Π■S'Jj^.5 ^.8a ^ TetΓahvdΓ0-5-phenyl-1.3-di yridm-4^^ ciri.41oxazm-8f3.¾Vone EBE 06136.

A solution of (i?)-5-phenylmorpliolinon-2-one EBE 06134 (3.0 g, 16.9 mmol) andpyridine-4-carboxaldehyde (5.43 g, 50.7 mmol) in toluene (75 mL) was refluxed in a soxhlet extractor filled with molecular sieves 4A (25 g) for 16 hours. All the volatiles were evaporated and the desired product was purified by column chromatography (S1O2) using a gradient of 80 % to 100 % [v v] EtOAc in cyclohexane to give after evaporation (ljS,3R,5R,8aR)-tetrahydro-5-phenyl-l,3-di(pyridm-4-yl)oxazolo[4,3-c][l,4]oxazm-8(3fl one EBE 06136 (1.7 g, 46 % yield) as a pale yellow solid.

EBE 06136 MW: 373.4; Yield: 46 %; Pale Yellow Solid; Mp (°C): 155.6 R7: 0.20 (EtOAc). 173 ¾- MR (CDCI3, δ): 4.10-4.17 (m, IH, N-CH), 425 (dd, IH, J - 3.3 Hz, N-CH), 4.36-4.54 (m, 2H, O-CH), 5.38 (d, IH, O-CH, 8.2 Hz), 5.53 (s, IH, N-CH), 7.20-7.35 (m, 8H, ArH), 7.40-7.50 (m, IH, ArH), 8.51 (dd, 2H, J= 1.4 Hz, 7= 4.5 Hz), 8.57 (dd, 2H, J= 1.4 Hz, J= 4.5 Hz, ArH). f(2^A?.5in-3-rfig 2-Hvdroxy-l-Dh^ vPfpyiTolidin-l-v methanone EBE 06138.

To a solution of (lS,3.R,5£,8aK)-tetrahydro-5-p^ yl)oxazolo[4,3-c][l,4]oxazin-8(3/ -one EBE 06136(1.7 g, 4.55 mmol) in CH2C12 was added pyrroUdine (1.90 mL, 22.8 mmol) and the solution was stirred under nitrogen at 25 °C for 16 h. All the volatiles were evaporated and the resulting product was isolated using column chromatography (S1O2) with a gradient of 0-20 % [v/v] MeOH in EtOAc to give after evaporation (i2R,4S,5R)-3-(( )-2-hyclroxy-l-pheny yl)(pyrroUdin-l-yl)methanone EBE 06138 (0.665 g, 33 % yield) as a white solid.

EBE 06138 MW: 444.5; Yield: 33 %; White Solid; Mp (°C): 63.6. 0.25 (MeOHrEtOAc = 20:80). 1H-NMR (CDCI3, δ): 1.70-1.90 (m, 4H, 2χ(¾), 2.25 (bs, IH, OH), 2.75-2.85 (m, IH, CH-N), 2.95-3.05 (m, IH, N-CH), 3.50-3.60 (m, 2H, Ν-0¾), 3.80-4.15 (m, 4H, 2xCH +C¾-0), 5.10 (d, IH, /= 4.7 Hz, CH), 6.32 (s, IH, CH), 7.18- 174 7.32 (m, 7H, ArH), 7.45 (d, 2H, J= 5.9 Hz, ArH), 8.54 (d, 2H, J= 6.0 Hz, ArH), 8.64 (d, 2H, J= 6.0 Hz). 13C- MR (CDC13, δ): 23.9, 26.0, 46.3, 46.6, 60.3, 63.8, 65.2, 94.1, 121.1 (2xQ, 123.0 (2xC), 128.0, 128.3 (2xC), 128.5 (2xC), 137.8, 147.8. MS-ESI m/z (% rel. Int.): 445.1 ([MH]+, 20).

HPLC: Method A, detection at 254 nm, EBE 06138 RT * 3.50 rain, peak area 99%. [α]Μ0 = -16.0 0 (c = 1.00, CHCI3). (2R.3!S1-2-(fflV2-Hvc¾oxy-l-phenvIemylammo 3-hvdroxy-(pyrroHdin-1-v pTopan-l-one dihvdiocMoride Compound 234.

To a solution of ((2J?,4^5i?)-3-((ii)-2-hydroxy-l-phenylethyl 2,5-di^yri(hn-4-yl)oxazolidin-4-yl)(pyri Udm-l-yl)m EBE 06138 (600 mg, 1.34 rnmol) in MeOH (6 mL> was added a solution of 1 N HC1 (6 mL) and the reaction mixture was stirred at 60 °C for 2 h, evaporated to dryness to give a white solid (745 mg). This crude product was dissolved in CH2CI2 (10 mL) and Na2C03 (sat sol.). The organic layer was separated was separated and the aqueous layer was washed with CH2CI2 (5*2 mL). The combined organic layer were dried over Na2S04, filtered over cotton mixed with silica gel (600 mg), evaporated and loaded on a silica gel column of 25 g. The desired product was eluted using a gradient of MeOH 0 % to 20 % in EtOAc to give after evaporation (2i2,36 -2-((i?)-2-hydroxy-l-phenylemylarmno)-3-hydroxy-3-(pyridin-4-yl)-l-(pyrroHdin-l-yl)propan-l-one (320 mg, 67 % yield) as a white solid. 175 Compound 234 MW = 355.43; Yield: 67 %; White Solid; Mp (°C) = 76.4 ¾: 0.3 (MeOH:EtOAc = 20:80).

!H R (CDC13, δ): 1.18-1.30 (m, 2H, C¾), 1.30-1.48 (m, 2H, CH2), 1.80-1.90 (m, IH, CH2), 2.23-2.33 (m, IH, N-C¾), 2.85-2.95 (m, 2H, N-C¾), 3.00-3.12 (m, 2H, N-CH + N-CH), 3.72 -3.85 (m, 3H, 0-CH2 + NH), 4.58 (d, IH, 8.4 Hz, O-CH), 7.18-7.35 (m, 7H, ArH), 8.51 (d, 2H, J= 6.0 Hz, ArH). [aJ^D = - 68.8 0 (c = 1.00, CHCI3).

To a solution of (2£,3S>2-((fl)-2-hy3xoxy-l-ph^ hydroxy-3-(pyri<^-4-yl)-l-(pyrroUdm-l-yl)propan-l-one inMeOH (100 mg), in MeOH (1 mL) was added a solution HC1 (1 N, 1.1 mL) at 0 °C and Hie solution was stirred for 10 min to give after evaporation (2i?,3S)-2-((R)-2-hydroxy-l-phenylethylamino)-3-hydroxy-3-(pyridm-4-yl)-l-(pynO yl)propan-l-one dihydrochloride Compound 234 (120 mg, 99 % yield) as a white solid. 2 HCI Compound 234 176 MW: 430.4; Global Yield: 66 %; White Solid; Mp (°C): 38.6. 1H-NMR (CD3OD, δ): 1.38-1.58 (m, 4H, CH2), 2.12-2.22 (m, IH, N-C¾), 2.80-2.90 (m, IH, N-CH2), 3.00-3.10 (m, 2H, N-CH2), 3.91 (dd, IH, J= 4.3 Hz, J= 11.3 Hz, CH2-O), 4.02-4.12 (m, IH, CH2-0), 4.55-4.65 (m, 2H, N-CH), 5.27 (d, IH, J= 8.9 Hz, 7.35-7.45 (m, 3H, ArH), 7.45-7.58 (m, 2H, ArH). ,3C-N R (CD3OD, 6): 24.5, 26.3, 47.2, 48.0, 63.5, 64.4, 7.3, 72.6, 126.7, 130.2, 131.5, 132.3, 143.3, 160.7, 163.8.

Preparation of N-( (± Areo-l-hvdroxy-3-oxo- l-(pyridin-4-vn-3-(pVffohdin- 1 -yl)propan-2-yl)acetamide hydrochloride Compound 235.

To a suspension of (±)-iAreo-2-ammo-3-hydroxy-3-(pYridin-4-yl)-l-Opyrrolidin-l-yl)propan-l-one dihydrochloride Compound 22 (300 mg, 0.89 mmol) in CH2C12 (6 mL) was added Et3N (370 uL, 2.67 mmol) and the mixture was stirred for 10 rmn, cooled at 4 °C and a solution of acetic anhydride (65 mL, 0.89 mmol) in CH2C12 was added dropwise for 10 min. The reaction mixture was brought to room temperature, stirred for 16 h and washed with water (3x4 mL), NaOH (0.5 N) (3x4 mL) evaporated to give an oily residue that was purified using column chromatography (SiO^ with a gradient of 0 % to 20 % MeOH in EtOAc. The product in MeOH at 4 °C was treated with a solution of 1 N HCI (4 mL) and all the volatiles were evaporated. Product was precipitated using a mixture of methanol in EtOAc to obtain after evaporation N-((±)-fAreo-l-hydroxy-3-oxo-l-(pyridm yl)acetamide hydrochloride Compound 235 (209 mg, 52 % yield). (±) 177 Compound 235 MW: 313.78; Yield: 52 %; White Solid; Mp (°C): 181.3 I : 0.20 (MeOH:EtOAc = 20:80, free base).

^-NMR (CD3OD, δ): 1.82-2.05 (m, 7H, 2xC¾ & CH3), 3.35-3.45 (m, 2H, CH2), 3.50-3.65 (m, 2H, CH¾), 5.10 (d, 1H, J= 3.8 Hz, N-CH), 5.39 (d, 1H, J 3.9 Hz, O-CH), 8.16 (d, 2H, J= 6.2 Hz, ArH), 8.81 (d, 2H, J= 6.7 Hz, ArH). I3C-NMR (CD3OD, δ): 22.1, 25.0, 27.0, 47.5, 48.2, 57.0, 72.0, 126.6 (2xC), 142.0 (2C), 142.0 (2xQ, 164.4, 169.0, 173.0.

Preparation of fi^2-amino-3-(pvriclin-4-vlVl-(p dihvdrochloride Compound 236.

N-Boc-(S)-3-(pyridm-4-yl)alanine (0.500 g, 1.88 mmol) was dissolved in CH2C12 (15 mL) and DIEA (361 jiL, 2.07 mmol) was added. The mixture was cooled to 0 °C and isobutyl chloroformate (270 uL, 2.07 mmol) was added. The mixture was stirred for 10 min and pyrroHdine (267 mg, 3.76 mmol) in CH2CI2 (5 mL) was added. This mixture was stirred for 15 min at 4 °C, 12 h at 25 °C, washed successively with NaH2p04, saturated sodium hydrogen carbonate, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue obtained was purify by column chromatography (Si02) using a gradient of MeOH 0-10% [v/v] in EtOAc to give terf-butyl (R)-l-oxo-3-(pyridin-4-yl)-l-(pyrroUdin-l-yl)propan-2-ylcarbamate EBE 06172 (146 mg, 24 % yield) as a white solid. 178 MW: 319.4; Yield: 24 %; White Solid; Mp (°Q: 52.5.

I : 0.30 (MeOHrEtOAc - 20:80). 1H-NMR (CDCI3, 8): 1.40 (s, 9H, (CH3)3), 1.65-1.90 (m, 4H, CHj), 2.80-2.90 (m, 1H, CH), 2.90-3.00 (m, 2H, CH2), 328-3.38 (m, 1H, N-CH), 3.40-3.50 (m, 2H, N-CH2), 4.60-4.70 (m, 1H, N-CH), 5.38-5.48 (m, 1H, NH), 7.16 (d, 2H, J= 4.5 Hz, ArH), 8.50 (d, 2H, 4.5 Hz, ArH).

MS-ESI m z (% rel. Int): 320.2 ([MH]+, 20).

HPLC: Method A, detection at 254 nm, EBE 06172 RT = 3.82 min, peak area 85 %.

CRV2- Amino-3- pvridin-4- vD- 1 -f vrrolidin- 1 -vHpropan- 1 -one dihvdrochloride Compound 236.

To a solution of TFA (2 mL) in CH2C12 (8 mL) was added (2?)-l-oxo-3-(pyridin-4-yl)-l-(pyn-oIidin-l-yl)propan-2-yl^ EBE 06172 (146 mg, 0.654 mmol) and the mixture was stirred for 2 h at 25 °C. The volatiles were evaporated and the product was treated with a suspension on amberlite-400 (OH" form, 2 g) in MeOH. The suspension was filtered and washed with MeOH (3 x 5 mL). The combined methanol fractions were evaporated under reduced pressure and the desired product was isolated using column chromatography (Si02) with a rmxture of EtO Ac:MeOH:NH40H = 70:30:4 to give an oily residue that was treated with a solution of 0.1 N HQ in iPrOH for 10 min. Evaporation of the volatile afforded ( ?)-2-amino-3 -(pyridin-4-yl)- 1 -(pyrrolidin- 179 l-yl)propan-l-one dihydrocMoride Compound 236 (78 mg, 47 % yield) as a pale yellow solid. 2 HCI Compound 236 MW: 255.75; Yield: 47 %; Pale Yellow Solid; Mp (°C): 127.5 I : 0.30 (EtOAc:MeOH:NH40H - 70:30:4, free base).

'H-NMR (CD3OD, δ): 1.80-2.05 (m, 4H, CH2), 3.28-3.80 (m, 6Ή, C¾, N-C¾), 3.70 (t, 1H, J= 6.7 Hz, CH-N), 8.10 (d, 2H, J 5.9 Hz, ArH), 8.88 (d, 2H, J= 5.6 Hz, ArH).

"C-NMR (CD3OD, δ): 23.4, 25.4, 35.6, 46.1, 46.5, 51.1, 128.5 (2xQ, 146.3 (2xQ, 156.1, 165.0.

Preparation of fert-butyl 5-f i:V^rgo-l-hvdroxv-3-oxo-l- pvridiD-4-vlV3- pmolidin-l-vl>propan-2-vlcarbamovl')pentvlcarbamate Compound 237.

To a solution of JV-Boc-arninohexanoic acid (342 mg, 1.48 mmol) in THF (10 mL) was added N-methylmorpholine (163 μ , 1.48 mmol). The solution was stirred for 5 min, cooled at -15 °C and treated dropwise with isobutyl chloroformate (211 μΐ., 1.48 mmol). This solution was added via a stainless steal cannula to a solution of (±)-/Arec^2-amino-3-hychOxy-3 -(pyridin-4-yl)- 1 -(pyrroUdin-l-yl)propan-l-one dihydrochloride Compound 22 (500 mg, 1.48 mmol) and JV-methyl-morpholme (489 mg, 1.47 mmol) in THF (10 mL) at -15°C. The reaction imxture was kept for 0.5 h at -15 °C followed by 2 h at 25 °C with continuous stirring. After evaporation of the solvent, the residue was partitioned between EtO Ac and ¾0, washed with NaH PC^, saturated aqueous 180 NaHC03, dried over sodium sulfate and purified by column chromatography (S1O2) with a gradient of 0 % to 10 % [v/v] MeOH in EtOAc to give iert-butyl 5-((±)-ihreo- 1 -hydroxy-3-oxo- 1 -(pyridin-4-yl)-3-(pyrroUdin- l-yl)propan-2-ylcarbamoyl)pentylcarbamate Compound 237 (455 mg, 69 % yield) as a white solid.

Compound 237 MW: 448.6; Yield: 69 %; White Solid, fy: 0.20 (EtOAc:MeOH = 90: 10). 1H-NMR (CD3OD, δ): 1.05-1.15 (m, 2H, C¾), 1.35-1.55 (m, 13H, 2*CH2 + C(CH3)3), 1.75-1.95 (m, 4H, 2xCH2), 2.00-2.20 (m, 2H, OCCH2), 3.05 (q, 2H, J= 6.7 Hz, N-CH2), 3.20-3.35 (m, 1H, N-CH), 3.38-3.50 (m, 2H, N-CHj), 3.65-3.75 (m, 1H, N-CH), 4.72 (bs, 1H, NH), 4.98 (dd, 1H, J - 8.8 Hz, J= 3.6 Hz), 5.08 (d, 1H, J= 3.3 Hz, OCH), 5.23 (bs, 1H, OH), 6.50 (d, 1H, J = 8.7 Hz, NH), 7.35 (d, 2H, J= 6.0 Hz, ArH), 8.58 (d, 2H, J- 4.6 Hz, J= 1.4 Hz, ArH).

MS-ESI m/z (% rel. Int): 449.2 ([MH] +, 30), 349.2 (100).

HPLC: Method A, detection at 254 nm, Compound 237 RT = 4.03 min, peak area 99.9 %.

Preparation of 6-amino-N-f ±Vt/ireo-l-hvdroxv-3-oxo-l- pvridin-4-vlV3-^yrroHam-l-yl>propan-2-yl)hexanamide Compound 238.

To a solution of tert-butyl 5-((±)-i ireo- l-hydroxy-3-oxo- 1 -(pyridin-4-yl)-3-(pyrrolidm-l-yl)propan-2-ylcarbamoyl)pentylcarbamate Compound 237 (81 181 mg, 0.181 mmol) in CH2C12 (8 mL) was added TFA (2 mL) at 0 °C and stirred for 2 h at 0 °C. All the volatiles were evaporated to give a residue that was treated with a suspension of Amberlite-400 (OH") in MeOH. After filtration, the filtrate was evaporated and the product was isolated by column chromatography (Si02) with CH2Cl2:MeOH:N¾OH = 10:5:0.4 to afford 6-wm o-N-((±)-threo-1 -hydroxy-3-oxo- 1 -(pyridin-4-yl)-3 -(pyrrolidin- 1 -yl)propan-2-yl)hexanamide Compound 238 (40 mg, 64 % yield) as a white solid.

Compound 238 MW: 448.6; Yield: 64 %; White Solid; Mp (°C): 134.4 I - 0.30 (CH2Cl2:MeOH: H40H - 10:5:0.4). 1H MR (CDC13, 5): 1.12-1.30 (m, 2H, CH2), 1.30-1.50(m, 2H, CH2), 1.50-1.65 (m, 2H, CH2), 1.65-1.95 (m, 4H, CH2), 2.10-2.30 (m, 2H, CH2), 2.55-2.70 (t, 2H, J = 6.9 Hz, CH2), 3.10 -3.20 (m, 2H, CH2), 3.28-3.50 (m, 2H, CH2), 3.60-3.70 (m, 1H, CH), 4.95 (dd, 1H, J= 5.1 Hz, 8.4Hz, O-CH), 5.02 (d, 1H, J= 5.0 Hz, OH), 7.11 Hz (d, J= 8.48 Hz, 1H, ArH), 7.35 (dd, 2H, J= 4.4 Hz, J= 1.5 Hz, ArH), 8.55 (dd, j= 1.5 Hz, J= 4.6 Hz, 2H, ArH). 13C NMR (CDCI3, 5): 24.0, 25.1, 25.8, 25.9, 32.5, 35.8, 41.7, 46.0, 46.9, 55.6, 72.6, 121.3 (2xC), 149.2, 149.5 (2xQ, 168.9, 173.7.

Preparation of (iVerv^ro-2-amino-3-hvdroxv-3- pvridin-4-vlV 1 -(pyrrolidin- -vDbutan-l-one dihvdrochloride Compound 239. 182 methanone EBB 06180.

To a stirred solution of KOH (223 mg, 39.7 mmol) in MeOH was added 4-acetylpyridine (478 mg, 39.7 mmol) and 2-isocyano-l-(pvnolidin-l-yl)ethanone BLE 04098 (500 mg, 3.2 mmol). The reaction mixture was stirred for 3 h at 0 °C and then concentrated. The residue was partitioned between EtOAc and ¾0. The organic layer was washed with brine, dried over MgS04, filtered and evaporated to give a yellow oil that was purified by column chromatography (S1O2) with 20 % [v/v] MeOH in EtOAc to give cis- and trans-(±)-(5-methyl-5-pyridk-4-yl-4,5-dihydro-oxazol-4-yl)-pyrro methanone. The mixture was further purified by column chromatography (Si02) using a gradient of 2 % to 5 % [v/v] MeOH [v/v] in CH2C12 to obtain the pure cw-(±)-(5-methyl-5-pyridin-4-yl-4,5 1 -yl-methanone EBE 06180 (122 mg, 51 % yield) as white solid.

EBE 06180 MW: 259.3; Yield: 51 %; White Solid; Mp (°C): 140.9 I : 0.30 (EtOAcMeOH = 80:20). Ή-NMR (CDCI3, 6): 1.45-1.75 (m, 4H, 2xC¾)» 1.81 (s, 3H, CH3), 2.75-2.90 (m, 1H, N-CH2), 3.10-3.22 (m, 1H, N-CH2), 3.30-3.40 (t, 2H,/= 6.7 Hz, N-C¾), 4.83 (d, 1H, J= 1.7 Hz, NCH), 7.22 (d, 1H, /= 1.4 Hz, N=CH), 7^7 (d, 2H, 7= 6.0 Hz, Ar), 8.57 (d, 2H, J = 6.1 Hz, ArH). 13C-NMR (CDCI3, δ): 23.6, 26.0, 27.9, 46.0, 46.5, 77.8, 87.2, 120.2, 148.9, 149.6 (2xC), 155.6 (2xQ, 165.4. 183 T--: en;/^ro-2- Amino-3-hvdroxv-3- pvridin-4-v - 1 -Cpvrrolidin- 1 -vPbutan- 1 -one dihvdrochloride Compound 239.

To a solution cfc-(±)-(5-merayl-5-pyridm^ pyrroUdin-l-yl-methanone EBE 06180 (50 mg, 0.19 mmol) in MeOH (1 mL) was added a solution of 1 N HCl (1 mL) and the reaction mixture was heated at 60 °C for 2 h. All the volatiles were evaporated to give (±)-erytAro-2-amino-3-hydroxy-3-(pyridm-4-yl)-l-(pynohd^ Compound 239 (54 mg, 87 % yield) as a white solid.

Compound 239 MW: 322.23; Yield: 87 %; White Solid; Mp (°C): 140,9 : 0.1 (EtOAcrMeOH = 80:20, free base). 1H-NMR (CDCI3, δ): 1.85-2.05 (m, 7H, CH3+ 2xC¾), 3.35-3.65 (m, 4H, 2*N-C¾), 4.61 (s, 1H, O-CH), 8.23 (d, 2H, J= 4.5 Hz, ArH), 8.89 (d, 2H, J= 4.3 Ηζ, ΑτΗ).

Preparation of (-S)-2-amino-3-fpvridin-4-vlVl -(pvrrolidin- 1 -vl^propan- 1-one dihydrochloride Compound 240. terfrBiityl f.SVl-oxo-3-fpyridm-^^ EBE 06190.

To a solution of AT-Boc-(2^-3-^yridin-4-yl)alanine (500 mg, 1.9 mmol) in THF (12 mL) was added N-methylmorpholine (200 uL, 1.9 mmol) andtitte 184 solution was stirred for 5 min, cooled at - 15 °C and treated dropwise with isobutyl chloroformate (249 uL, 1.9 mmol). The mixture was stirred for 10 rain and pyrrolidine (1.08 g, 15.2 mmol) was added and allowed to warm to 25 °C with stirring for 3 h. The solvent were removed under reduced pressure and the residue was partitioned between EtOAc and NaHfePC^ pH = 7.2. The aqueous layer was discarded and the organic layer was washed with aqueous saturated NaHC03, dried over Na2S0 , filtered and evaporated. The resulting solid was purified by column chromatography (S-O2) with a gradient of 0 % to 10 % [v/v] MeOH in EtOAc to give ieri-butyi (iS)-l-oxo-3-(pyridm^yl)-l-(pynOlidin-l-yl)propan-2-ylcarbamate EBE 06190 (167 mg, 28 % yield) as a white solid.

EBE 06190 MW: 319.4; Yield: 28 %; White Solid Mp (°C): 130.0 ]¾·: 0.30 (EtOAc:MeOH = 90: 10). 1H-NM (CDCI3, δ): 1.40 (s, 9H, C(C , 1.65-1.90 (m, 4H, C¾), 2.80-2.95 (m, 1H, CH), 2.95-3.05 (m, 2H, CH2), 3.30-3.45 (m, 1H, NCH), 3.45-3.55 (m, 2H, N-C¾), 4.60-4.75 (m, 1H, N-CH), 5.42 (d, 1H, J= 8.8 Hz, NH), 7.16 (dd, 2H, J= 4.5 Hz, J= 1.5 Hz, ArH), 8.51 (dd, 2H, J= 1.5 Hz, J= 4.5 Hz, ArH). 13C-NMR (CDC13, δ): 24.1, 25.8, 28.3 (3xQ, 39.1, 45.8, 46.5, 52.6, 79.9, 124.8 (2*C), 145.7, 149.8 (2xQ, 155.0, 169.2. iS^-2-Amino-3-fpvrio^n-4-vlVl-fpvrrolid-n-l-v t7ropan-l-one dihvdrochloride Compound 240. 185 To a solution of tert-but l (S)- 1 -oxo-3 -(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan-2-ylcarbamate EBE 06190 (100 mg, 0.313 mmol) in CH2C12 (3 mL) at 4 °C was added TFA (479 uL, 6.26 mmol) and MeOH (0.3 mL) and the reaction was stirred for 2 h. All the volatiles were evaporated to give a product that was treated with a suspension of amberlite-400 (OH" form, 5 g) in MeOH. The suspension was filtered and washed with MeOH (5x5 mL). The combined methanol fractions were evaporated under reduced pressure and the desired product was isolated by column chromatography (S1O2) with a gradient of 0 % to 30 % [v/v] MeOH in EtOAc to give (iS)-2-ammo-3-(pyridin-4-yl)-l-(pyrrolidin- 1 -yl)piopan- 1 -one. The product was dissolved in MeOH, cooled at 5 °C and a solution of HQ (0.1 N) (9 mL) was added dropwise. All the volatiles were evaporated to give (S)-2-amino-3 -(p yridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan-1-one ^hydrochloride Compound 240 (91 mg, 99 % yield) as a white solid. 2 HCI Compound 240 MW: 292.21; Yield: 99 %; White Solid; Mp (°C): 195.9 : 0.10 (EtOAc:MeOH = 90: 10, free base). lH-NMR (CD3OD, δ): 1.80-2.05 (m, 4H, CH2), 3.30-3.40 (m, 5H, N-CH2 + N-CH), 3.60-3.75 (m, 1H, CH), 4.72 (t, 1H, 7.3 Hz, CH), 8.08 (d, 2H, J= 5.4 Hz, ArH), 8.87 (d, 2H, J= 5.3 Hz, ArH).

I3C- MR (CD3OD, δ): 25.0, 26.9, 37.2, 47.6, 48.0, 57.2, 130.0 (2xQ, 143.1 (2xC), 157.3, 166.6.

MS-ESI m/z (% rel. Int.): 220.1 ([MH]+, 10), 203.1 (50). 186 Preparation of r-fcV^reo-2-amino-3- 6- trifluOTomBthvnpvridiii-3-vIV3-hvdroxy-l-fpyrroUdin-l-vDpropan-l-one dihvdrochloride Compound 241. ylVpyn:oHdin-l-vDmethanone EBE 06196.

To a solution of KOH (184 mg, 3.28 mmol) in MeOH (10 mL) at 4 °C was added 6-(trifluoromethyl)pyricline-3-carbaldehyde (575 mg, 3.28 mmol) and and 2-isocyano-l-(pyirolidin-l-yl)ethanone BLE 04098 (500 mg, 3.28 mmol). The mixture was stirred for 2 h at 4 °C and allowed to warm to 25 °C. All the volatiles were evaporated and the resulting product was partitioned between brine and EtOAc. The organic layer was separated, dried over Na2S0 , filtered to give after evaporation of the solvent (±)-trans-(5-(6-(trifluoromethyl)pyridin-3-yl)-4,5-di ydrooxazol-4-yl)(pyr^ yl)methanone EBE 06196 (801 mg, 78 % yield) as a pale brown solid.

EBE 06196 MW: 310.13; Yield: 78 %; Pale brown solid. 1H- MR (CDCI3, δ): 1.75-2.10 (m, 4H, 2xCH¾), 3.40-3.60 (m, 3H, 2*N-C¾), 3.90-4.00 (m, IH, N-CH), 4.57 (dd, IH, 8.0 Hz, J= 2.2 Hz, N-CH), 6.31 (d, IH, J= 8.0 Hz, O-CH), 7.06 (d, IH, J = 2.2 Hz, N=CH), 7.71 (d, IH, J= 8.1 Hz, ArH), 7.84 (dd, IH, J= 1.8 Hz, = 8.1 Hz, ArH), 8.70 (d, 1H, J= 1.5 Hz, ArH). 187 l-yl^propan-l-one dihvdrochloride Compound 241.

To a solution of (±)-/r w-(5-(6 trifluorome&^ dihydrooxazol-4-yl)(pyrrolidin- 1 -yl)me hanone EBE 06196 (400 mg, 1.28 mmol) in MeOH (2 mL) was added HCl (37 %) (10 mL) and the mixture was heated at 60 °C for 2 h with continuous stirring. After evaporation the resulting white solid was treated with a suspension of amberlite-400 (Off form) in MeOH. The suspension was filtered and washed with MeOH (5x5 mL). The combined methanol fraction were evaporated under reduced pressure and the desired product was isolated by column chromatography (S1O2) with a gradient of 0 % to 8 % [v/v] MeOH in EtOAc to obtain (±)-*A/¾o-2-amino-3-(6-( fluoromethyl)pyridin-3-yl)-3-hydroxy-l-(pyrrolidui-l-yl)propan-l-one (287 mg). To a solution (±)-/Areo-2-arnino-3-(6-(trifluoromethyl)pyridin-3-yl)-3-hydroxy-l-(pyrrolidin-l-yl)propan-l-one (209 mg, 0.69 mmol) in MeOH (2 mL) at 4 °C and treated HCl 37 % (10 mL). All the volatiles were evaporated to give (±)-i^eo-2-amino-3-(6-(trifluoromethyl)pyridin-3-yl)-3-hydroxy- 1 -(pyn:oHdin-l-yl)propan-l-one dihydrochloride Compound 241 as a white solid (269 mg, 74 % yield).

Compound 241 MW: 376.2; Yield: 74 %; White Solid; Mp (°C): 190.0. fy: 0.3 (EtOAc:MeOH = 92:8, free base). 1H-NMR (CD3OD, δ): 1.40-1.70 (m, 2H, CH2), 1.70-1.90 (m, 2H, C¾), 2.35-2.50 (m, 1H, N-CH), 3.15-3.35 (m, 1H,N-CH2), 3.35-3.45 (m, 2H, N-CH2), 188 4.32 (d, IH, J= 8.3 Hz, N-CH), 5.11 (d, IH, J= 8.2 Hz, O-CH), 7.88 (d, IH, J - 8.3 Hz, ArH), 8.16 (d, IH, J= 8.0 Hz, ArH), 8.73 (s, IH, ArH). ,3C-NMR(CD3OD, δ): 24.8, 26.6, 47.4, 47.9, 58.7, 71.3, 121.7, 122.9 (d, 1C, J = 273.2 Hz, CF3), 137.9, 140.3, 149.0, 149.7, 165.8.

Preparation of f-fcV f½reo-2-arnmo-3-hvdroxv- 1 -fthiazolidin-3 - vD-3 -fpvridin-4-yPpropan-l-one dihvdrochloride Compound 242. (Α ^Γ6θ-2-Αττι½η-3-ΗνάΓθ ν-3-(ονή<ϊ-η-4-ν1^ΓθΡ8ηοίο acid dihvdrochloride EBE 10038B.

To a stirred solution of KOH (2.57 g, 35.4 mmol) in MeOH (35 mL) at 0 °C was added 4-pyridinecarboxaldehyde (3.80 g, 35.4 mmol) and tert-butylisocyano acetate (5 g, 35.4 mmol). The solution was stirred for 3 h at 0 °C and concentrated to obtain intermediate trans-4,5-dihydro-5-(pyridin-4-yl)oxazole-4-carboxylate as a pale yellow solid EBE 10038A.

EBE 10038A lH NMR (CD3OD, δ): 4.29 (dd, IH, ./= 1.7 Hz, 7.6 Hz, N-CH), 5.67 (d, IH, 7= 7.6 Hz, O-CH), 7.29 (d, IH, 1.9 Hz, N=CH), 7.46 (d, 2H, 7= 4.7 Hz, ArH), 8.55 (dd, 2H, = 1.7 Hz, 7= 4.4 Hz, ArH).

The solid EBE 10O38A was dissolved in MeOH (100 mL), stirred 5 min at 0 °C and treated with HC1 (12 N) (10.5 mL). The reaction was heated at 60 °C for 2 h, cooled down to 4 °C to form a precipitate that was filtered. The filtrate was evaporated and dried to obtain (±)-i/ireo-2-amino-3-hydroxy-3 -(pyridm-4-yl)propanoic acid dihydrochloride EBE 10038B with 20 % of (±)-eryth.ro isomer (9 g, 99 % crude yield) as a pale beige solid. 189 MW: 255.10; Yield: 99 %; Pale Beige Solid. 1H-NMR (CD3OD, δ): 3.94 (d, 1H, J= 3.9 Hz, N-CH), 4.61 (t, 1H, J= 3.0 Hz, O-CH), 8.31 (d, 2H, ArH), 8.95 (m, 2H, ArH). Only the formula and the ¾-NMR description of major threo isomer is shown.

MS-ESI m/z (% rel. Int.): 183.1 ([MH]+, 5). fiV^reo-N-Boc-2-amino-3-(pvridin-4-vlV3-hvdroxv-propioriic acid EBE 10040.

A solution of di-terf-butyldicarbonate (9.28 g, 42.5 mmol) in dioxane (40 mL) was added to a pre-mixed ice cold solution of (±)-/Areo-2-ammo-3-hyfroxy-3-(pyridm-4-yl)propanoic acid dihydrochloride EBE 10038B (9.01 g, 35.4 mmol) in a solution of 1 Ν NaOH (145 mL). The biphasic mixture was stirred at 5 °C for 30 min and allowed to warm to room temperature for 3.5 h, concentrated, cooled in an ice bath, acidified to pH 4-5 and extracted with n-butanol. The combined extracts were dried over Na2S0 and filtered to give (±)· i¾reo-N-Boc-2-arnmo-3-(pyri EBE 10040 MW: 282.2; Yield: 33 %; Pale Yellow Solid. 190 lH-NMR (DMSO-d6, δ): 1.24 (s, 9H, C(CH3)3), 4.32 (d, 1H, J = 9.4 Hz, N-CH), 5.13 (s, 1H, O-CH), 6.35 (d, 1H, 7= 9.4 Hz, H), 7.37 (d, 2H, J= 3.8 Hz, ArH), 8.48 (d, 2H, 3.6 Hz), 2 OH not seen. 13C-NMR (DMSO-d6, δ): 27.9 (3xC), 59.0, 71.3, 78.2, 121.4, 122.8, 148.9, 150.3, 151.0, 155.2, 171.6.

MS-ESI m/z (% rel. Int.): 283.2 ([MH] +, 10).

HPLC: Method A, detection at 254 nm, EBE 10040 RT - 3.17 min, peak area 95.9 %. ylforopan-2-ylcarbamate EBE 10042.

To a solution of (±)-/^e( N-Boc-2-ammo-3- >yridin-^yl)-3-hydroxy-propionic acid EBE 10040 (500 mg, 1.77 mmol) in CH2C12 (10 mL) at 0 °C was added triethylamine (253 μί,, 3.54 mmol), hydroxybenzotriazole (239 mg, 1.77 mmol), l-(3-dimemylammopropyl)-3-emylcarbo-diimi EBE 10042 MW: 353.4; Yield: 32 ; Yellow Oil.

R,: 0.2 (CH2Cl2:MeOH - 97:3). 1H-NMR (CDC13> 5): 1.29 (s, 9H, (CH3)3), 2.90-3.05 (m, 2H, S-CHz), 3.60-3.95 (m, 2H, N-CH2), 4.40-4.72 (m, 3H, N-CH + S-CH2-N), 5.10-5.15 (m, 1H, OCH), 5.68 (m, 1H, NH), 7.34 (d, 2H, J= 6.0 Hz, ArH), 8.53 (d, 2H, J= 6.0 Hz, ArH), OH not seen. 13C-NMR (CDCI3, δ), minor rotamer in parenthesis: 28.1 (29.2) [3xC], 31.1, (48.5) 48.7, 49.0 (49.1), (56.4) 56.7, 72.3, 80.5, 121.4 [2xC], 148.7, 149.4 [2xC], 155.5, (169.0) 169.2.

MS-ESI m/z (% rel. Int.): 354.2 ([MH , 20).

HPLC: Method A, detection at 254 nm, EBE 10042 RT = 3.87 min, peak area 98.1 %. dihvdrochloride Compound 242.

To a solution of ferf-butyl (±)-iAreo-l-hydroxy-3-oxo-l-(pyridin-4-yl)-3-(tm^lidm-3-yl)propan-2-ylcarbamate EBE 10042 (150 mg, 424 mg) in MeOH (10 mL) at 4 °C was added a solution of 1 N HC1 in MeOH (12 mL). The reaction mixture was allowed to warm at room temperature and stirred for 1 h. All the volatiles were evaporated to give an oily residue that was dissolved in MeOH and treated with EtOAc to form a precipitate. The volatiles were evaporated to give (±)-tfcreo-2-ammo-3-hydroxy-l-(thi 192 4-yl)propan-l-one ^hydrochloride Compound 242 (135 mg, 98 % yield) as a pale yellow solid.

Compound 242 MW: 326.24; Yield: 98 %; Pale Yellow solid; Mp (°C): 210.6 'H-NMR (CDC13, δ): 2.90-3.15 (m, 2H, S-CH2), 3.55-3.90 (m, 1H, N-CH), 4.00-4.15 (m, IH, N-CH), 4.18-4.53 (m, IH, N-CH), 4.62-4.78 (m, 2Η, N-C¾-S), 5.38-5.49 (m, IH, O-CH), 8.25 (d, 2H, = 5.7 Hz, 2H, ArH), 8.94 (d, 2Η, = 5.7 Hz, ArH). ,3C-NMR(CDC13, δ), roinor rotamer in parenthesis: (29.9) 31.8, 34.8, (51.1) 52.1, (57.8) 58.2, 71.0 (71.3), 126.8 [2xC], 143.2 [2xC], 161.4, (164.8) 165.2. MS-ESI m/z (% rel. Int): 254.2 ([MH]+, 15).

Preparation of (-fcVt trgo-2-amino-3-hvdroxv- 1 -findolin- 1 -vlV3-('pvridin-4-vDpropan-l-one dihydrochloride Compound 243.

To a solution of potassium /r ni-4,5-dmydrcH5-(pyridin-4-yl)oxazole-4-carboxylate EBE 10038A (500 mg, 2.60 mmol) in CH2C12 (13 mL) were added HOBT (352 mg, 2.60 mmol), EDCI (499 mg, 2.60 mmol) and indoline (292 mL, 2.60 mmol). The reaction mixture was stirred 2 h at 0 °C, allowed to warm to RT and stirred for 16 h. The reaction mixture was diluted in CH2CI2 (100 mL), wash with brine (3x25 mL), NaOH IN (3x25 mL), dried over MgS04, filtered to give after evaporation fr wj-(4,5-dmydro-5-(pyjidin-4-yl)oxazol-4-yl)(lff-indol-l-yl)methanone SLA 09182 (533 mg, 70 % yield) as a pale brown oil. To a solution of SLA 09182 (533 mg, 2.6 mmol) in MeOH (12 mL) was 193 added a solution of HCl 37 % (880 uL). The reaction was stirred for 3 h at 50 °C and concentrated under reduced pressure. The resulting product was dissolved in MeOH and treated with amberlite (OH* form), filtered to give after evaporation a residue that was purified using silica gel chromatography with a gradient of MeOH 0 % - 10 % in CH2C12 to yield (-fc)-iAreo-2-amino-3-hydroxy-l-(mdolm-l-yl)-3-( vridin-4-yl)propan-l-one. The hydrochloride salt was formed by treatment with a solution of 1M HCl in MeOH (3.2 mL) to give after evaporation (±)-iAreo-2-armno-3-hydroxy- l-(mdoHn-l-yl)-3-(pyjidin-4-yl)propan-l-one dihydrochloride Compound 243 (149 mg, 16 % yield) as a white solid.

Compound 243 MW: 356.25; Yield: 16 %; White Solid; Mp (°Q: 202.5 fy: 0.30 (CH2C12: MeOH = 90:10, free base) Ή-NMR (CD3OD, δ): 3.65-3.80 (m, 1H, N-CH2), 4.15-428 (m, 1H, C¾), 3.65-3.80 (m, 1H, CH2), 4.15-4.30 (m, 1H, N-CH2), 4.64 (d, 1H, = 5.4 Hz, N-CH), 5.45 (d, 1H, J= 5.3 Hz, O-CH), 6.70 (t, 1H, J= 7.4 Hz, ArH), 7.12 (dd, 2H, 7= 7.7 Hz, ArH), 8.07 (d, 1H, = 7.9 Hz, ArH), 8.15 (d, 2H, J= 6.2 Hz, ArH), 8.79 (d, 2H, = 6.2 Hz, ArH). 13C-NMR (CD3OD, δ): 28.9, 30.8, 58.4, 71.1, 118.5, 126.1, 126.4, 126.5 (2xQ, 128.4, 133.6, 142.9, 143.6 (2xQ, 161.0, 164.7.

MS-ESI m/z (% rel. Int.): 284.2 ([MH]+, 10).

Preparation of (± ½reo-2-amino-3-(3 -dicMoropyridin-4-ylV3-hvdroxy-l-( 2H-p vrrol- 1 f5H)- v propan- 1 -one dihydrochloride Compound 245. 194 ylto_ethanone SLA 09022.

To a stirred and cooled (0 °C) solution of KOH (0.315 g, 5.62 mmol) in methanol (70 mL) was added a mixture of 3,5-dichloropyridine-4-carbaldehyde (0.989 mg, 5.62 mmol) and 2-isocyano-l-(2Ji-pyrrol-l(5/ -yl)et^ ne SLA 07178 (0.696 g, 5.11 mmol). The solution was stirred 2 h with continued cooling and then concentrated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was combined with additional EtOAc extracts (3x50 mL), washed with brine (70 mL) and dried with MgS04, filtered and evaporated to obtain a crude product which was purified by column chromatography (florisil, EtOAcrcyclohexane = 80:20) to obtain after evaporation ^-m-(5-(3J5 -icWoropyridin-4-yl)-4,5-dihydrooxazol-4-yl)(2H-pyrrol-l(5H)-yl)methanone SLA 09022 (1.267 g, 80 % yield) as a pale yellow solid. (±yt ns SLA 09022 MW: 312.15; Yield; 80 %; Pale Yellow Solid.

R^: 0.15 (EtOAc: cyclohexane = 80:20). 1H-NMR (CDCI3, δ): 4.30-4.32 (m, 3H, 1.5χΟ¾), 4.77-4.83 (m, 1H, 0.5xCH2), 4.86 (dd, IH, J= 2.2 Hz, J= 8.8 Hz, CH-N), 5.84-5.88 (m, 2H, CH=CH), 6.86 (d, IH, J= 8.7 Hz, CH-O), 6.96 (d, IH, J 2.2 Hz, 0-CH= ), 8.52 (s, 2H, ArH).

I3C- MR (CDC13, δ): 52.1, 52.6, 59.2, 75.1, 123.9, 124.4, 131.5, 139.5, 147.6, 148.3, 151.0, 153.9, 164.3. 195 f± et 2-AnTmo-3-f3.5-dicMoropy^ yl)propan-l-one dihvdrochloride Compound 245.

To a stirred solution of i flni-(5^3,5- To a stirred solution of triphenylphosphine (200 mg, 0.76 mmol) in 5 mL of CH3CN were added at 20 °C diethylazodicarbonate (120 μΐ, 0.76 mmol), Et3N (55 μΐ, 0.38 inmol) and N-((±)-^reo-l-hydroxy-3-oxo- l-(pyridin-4-yl)-3-(pyrroUdin-l-yl)propan-2-yl)fonnamide hydrochloride Compound 216 (115 mg, 0.38 mmol). The mixture was stirred 2 h at 70 °C men solvent was evaporated. The obtained residue was purified by column chromatography (S1O2, EtOAc:MeOH = 9:1) to give N-(l -oxo-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)prop-2-en-2-yl)forinamide TTA 08074A (80 mg, 43 % yield). HCl treatment in EtOAc with HCl 0.4 N in diethyl ether (1 mL, 0.4 mmol) gave after evaporation and drying N-(l-oxo-3-(pyridin^-yl)-l-(pyrrolidin-l-yl)prop-2-en-2-yl)formarnide hydrochloride (trans'.cis isomers mixture) Compound 246 (60 mg, 28 % yield) as a pale yellow pasty product. cis:trana mixture Compound 246 MW: 281.74; Yield: 28 %; Pale Yellow Pasty Product ¾- : 0.24 (EtOAc:MeOH * 9:1).

'H-NMR (CD3OD, δ): 1.80-2.05 (bs, 4H, 2χΟ¾), 3.25-3.45 (bs, 2H, 0¾-Ν), 3.55-3.70 (bs, 2H, C¾-N), 6.87 (s, 1H, CH), 7.82 (d, 2H, = 5.0 Hz, ArH), 8.31 (s, 1H, HOO), 8.65 (d, 2H, = 5.0 Hz, ArH). 13C-NMR (CD3OD, δ): 25.1, 26.5, 47.1, 48.9, 109.0, 125.6 (2xC), 127.7, 142.2 (2xC), 142.6, 154.9, 161.6. 197 MS-ESI m/z (% rel. Int.): 246.1 ([MHf , 5), 175.1 (100).

HPLC: Method A, detection UV 254 nm, Compound 246 RT = 1.90 min, peak area 95.0 %.

Preparation of (2S3R & (2 3,fl-2-amfao-l-((RV3-hv(froxY^ hvdroxy-3-fpyridin- -yl)propan-l-one dihydrochlorides Compound 247. l-ffii!V3-hvdroxyDmolidm-l-ylV2 socvanoethanone VIB 01172.

To stirred and cooled (0 °C) methyl isocyanoacetate (96 % technical grade, 1.7 g, 17.21 mmol) was slowly added ( ?)-(+)-3-pyrrolidinol (1.5 g, 17.21 mmol) and MeOH (5 mL). The mixture was stirred for 3 h at RT and concentrated. Brine was added (30 mL) and the mixture was extracted with EtOAc (3x50 mL), dried over MgSO-j, filtered and evaporated to obtained crude l-((i? 3½droxypynoHdin-l-yl)-2-isocyanoethanone VB 01172 (1.3 g, 49 % yield) as a yellow solid.

MW: 154.17; Yield: 49 %; Yellow Solid; Mp (°C) - 55.9 1H-NMR(CDC13, δ): 1.95-2.20 (m, 2H, CH2), 2.60-2.82 (m, 1H, OH), 3.30-3.68 (m, 4H, 2χΟ¾), 4.20-4.36 (m, 2H, CH2), 4.49-4.65 (m, 1H, CH-O).

MS-ESI m/z (% rel. Int.): 155.1 ([MH]+, 90). frg/M-f(jgV3-hvdroxyDmohdin-l-vn((4.?.5igV & f4. e.55)-4.5-dihvdro-5- p\ddm-4-ynoxazol-4-ynmethanones VIB 01174.

To a stirred and cooled (0 °Q solution of KOH (0.40 g, 7.13 mmol) in MeOH (8 mL) were added successively pyridine-4-carbaldehyde (0.84 g, 7.84 198 mmol) and l-((i?)-3-hydroxypyrrolidm-l-yl)-2-isocyanoemanone VIB 01172 (1.10 g, 7.13 mmol). The mixture was stirred at 0 °C to RT for 24 h. After evaporation of MeOH, the mixture was partitioned between EtOAc (50 mL) and H20 (10 mL). The aqueous layer was further extracted with EtOAc (2x50 mL). The EtOAc fractions were combined, washed twice with brine (2x10 mL), dried over MgSOi, filtered and evaporated. After evaporation and drying trans-((R)-S-hydroxypyrrolidin-l-yl)^^^)- & (4Λ,5¾- ,5-^<^ο-5- ^(ηη-4-yl)oxazol-4-yl)methanones VIB 01174 (490 mg, diastereoisomeric mixture in ratio 1: 1, 26 % yield) were obtained as a crude pale yellow solid.

VIB 01174 MW: 261.28; Yield: 26 %; Pale Yellow Solid. 1H NMR (CDC13, 8): 1.88-2.22 (m, 2H, C¾), 3.50-3.80 (m, 3H, 1.5xCH2), 3.95-4.20 (m, 1H, 0.5xCH2), 4.40-4.65 (m, 2H, CH-N & CH-O), 4.74 (s, 1H, OH), 6.18-6.22 (m, 1H, CH-O), 7.00-7.12 (m, 1H, HON), 7.20-7.30 (m, 2H, ArH), 8.52-8.68 (m, 2H, ArH).

MS-ESI m/z (% rel. Int.): 262.2 ([MH]+, 45), 235.2 (75), 148 (100). (2S.3K)- & r2R.3S -2-Amino- 1 -( (R)-3 -hvdroxvp vrrolidin- 1 -vl -3 -hvdroxv-3-fpyridin-^-yl^ropan-l-one dihvdrochlorides Compound 247.

To a solution of /raw-^-S-hydroxy ynOlidm-l-yl)^^^)- & (4Λ.55)-4,5-dihydro-5-^yridm-4-yl)oxazol-4-yl)methanones \OB 01174 (0.49 g, 1.87 mmol) in methanol (6.5 mL) was added hydrochloric acid 37 % (575 fiL). After heating (50 °Q the mixture for 2 h the reaction mixture was concentrated and 199 the crude product was coevaporated twice with EtOAc. After trituration with EtOAc, filtration and drying (2S,3R)- & (22?,35)-2-armnc-l-((/?)-3-hydroxypyrrolidin- 1 -yl)-3 -hydroxy-3 -(pyridin-4-yl)propan- 1 -one dihydrochlorides (420 mg, diastereoisomeric mixture in ratio 1: 1, 69 % yield) were obtained as a pale pink solid.

Compound 247 MW: 324.2; Yield: 69 %; Pale Pink Solid; Mp (°Q: 177.0 1H- MR (CD3OD, δ): 1.88-2.22 (m, 2H, <¾), 2.70-3.80 (m, 4H, 2χ(¾), 4.20-4.65 (m, 2H, CH-0 & CH-N), 520-5.45 (m, 1H, CH-O), 8.10-8 5 (m, 2H, ArH), 8.80-9.00 (m, 2H, ArH), 2xOH & H2 not seen.

MS-ESI m/z (% rel. Int.): 252.2 ([MH]+, 37), 235.1 (63), 148.0 (100).

Preparation of f- ftreo^-ammo-l-ff^S-fl^ (pyridin-4-yl propan-l-one dihvdrochloride Compound 248 and (+)-threo-2-amino- 1 - CS>-3-fluoropvrrolidin- 1 -vlV3-hvdroxv-3-(pvridin-4-vDt>ropan- 1-one dihvdrochloride Compound 249.

Extraction of the free base: (2S,3R)- & (2fl,3¾-2-armno-l-((S)-3-flTO (pyridin-4-yl)propan-l-one dihydrochlorides Compound 214 (300 mg, 0.92 mmol) were dissolved in 10 mL of a ajCOa (10 %) solution and the aqueous mixture was then saturated with NaCl. The aqueous phase was extracted by 5 x 200 15 mL of a mixture CH2Cl2:2-PrOH (9:1). The organic phase was dried over MgSC>4 and evaporated to afford 163 mg (70 %) of the corresponding free base of Compound 214.

Analytical chiral separation: 20 uL of a 1 mg mL solution of Compound 214 were injected on Chiralpak AD: flow-rate = 1 mL min, temperature = 25 °C, mobile phase hexane:ethanol = 7:3, detection on UV 220 nm and on polarimeter, first eluted diastereoisomer Compound 248 Rtl(-) = 20.94 min, second eluted diastereoisomer Rt2(+) = 24.77 min, kl(-) - 5.93, k2(+) = 7.20, a = 1.21 and resolution Rs = 1.21. The integration of the UV signal gives 42 % for the first diastereoisomer compound 248 and 58 % for the second Compound 249 (the UV response is different for the two diastereoisomers).

Semi-preparative chiral separation: 170 mg of the free base of Compound 214 were dissolved in 6 mL of ethanol, and 30 \iL of this solution were injected every 9 min on Oiiralpak AD-H, flow-rate = 2 mL/min, mobile phase hexane: ethanol = 7:3, detection on UV 220 nm. 195 successive injections were done. The two main fractions were identified on UV and collected in two different flasks. The solvent was removed in vacuo at 30 °C. The resulting solid was dissolved in 50 mL of CEfeCfe and then filtered on a 0.45 μιη millipore membrane. After evaporation of CH2C12, the solid was dissolved in 50 mL of methanol and then filtered. For the free base of the first diastereoisomer, a new series of injections was needed to remove two UV-visible impurities collected in the same flask: in the same chromatographic conditions, 30 injections of 100 uL of a 25 mg/mL solution were made every 20 min. The salts Compound 248 and Compound 249 were 201 regenerated according to the same procedure reported for Compound 203 and Compound 204.

The regenerated salts Compound 248 and Compound 249 were injected in analytical conditions, the diastereoisomeric excesses for Compound 248 and Compound 249 were determined to be higher than 96 %.

( -Ythreo-2-AmLn - 1 -( S)-3-fluoropvrrolidin-l-vlV3-hvdroxv-3-(pvridin-4-yl)propan-l-one hydrochloride Compound 248.

Compound 248 MW: 326.19; 70 mg obtained; Pale Yellow Solid; Mp (°C): too hygroscopic. Diastereoisomeric excess > 96 % measured by HPLC at 220 nm (Chiralpak AD). ct^D = - 2.0 (methanol, c = 1).

^-NMR (CD3OD, 5): 1.85-2.38 (m, 2H, CH2), 2.72-4.05 (m, 4H, 2χΟ¾), 4.49-4.62 (m, 1H, CH"N), 5.10-5.48 (m, 2H, CH-0 & CH-F), 8.11-8.25 (m, 2H, ArH), 8.82-8.98 (m, 2H, ArH). ( ;/treo-2-Airim()-l-((^^ yPpropan-l-one dihvdrochloride Compound 249.

Compound 249 202 MW: 326.19; 85 mg obtained; Pale Yellow Solid; Mp (°C): too hygroscopic. Diastereoisomeric excess > 96 % measured by HPLC at 220 nm (Chiralpak AD). a25D = + 31.7 (methanol, c = 1).

!H-NMR (CD3OD, 5): 1.82-2.38 (m, 2H, CH2), 2.90-4.00 (m, 4H, 2xCH2), 4.35-4.60 (m, 1H, CH-N), 5.00-5.48 (m, 2H, CH-0 & CH-F), 8.11-825 (m, 2H, ArH), 8.82-9.00 (m, 2H, ArH).

Preparation of -j-VrArg^-?-ATnirir^N-ethvl-3-hvdroxv-N-methvl-3-pvridin-4-vl-propanamirifi dihydrochloride Compound 250. frgy»j-N-emyl-4.5-dmvdro-N-methyl-5-fpyridm-4-vnoxa∞ SLA 09190.

To a solution of potassium i - ns-4,5-dmydro-5-(pYridin-4-yl)oxazole-4-carboxylate EBE 10038A (501 mg, 2.60 mmol) in CH2C12 (12 mL) were added HOBT (352 mg, 2.60 mmol), EDCI (500 mg, 2.60 mmol) and N-methylethanainine (223 mL, 2.60 mmol). The reaction mixture was stirred 2 h at 0 °C, allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted in CH2C12 (100 mL), washed wim brine (2x25 mL), 1 N NaOH (2x25 mL), dried over MgSO-j, filtered to give after evaporation trans-N-ethyl-4 , 5 -dihydro-N-metliyl-5- (pyridin-4-yl)oxazole-4- carboxamide SLA 09190 (144 mg, 24 % yield) as a pale brown oil. (tytrans SLA 09190 203 MW: 233.27; Yield: 24 %; Pale Brown Oil. Ή NMR (CDC13, δ): 1.15-1.30 (m, 3H, CH3), 3.22 (s, 3H, CH3-N), 3.40-3.80 (m, 2H, N-CHz), 4.59 (dd, 1H, /= 2.2 Hz, 7= 7.8 Hz, N-CH), 6.24 (d, J= 7.7 Hz, OCH), 7.02 (d, 1H, J= 1.0 Hz, N=CH), 7.23 (d, 2H, J= 4.8 Hz, ArH), 8.61 (d, 2H, .7= 4.6 Hz, ArH).

MS-ESI m z (% tel. Int.): 234.2 ([MH]+, 30). f±V^rec^2-Amino-N-ethvl-3-hv(iroxv-N-methvl-3-pvridin-4-vl-pro dihvdrochloride Compound 250.

To a solution of N-ethyl-4,5-dihydro-N-methyl-5-(pyridin-4-yl)oxazole-4-carboxamide SLA 09190 (144 mg, 0.6 mmol) in MeOH (5 mL) was added a solution of HC1 37 % (240 \iL). The reaction was stirred for 3 h at 50 °C and concentrated under reduced pressure. The resulting product was dissolved in MeOH and treated with amberlite (OH" form), filtered to give after evaporation a residue that was purified by column chromatography (S1O2, with a gradient of MeOH 10 % in CH2CI2) to yield to 2-amino-^-emyl-3-hydroxy-iV-methyl-3-pyridin-4-yl-propionamide. The hydrochloride salt was formed by treatment of this free base with a solution of HCl 1 M in MeOH (1 mL) to give after evaporation 2-armno-N^thyl-3-hyckoxy-N-meth^ dihydrochloride Compound 250 as a pale yellow solid (80 mg, 44 % yield).

Compound 250 MW: 296.19; Yield: 44 %; Pale Yellow Solid; Mp (°C): 114.7 Py: 0.30 (CH2Cl2:MeOH - 90:10, freebase). 204 ^-NMRCdbOD, δ): 0.96-1.10 (m, 3H, CH3), 2.81 (s, 1.8H major rotamer, 0.6xCH3), 2.88 (s, 1.2H minor rotamer, 0.4CH3), 3.18-3.55 (m, 2H, CH2), 4.66 (d, 0.4H minor rotamer, J= 6.6 Hz, 0.4xN-CH), 4.69 (d, 0.6H major rotamer, J = 6.3 Hz, 0.6xN-CH), 5.24 (d, 0.4H minor rotamer, J= 6.9 Hz, 0.4xO-CH), 5.27 (d, 0.6H major rotamer, J= 6.3 Hz, 0.6xO-CH), 8.08 (t, 2H, J= 6.5 Hz, ArH), 8.86 (d, 2H, J= 5.0 Hz, ArH). 13C-NMR (CD3OD, δ): 12.0, (13.6), (33.4), 35.3, 44.5, (45.6), 56.1, (56.2), 71.6, (72.1), 126.2 (2xQ, 144.5, 144.6, 159.6, 166.5. ( ) Minor rotamer in parenthesis.

Preparation of (2i?.3iSV2-(3.4-chchlorobenzylam^ vlV l-fovrrolidin- 1 -vDpropan- 1-one dihvdroohloride Compound 251.

To a solution of (- (2i?^5)-2-ami o-3-hydroxy-3-(pyridin-4-yl)-l-(pyrrolidin-l-yl)propan-l-one dihydrochloride Compound 203 (175 mg, 0.57 mmol) and Et3N (175 μΙ_, 1.25 mmol) in MeOH (5 mL) in a 50 mL round bottom flask equipped with a magnetic stirrer and under nitrogen atmosphere was added slowly at RT 3,4-dichlorobenzaldehyde (112 mg, 0.63 mmol). The reaction mixture was stirred at RT for 20 h. Then AcOH (65 uL, 1.15 mmol) and NaBH3CN (50 mg, 0.74 mmol) were added. The reaction mixture was stirred at RT for another 15 h. MeOH was evaporated and EtOAc (100 mL) was added. The organic phase was washed with a mixture of saturated sodium carbonate (5 mL) and brine (20 mL), then with brine (10 mL) and dried over MgSO-}, filtered and evaporated. The crude product was purified by column chromatography (Si02, eluent EtOAc:MeOH = 95:5) to give an oil (- (2Λ,3.¾-2-amino-3-hydroxy-3 -(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)propan- 1 -one (182 mg, 81 % yield). This free base (182 mg, 0.46 mmol) was dissolved in MeOH (2 mL) at 4 °C and a solution of HC1 0.1 N in isopropanol (10.2 mL, 1.01 mmol) 205 was added. After evaporation at 30 °C, a mixture of EtOAc:MeOH = 95:5 was added to yield, after evaporation and drying, to (2_R,3 Compound 251 MW: 467.22; Yield: 78 %; White Solid; Mp (°C): 195.1 fy: 0.22 (EtOAc:MeOH = 95:5, free base). 1H-NMR (CD3OD, δ): 1.55-1.77 (m, 4H, 2xC¾), 2.46-2.53 (m, 1H, 0.5xN-C¾), 3.20-3.30 (m, 3H, xN-CHz), 4.25 (d, 1Η, = 13.3 Hz, 0.5xN-CH2), 4.38 (d, 1H, J= 13.3 Hz, 0.5xN-CH2), 4.52 (d, 1H, J= 7.7 Hz, N-CH), 5.33 (d, 1H, J= 7.7 Hz, O-CH), 7.48 (dd, 1H, J= 8.3 Hz, 7= 1.7 Hz, ArH), 7.62 (dd, 1H, J= 8.3 Hz, J= 1.2 Hz, ArH), 7.74 (s, 1H, ArH), 8.15 (d, 2H, J= 5.6 Hz, ArH), 8.91 (d, 2H, J= 5.6 Hz, ArH). ,3C- MR (CD3OD, δ): 24.7, 26.6, 47.6, 48.2, 50.4, 64.0, 72.2, 126.8 (2xQ, 131.7, 132.2, 132.3, 133.8, 133.9, 135.1, 143.5 (2xC), 160.6, 163.8.

MS-ESI m z (% rel. Int.): 394.1/396.1/398.1 ([MH]+, 60/45/10), 219.2 (100). HPLC: Method A, detection UV 254 nm, Compound 251 RT = 3.83 min, peak area 99.5 %.

Preparation of f2!y.3¾ -2-r3.4-dichloro¾enzylaminnV3-hvdroxy-3^yri&^ yn-l-CpV-Tolidin-l-vnpropan-l-one dihydrochloride Compound 252. 206 Same experimental as forCompound 251 preparation starting from (+)-(2S,3-R)-2-amino-3-hydroxy-3-(pyri^ dihydrochloride Compound 204 (175 mg, 0.57 mmol). After purification by column chromatography (25,3i¾)-2-(3,4-dicWorobenzylarnino)-3-hydroxy-3-(pyri(h"n-4-yl)-l-(pyiToUoin-l-yl)propan-l-one was obtained (187 mg, 83 % yield). This free base (187 mg, 0.47 mmol) was dissolved in MeOH (2 mL) at 4 °C and a solution of HCl 0.1 N in isopropanol (10.4 mL, 1.04 mmol) was added. After evaporation at 30 °C, a mixture of EtOAc:MeOH = 95:5 was added to yield, after evaporation and drying, to Compound 252 as a white solid (212 mg, 80 % yield).

Compound 252 MW: 467.22; Yield: 80 %; White Solid; Mp (°Q: 187.5 fy: 0.22 (EtOAc:MeOH = 95:5, free base). 1H- MR (CDC13, δ): 1.55-1.77 (m, 4H, 2xC¾), 2.46-2.53 (m, IH, 0.5xN-CH2), 3.20-3.30 (m, 3H, 1.5xN-CH2), 4.25 (dd, IH, J= 13.3 Hz, 0.5xN-CHa), 4.40 (d, IH, J= 13.3 Hz, 0.5xN-CH2), 4.52 (d, IH, 7.7 Hz, N-CH), 5.33 (d, IH, J= 7.4 Hz, O-CH), 7.48 (d, IH, J= 8.3 Hz, ArH), 7.62 (dd, IH, = 8.3 Hz, J - 0.8 Hz, ArH), 7.74 (s, IH, ArH), 8.15 (d, 2H, 5.7 Hz, ArH) 8.91 (d, 2H, 7= 5.7 Hz, ArH).

"C-NMR (CD3OD, δ): 24.7, 26.6, 47.6, 48.2, 50.4, 64.0, 72.3, 126.8 (2xC), 131.7, 132.2, 132.3, 133.8, 133.9, 135.1, 143.5 (2xC), 160.6, 163.8.

MS-ESI m/z (% rel. Int.): 394.1/396.1/398.1 ([MH]+, 60/45/10), 219.2 (100). 207 HPLC: Method A, detection UV 254 nm, Compound 252 RT = 3.83 min, peak area 99.5 %.

Preparation of (E)-3 -fpvridin-4- vD- 1 -fpvrrolidin- - vDprop-2-en- 1 -one hydrochloride Compound 253.

To a solution of 3-(4-pyridinyl)acrylic acid ( 1.01 g, 6.77 mmol) in CHCI3 (20 mL) in a 100 mL round bottom flask equipped with a magnetic stirrer and under nitrogen atmosphere was added 1 -hydroxy enzotriazole (1.11 g, 8.21 mmol). The reaction mixture was stirred at RT for 10 min. Then l-(3-d¾methylammopropyl)-3^thylcaibodiirmde (1.56 g, 8.15 mmol) was added. The reaction mixture was stirred at 4 °C for 10 min. Then pyrrolidine (1.11 mL, 18.3 mmol) was added slowly and the reaction mixture was stirred for 15 h at +4 °C to RT. Dichloromethane (200 mL) was added and organic phase was washed with brine (100 mL), a solution of NaOH 0.5 N (100 mL) and brine (50 mL). The organic phase was dried over MgS04, filtered, and evaporated to obtain (.¾-3-(pyridm-4-ylH-(py^ (1-30 g, 94 % yield).

This free base (1.3 g, 6.40 mmol) was dissolved in MeOH (10 mL) at 4 °C and a solution of HC1 0.1 N in isopropanoi (79 mL, 7.9 mmol) was added. After evaporation at 30 °C and drying, (£)-3-(pyridin-4-yl)- 1 -(pyrrolidin- 1 -yl)prop-2-en-l-one hydrochloride Compound 253 was obtained as a beige solid (1.40 g, 87 % yield).

Compound 253 MW: 238.71; Yield: 87 %; Beige Solid; Mp (°C): 229.4 R : 0.35 (EtOAc : MeOH = 95:5, free base). 208 'H-NMR (CD3OD, δ): 1.92-2.10 (m, 4H, 2xCH2), 3.56 (t, 2H, J= 6.7 Hz, N-CH2), 3.80 (t, 2H, J= 6.7 Hz, N-CH2), 7.59 (d, 1H, 7= 15.6 Hz, CH=Q, 7.68 (d, 1H, J= 15.6 Hz, CH=C), 8.35 (d, 2H, J= 5.7 Hz, ArH) 8.86 (d, 2H, J= 5.6 Hz, ArH). 13C- MR (CD3OD, δ): 25.2, 27.0, 47.6, 48.2, 126.7 (2xC), 131.9, 136.5, 143.1 (2xC), 154.5, 164.6.

MS-ESI m z (% rel. Int.): 203.2 ([MH]+, 100).

HPLC: Method A, detection UV 254 nm, Compound 253 RT - 3.18 min, peak area 99.5 %.

Preparation of d=Vt/treo-2-amino-3-hvdroxv-3-( 1 -methvl- lH-imidazol-2-νΠ- 1 -(pyrrolidin-l-ynpropan-l-one dihvdrochloride Compound 254. fra ij-(4.5-Dmv(ko-5- i-memyl-l-g-irm yltoiethanone LPO 01190B.

To a stirred and cooled (0 °Q solution of potassium hydroxide (0.33 g, 5.0 mmol) in MeOH (6 mL) were added a mixture of 1 -met yl-2-imidazole carboxaldehyde (0.56 g, 5.0 mmol) and 2-isocyano- 1 -(pyrrolidin- l-yl)ethanone BLE 04098 (0.70 g, 5.0 mmol). The solution was stirred 3 h at 4 °C and men concentrated. The residue was partitioned between EtOAc (100 mL) and water (20 mL). The organic layer was washed with brine (10 mL) and dried over MgS04, filtered and evaporated. Concentration afforded a crude product which was purified by column chromatography (florisil, EtOAc:MeOH = 95:5 to 90:10) to yield, after evaporation and drying, to ira¾y-(4,5-dihydro-5-(l-methyl-l#-iirH&izol-2-yl)oxazol^ LPO 01190B (0.32 g, 25 % yield) as a brown oil. 209 (±ytran8 LPO 01190B MW: 24828; Yield: 25 %; Brown Oil.

Kfi 0.30 (EtOAc:MeOH - 9: 1, free base). 1H-NMR (CDC13, δ): 1.94-2.12 (m, 4H, 2xC¾), 3.50 (t, 2H, /=» 6.5 Hz, N-C¾), 3.69-4.13 (m, 5H, N- C¾ ,N-CH3), 5.68 (dd, 1H, J= 7.7 Hz, J= 2.3 Hz, CH-N), 6.19 (d, 1H, = 7.7 Hz, CH-O), 6.82 (d, 1H, J= 2.2 Hz, CH=N), 6.94 (d, 1H, J= 1.1 Hz, ArH), 7.00 (d, 1H, J= 1.1 Hz, ArH). 13C- MR (CDCI3, δ): 24.2, 26.0, 32.9, 46.4, 46.7, 71.2, 72.7, 123.0, 127.9, 143.7, 153.7, 166.6.

MS-ESI m/z (% rel. Int.): 267.3 ([MH+18]+, 10), 196.2 (100).

HPLC: Method A, detection UV 254 nm, LPO 01190B RT = 3.92 min, peak area 99.5 %.

( ±V^reo-2-Amino-3-hvdroxv-3-(' 1 -methyl- lH-imidazol-2-vlV 1 -ipvrrolidin- 1 -yl)propan-l-one dihvdrochloride Compound 254.

A solution of irarc j-(4, 5-dihydro-5-( 1 -methyl- lii-imidazol-2-yl)oxazol-4-yl)(pyrrolidin-l-yl)methanone LPO 01190B (320 mg, 1.29 mmol) and HCl 37 % (0.4 mL, 13 mmol) in MeOH (6 mL) was stirred at 50 °C for 3 h in a 50 mL round bottom flask. The solvent was evaporated and the product was precipitated by a mixture of MeOH:EtOAc:Et20 = 3: 12:5 (20 mL). Solvents were evaporated at 30 °C to give, after evaporation and drying, (±)-threo-2-amino-3-hydroxy-3 -(1 -methyl- lH-imidazol-2-yl)- 1 - (pyrrolidin- 1 -yl)propan- 1 - 210 one dihydrochloride Compound 254 as a pale yellow solid (305 yield).

Compound 254 MW: 311.21; Yield: 76 %; Pale Yellow Solid; Mp (°C): 183.4 0.30 (CH2Cl2:MeOH » 95:5, free base).

!H-NMR (CD3OD, δ): 1.75-1.99 (m, 4H, 2xC¾), 2.80-2.88 (m, 1H, 0.5xN-CH2), 3.30-3.70 (m, 3H, 1.5xN-CH2), 3.95 (s, 3H, N-CH3), 4.62 (d, 1H,7= 8.3 Hz, N-CH), 5.51 (d, 1H, /= 8.3 Hz, O-CH), 7.66 (s, 2H, ArH).

"C- MR (CD3OD, δ): 24.9, 26.9, 36.0, 47.9 (2xC), 562, 65.1, 121.1, 126.5, 145.1, 164.4.

MS-ESI m/z (% tel. Int): 239.3 ([MH]+, 10), 134.1 (100).

HPLC: Method A, detection UV 254 nm, RT = 0.8 min, peak area 99.5 %.

Preparation of (2£3JKV & (2/? iS -2-armno-l-((-? -3-fluoropyrrolidm-l-vn-3-hvdroxy-3-fpyridin-3-yl propan-l-one dihydrochlorides Compound 255.

To a stirred and cooled 0 °C solution of KOH (0.216 mg, 4.22 mmol) in methanol (5 mL) was added l-((5)-3-fluoropyiToU 'H-NM (CDCI3, δ): 1.85-2.45 (m, 2H, CH2), 3.50-4.10 (m, 3H, CH2 & N-CH), 4.25-4.65 (m, 2H, N-CH2), 5.15-5.25 (m, 0.5H, 0.5xCHF), 5.35-5.45 (m, 0.5H, 0.5xCHF), 6.21 (d, 1H, J= 7.6 Hz, O-CH), 7.04 (d, 1H, /= 2.1 Hz, N=CH), 7.30-7.38 (m, 1H, ArH), 7.60-7.68 (m, 1H, ArH), 8.55-8.65 (m, 2H, ArH>. MS-ESI m/z (% rel. Int.): 264.1 ([MH]+, 18). (2S3Ri- & f2 3,SV2-Armno-l-f(5 3-fluor(^^ (pyridin-3-yl)propan-l-one dihvdrochlorides Compound 255.

To a solution of ^a/w-^-S-fluoro^yrroUdin-l-yO^.SjR)- & (4Λ,55)-4,5-dmydro-5-(pyridm-4-yl)oxazol-4-yl)methanones SLA 11014 (0.450 g, 1.71 mmol) in methanol (40 mL) was added HC1 37 % (5 mL). After heating at 50 °C for 3 h, the mixture was concentrated and the crude product was co-evaporated twice with EtOAc. Trituration with EtOAc and filtration yielded, after drying, to (2S,3R)- & (^^^^-animo-l-^-S-fluoropyrroUdin-l-yl)^- 212 hydroxy-3-(pyridin-3-yl)propan-l-one dihydrochlorides Compound 255 (540 mg, diastereoisomeric mixture in ratio about 1:1, 97 % yield) as a yellow solid. 2HCI 2HCI thmo thmo Compound 255 MW: 326.19; Yield: 97 %; Yellow Solid; Mp (°C): 168.9 1H-NMR (CD3OD, δ): 1.85-2.40 (m, 2H, C¾), 3.45-4.20 (m, 4H, 2xCRz), 4.40-4.75 (m, IH, N-CH), 5.30-5.60 (m, 2H, O-CH & CHF), 8.15-8.25 (m, IH, ArH), 8.70-8.80 (m, IH, ArH), 8.90-9.10 (m, 2H,.ArH).

MS-ESI m/z (% rel. Int): 254.1 ([MH]+, 81.38), 236.2 (25). (f^-3-fluoropyrrolidm-l-ylVr4.y.5igV & f4i?.5.^-4.5-dmvdro-5-(thiophen-3-vl)oxazol-4-vl)methanones SLA 11016.

To a stirred and cooled 0 °C solution of KOH (0.216 mg, 3.85 mmol) in methanol (8 mL) was added l-((i5)-3-fluoropyrrolidin-l-yl)-2-isocyanoethanone VIB 01166 (0.600 g, 4.22 mmol) and tbiophene-3-carbaldehyde (0.37 mL, 3.85 mmol). The solution was stirred for 20 h at 0 °C. After evaporation under reduced pressure, the residue obtained was partitioned between EtOAc and ¾0. The product was extracted with EtOAc (4x50 mL) and washed brine (25 mL), dried over MgS04, filtered and evaporated to yield to a product that was purified using chromatography (florisil, gradient EtOAc:MeOH = 95:5 to 85:15). ((^-S-fluoropyrrohdin-l-y ^S i)- and (4i?,5vS)-4,5-dmydro-5-(thiophen-3-yl)oxazol-4-yl)methanones SLA 11016 were obtained as a yellow solid (0.411 g, diastereoisomeric mixture in ratio about 1:1, 32 % yield) . 213 SLA 11016 MW: 268.31; Yield: 32 %; Yellow Solid; Mp (°C) = 132.9 !¾; 0.35 (EtOAc:MeOH = 80:20). 1H-NMR (CDCI3, δ): 1.80-2.45 (m, 2H, CH2), 3.50-4.10 (m, 3H, CH-N & CH2), 4.20-4.70 (m, 2H, CH2), 5.15-5.45 (m, 1H, CHF), 6.18-6.25 (m, 1H, O-CH), 6.99 (d, 1H, J= 2.2 Hz, N=CH), 7.00-7.15 (m, 1H, ArH), 7.28-7.35 (m, 1H, ArH), 7.32-7.40 (m, 1H, ArH).

MS-ESI m/z (% rel. Int.): 269.0 ([MH]+, 10). (2S3RY & (2 35 2-Ammo-l-(r.fl-3-flTO^^ (thiophen-3 - vDpropan- 1 -one dihvdrochlorides Compound 256.

To a solution of ((^-S-fluoropyiroUdin-l-yl)^^/?)- & (4Λ,55)-4,5-dihydro-5-(thiophen-3-yl)oxazol-4-yl)methanones SLA 11016 (0.400 g, 1.49 mmol) in methanol (50 mL) was added hydrochloric acid 37 % (4 mL). After heating at 50 °C for 3 h, the mixture was concentrated and the crude product was co-evaporated twice with EtOAc. Trituration with EtOAc and filtration and drying afforded (2S,3R)- & (2i?,35)-2-arnino-l-((5)-3-fl oropyrrolidin-l-yl)-3-hydroxy-3-(thiophen-3-yl)propan-l-one dmydrochlorides Compound 256 (451 mg, diastereoisomeric mixture about 1:1, 91 % yield) as a yellow solid. 2HCI 2HCI threo threo Compound 256 214 MW: 331.23; Yield: 91 %; Yellow Solid; Mp (°C): 221.6 lH-NMR (CD3OD, δ): 1.25-2.05 (m, 2H, C¾), 2.10-2.50 (m, IH, 0.5χ(¾), 3.20-3.65 (m, 3H, 1.5xC¾), 3.90-4.10 (m, IH, CH-N), 4.70-5.10 (m, 2H, O- CH «54; CHF), 6.92-6.99 (m, IH, ArH), 7.21-7.32 (m, 2H, ArH).

MS-ESI m/z (% rel. Int.): 259.1 ([MH]+, 25).

Claims (1)

1. 215 WHAT IS CLAIMED IS: 1. A compound of the formula Formula 1 where Ri is H or alkyl of 1 to 6 carbons, R2 is H, alkyl of 1 to 6 carbons or the R} and R2 groups together with the nitrogen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected fromN, 0 and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen groups, cyano groups, or with one or two alkyl groups having 1 to 6 carbons, or one or two carbons of said rings being attached to an oxygen to form keto groups and said 4, 5, 6 or 7 membered ring optionally being condensed with an aromatic or non-aromatic 5 or 6 membered ring that optionally includes 1 or heteroatoms selected from N, O and S; R3 is independently selected from H, alkyl of 1 to 20 carbons, cycloalkyl of 3 to 6 carbons, aryl or heteroaryl, aryl-alkyl where the alkyl moiety has 1 to 4 carbons, aryl-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons,, hetero aryl-alkyl where the alkyl moiety has 1 to 4 carbons, or hetero-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected 216 184725/2 from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, or R3 is CO-R7, S02R7 or CO-OR7 where R7 is H, alkyl of 1 to 20 carbons, alkyl of 1 to 20 carbons substituted with and NH2 group or with an NH-COalkyl group where the alkyl group has one to 6 carbons, aryl or heteroaryl, aryl-alkyl where the alkyl moiety has 1 to 4 carbons or heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons; R4 is H, alkyl of 1 to 6 carbons or CO-Rs where Rs is alkyl of 1 to 6 carbons; the wavy lines represent bonds connected to carbons having R or S configuration; the dashed lines represent a bond or absence of a bond with the proviso that the ring containing the dashed lines is aromatic; m, n and q are integers independently selected from 0, 1, 2 or 3 with the proviso that the sum of m, n and q is 2 or 3; s is zero (0) or when X is N then s is zero (0) or 1 ; W, X and Y independently represent a CH, CR5, CR6 or a heteroatom selected independently of N, O and S, and R5 and are independently selected from H, halogen, alkyl of 1 to 6 carbons, halogen substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, phenyl, or R5 and R6 together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; 217 said carbocyclic or heterocyclic ring jointly formed by ¾ and R« being optionally substituted with 1 to 6 ¾ groups where R9 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons or a pharmaceutically acceptable salt of said compound with the proviso that Formula 1 does not cover compounds where R4 is H, Ri and R2 jointly with the nitrogen form a pyrrolidino or morpholino ring, the sum of m, n and q is 3, and where none of W, X and Y represent a heteroatom with the further proviso that the formula does not cover the compounds of the formula below (±}-erythm 2. A compound in accordance with Claim 1 where the sum of the integers m, n and q is 3. 3. A compound in accordance with claim 2 where one of the W, X and Y groups is N. 4. A compound in accordance with Claim 3 where R5 and R* together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring. 5. A compound in accordance with Claim 2 where none of the W, X and Y groups is a heteroatom. 6. A compound in accordance with Claim 5 where R5 and Re together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring. 7. A compound in accordance with Claim 1 where the sum of the integers m, n and q is 2 and at least one of W, X and Y is a heteroatom. 218 8. A compound in accordance with Claim 7 where only one of W, X and Y represents a heteroatom. 9. A compound in accordance with Claim 7 where two of the W, X and Y groups each represent an independently selected heteroatom. 10. A compound in accordance with Claim 1 where R4 is H. 11. A compound in accordance with Claim 10 where both R3 groups are H. 12. A compound in accordance with Claim 10 where one R3 group is H and the other R3 group is CO-R7 or alkyl of 1 to 20 carbons. 13. A compound in accordance with Claim 10 where R3 is independently selected from H and alkyl of 1 to 10 carbons. 14. A compound in accordance with Claim 1 where R» is CO-Rg. 15. A compound in accordance with Claim 1 where Rj and R2 together with the nitrogen form a 4, 5, 6 or 7 membered ring. 16. A compound in accordance with Claim 15 where Ri and R2 together with the nitrogen form a 5 membered ring. 17. A compound in accordance with Claim 15 where Ri and R2 together with the nitrogen form a 6 membered ring. 18. A compound in accordance with Claim 1 where both R5 and 5 are hydrogen. 19. A compound of the formula where Ri is H or alkyl of 1 to 6 carbons, R2 is H, alkyl of 1 to 6 carbons or the Ri and R2 groups together with the 219 184725/2 nitrogen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen groups, cyano groups or with one or two alkyl groups having 1 to 6 carbons; R3 is H, CO-R7 or CO-O-R7 where R7 is H, alkyl of 1 to 20 carbons, cycloalkyl of 3 to 6 carbons, aryl or heteroaryl, aryl-alkyl, aryl(hydroxy)alkyl, heteroaryl-alkyl or heteroalkyl(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons; R4 is H, alkyl of 1 to 6 carbons, or CO-Rg where Rg is alkyl of 1 to 6 carbons, R5 and R$ are independently selected from H, halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, or R5 and R$ together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; said carbocyclic or heterocyclic ring jointly formed by R5 and Κ being optionally substituted with 1 to 6 R9 groups where R9 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, and the wavy lines represent bonds of the alpha or beta configuration, or any pharmaceutically acceptable salt of said compound. 20. A compound in accordance with Claim 19 where R4 is H. 21. A compound in accordance with Claim 19 where both R3 groups are H. 22. A compound in accordance with Claim 19 where both R5 and R$ are hydrogen. 220 compound in accordance with Claim 22 having the formula or a pharmaceutically acceptable salt of said compound. 24. A compound in accordance with Claim 23 where R4 is H. 25. A compound in accordance with Claim 23 where both R3 groups 26. A compound in accordance with Claim 23 that has the formula or a pharmaceutically acceptable salt of said compound. 27. A compound in accordance with Claim 23 that has the formula or a pharmaceutically acceptable salt of said compound. 28. A compound in accordance with Claim 23 having the formula or any other pharmaceutically acceptable salt of said compound. 29. A compound in accordance with Claim 23 having the formula 2.HCI 221 or any other pharmaceutically acceptable salt of said compound. 30. A compound in accordance with Claim 23 having the formula or any other pharmaceutically acceptable salt of said compound. 31. A compound in accordance with Claim 23 having the formula or any other pharmaceutically acceptable salt of said compound. 32. A compound in accordance with Claim 23 having the formula 2.HCI or any other pharmaceutically acceptable salt of said compound. 33. A compound in accordance with Claim 23 having the formula 2.HCI or any other pharmaceutically acceptable salt of said compound. 34. A compound in accordance with Claim 23 that has the formula 222 or any other pharmaceutically acceptable salt of said compound. 35. A compound in accordance with Gaim 23 mat has the formula or any other pharmaceutically acceptable salt of said compound. 36. A compound in accordance with Claim 23 that has the formula or any other pharmaceutically acceptable salt of said compound. 37. A compound in accordance with Claim 23 that has the formula {±)-eryt ro or a pharmaceutically acceptable salt of said compound. 38. A compound in accordance with Gaim 19 having the formula {±yerythra or any other pharmaceutically acceptable salt of said compound. 39. A compound in accordance with Claim 19 having the formula 223 or any other pharmaceutically acceptable salt of said compound. 40. A compound in accordance with Claim 19 having the formula or any other pharmaceutically acceptable salt of said compound. 41. A compound in accordance with Claim 19 having the formula 2 HCI or any other pharmaceutically acceptable salt of said compound. 42. A compound in accordance with Claim 19 having the formula 2. HCI (± fftreo or any other pharmaceutically acceptable salt of said compound. 43. A compound in accordance with Claim 19 having the formula or any other pharmaceutically acceptable salt of said compound. 44. A compound in accordance with Claim 19 having the formula (t thrao 224 or any other pharmaceutically acceptable salt of said compound. 45. A compound in accordance with Claim 19 having the formula or any other pharmaceutically acceptable salt of said compound. 46. A compound in accordance with Claim 45 having the formula or any other pharmaceutically acceptable salt of said compound. 47. A compound in accordance with Claim 45 having the formula or any other pharmaceutically acceptable salt of said compound. 48. A compound of the formula 225 184725/2 where Ri is H or alkyl of 1 to 6 carbons, R2 is alkyl of 1 to 6 carbons or the Rj and R2 groups together with the nitrogen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen groups, cyano groups, or with one or two alkyl groups having 1 to 6 carbons, R3 is H, CO-R7 or CO-0-R7 where R7 is H, alkyl of 1 to 20 carbons, aryl or heteroaryl, cycloalkyl of 3 to 6 carbons, aryl-alkyl aryl(hydroxy)alkyl, heteroaryl-alkyl or heteroaryl(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons; R4 is H, alkyl of 1 to 6 carbons, or CO-Rg where R8 is alkyl of 1 to 6 carbons; R5 and are independently selected from H, halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, thioxy of 1 to 3 carbons and phenyl, or R5 and R together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; said carbocyclic or heterocyclic ring jointly formed by R5 and R$ being optionally substituted with 1 to 6 R9 groups where R9 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, and the wavy lines represent bonds connected to carbons having R or S of configuration, 226 184725/2 with the proviso that the claim does not cover compounds where R4 is H, R] and R2 jointly with the nitrogen form a pyrrolidino or morpholino ring, or any pharmaceutically acceptable salt of said compound. 49. A compound in accordance with Claim 48 having the formula or any other pharmaceutically acceptable salt of said compound. 50. A compound of the formula where X is O or S; R] is H or alkyl of 1 to 6 carbons, R2 is H, alkyl of 1 to 6 carbons or the R] and R2 groups together with the nitrogen form a saturated or unsaturated 5 or 6 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen groups or cyano groups with one or two alkyl groups having 1 to 6 carbons, R3 is H, CO-R7 or CO-O-R7 where R7 is H, alkyl of 1 to 20 carbons, aryl or heteroaryl, aryl-alkyl, aryl(hydroxy)alkyl, heteroaryl-alkyl or heteroaryl(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy 227 of 1 to 6 carbons and thioxy of 1 to 3 carbons; R is H, alkyl of 1 to 6 carbons, or CO-Rs where Rg is alkyl of 1 to 6 carbons; Rs and R$ are independently selected from H, halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to3 carbons, or Rs and Rs together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; said carbocyclic or heterocyclic ring jointly formed by Rs and Rs being optionally substituted with 1 to 6 9 groups where R9 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, and the wavy lines represent bonds connected to carbons having R or S configuration, or any pharmaceutically acceptable salt of said compound with the further proviso that the claim does not cover the compound shown below 51. A compound in accordanc aving the formula or a pharmaceutically acceptable salt of said compound. 52. A compound in accordance with Claim 51 having the formula 228 184725/2 or a pharmaceutically acceptable salt of said compound. 53. A compound in accordance with Claim 51 having the formula or any other pharmaceutically acceptable salt of said compound. 54. A compound in accordance with Claim 53 having the formula or any other pharmaceutically acceptable salt of said compound. 55. A compound in accordance with Claim 53 having the formula 56. Use of compound I, as described in Claim 1, in the preparation of medicament having an analgesic effect, for treating a mammal in need of such treatment with a pharmaceutical composition. 57. The medicament in accordance with Claim 56, for treating a mammal in need of such treatment with a pharmaceutical composition having an analgesic effect, the composition including a compound in accordance with Claim 34. 58. The medicament in accordance with Claim 56, for treating a mammal in need of such treatment with a pharmaceutical composition having an analgesic effect, the composition including a compound in accordance with Claim 36. 59. The use of a pharmaceutical composition having an immunostimulant effect, the composition including a compound in accordance with Claim 1, in 229 184725/2 the preparation of a medicament for stimulating the immune system of a mammal in need of such treatment. 60. The use of the medicament in accordance with Claim 59 for stimulating the immune system of a mammal in need of such treatment with a pharmaceutical composition having an immunostimulant effect, the composition including a compound in accordance with Claim 35. 61. The use of the medicament in accordance with Claim 59 for stimulating the immune system of a mammal in need of such treatment with a pharmaceutical composition having an immunostimulant effect, the composition including a compound in accordance with Claim 37. 62. A compound of the formula Formula 1 where Ri is H or alkyl of 1 to 6 carbons, R-2 is H, alkyl of 1 to 6 carbons or the R] and R2 groups together with the nitrogen form a saturated or unsaturated 4, 5, 6 or 7 membered ring that optionally includes one or two heteroatoms independently selected from N, O and S, said 4, 5, 6 or 7 membered ring optionally being substituted with one or two COOH, CH2OH, OH, B(OH)2, halogen or cyano groups groups or with one or two alkyl groups having 1 to 6 carbons, or one or two carbons of said rings being attached to an oxygen to form keto groups and said 4, 5, 6 or 7 membered ring optionally being condensed with an aromatic or non-aromatic 5 or 6 membered ring that optionally includes 1 or heteroatoms selected from N, O and S; 230 184725/2 R3 is independently selected from H, alkyl of 1 to 20 carbons, cycloalkyl of 3 to 6 carbons, aryl or heteroaryl, aryl-alkyl where the alkyl moiety has 1 to 4 carbons, aryl-(hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons or hetero- (hydroxy)alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, or R3 is CO-R7, S02R7 or CO-OR7 where R7 is H, alkyl of 1 to 20 carbons, alkyl of 1 to 20 carbons substituted with and NH2 group or with an NH-COalkyl group where the alkyl group has one to 6 carbons aryl or heteroaryl, aryl-alkyl where the alkyl moiety has 1 to 4 carbons or heteroaryl-alkyl where the alkyl moiety has 1 to 4 carbons, said aryl or heteroaryl groups being optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons; the wavy lines represent bonds connected to carbons having R or S configuration; the dashed lines represent a bond or absence of a bond with the proviso that the ring containing the dashed lines is aromatic; R9 and R]0 are one of the combinations selected from the group consisting of (1) R9 is NORii and RJ0 does not exist, (2) R9 is ORn and RJ0 is alkyl of 1 to 6 carbons, (3) when the dashed lines between carbons 2 and 3 of the propionic acid moiety represent a bond then R9 is H or alkyl of 1 to 6 carbons and R]0 does not exist; R] i is H, alkyl of 1 to 6 carbons or CO-Ri2 where Rj2 is alkyl of 1 to 6 carbons; m, n and q are integers independently selected from 0, 1, 2 or 3 with the proviso that the sum of m, n and q is 2 or 3; s is zero (0) or when X is N then s is zero (0) or 1; 231 184725/2 W, X and Y independently represent a CH, CR5, CR or a heteroatom selected independently of N, O and S, and R5 and R6 are independently selected from H, halogen, alkyl of 1 to 6 carbons, halogen substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons, phenyl, or R5 and together with the atoms to which they are attached jointly form a carbocyclic or a heterocyclic ring, the carbocyclic ring having 5 or 6 atoms in the ring, the heterocyclic ring having 5 or 6 atoms in the ring and 1 to 3 heteroatoms independently selected from N, O and S; said carbocyclic or heterocyclic ring jointly formed by R5 and ¾ being optionally substituted with 1 to 6 Ri2 groups where Ri2 is independently selected from halogen, alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons and thioxy of 1 to 3 carbons or a pharmaceutically acceptable salt of said compound. 63. A compound in accordance with Claim 62 where the sum of the integers m, n and q is 3. 64. A compound in accordance with claim 62 where one of the W, X and Y groups is N. 65. A compound in accordance with Claim 62 where the Ri and R2 groups together with the nitrogen form a 5-membered ring. 66. A compound in accordance with Claim 62 where R9 is NORn and R,0 does not exist. 67. A compound in accordance with Claim 62 where R9 is methyl and Ri0 is OR, ,. 68. A compound in accordance with Claim 62 where the dashed line between carbons 2 and 3 represents a bond. For the Applicant Sanford T. Colb & Co. C: 62641