WO2011147951A1 - Cycloamino derivatives as gpr119 antagonists - Google Patents

Abstract

Therapeutic compounds are disclosed having the general formula (I) that are useful for the treatment of metabolic disorders, including type II diabetes. The compounds have activity as agonists of GPR119. Compounds having the stereochemistry of formula (la) may also demonstrate DPP-IV inhibitory activity.

Description

CYCLOAMINO DERIVATIVES AS GPR119 ANTAGONISTS

BACKGROUND OF THE INVENTION

The present invention is directed to therapeutic compounds useful for the treatment of metabolic disorders including type II diabetes. In particular, the present invention is directed to compounds which have activity as agonists of GPR119.

Drugs aimed at the pathophysiology associated with non-insulin dependent type II diabetes have many potential side effects and do not adequately address the dyslipidaemia and hyperglycaemia in a high proportion of patients. Treatment is often focused at individual patient needs using diet, exercise, hypoglycaemic agents and insulin, but there is a continuing need for novel antidiabetic agents, particularly ones that may be better tolerated with fewer adverse effects.

Similarly, metabolic syndrome (syndrome X) places people at high risk of coronary artery disease, and is characterized by a cluster of risk factors including central obesity (excessive fat tissue in the abdominal region), glucose intolerance, high triglycerides and low HDL cholesterol, and high blood pressure. Myocardial ischemia and microvascular disease is an established morbidity associated with untreated or poorly controlled metabolic syndrome.

Obesity is characterized by an excessive adipose tissue mass relative to body size. Clinically, body fat mass is estimated by the body mass index (BMI; weight(kg)/height(m) ), or waist circumference. Individuals are considered obese when the BMI is greater than 30 and there are established medical consequences of being overweight. It has been an accepted medical view for some time that an increased body weight, especially as a result of abdominal body fat, is associated with an increased risk for diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis, stroke, gallbladder disease, muscular and respiratory problems, back pain and even certain cancers.

There is a continuing need for novel antidiabetic agents, particularly ones that are well tolerated with few adverse effects and in particular for agents which are weight neutral or preferably cause weight loss.

GPR119 (previously referred to as GPR116) is a GPCR identified as SNORF25 in WO00/50562 which discloses both the human and rat receptors, US 6,468,756 also discloses the mouse receptor (accession numbers: AAN95194 (human), AAN95195 (rat) and

ANN95196 (mouse)). In humans, GPR119 is expressed in the pancreas, small intestine, colon and adipose tissue. The expression profile of the human GPR119 receptor indicates its potential utility as a target for the treatment of diabetes.

GPR119 agonists have been shown to stimulate the release of GLP-1 from the GI tract. In doing so, GPR119 agonists (1) enhance glucose-dependent insulin release from the pancreas leading to improvements in oral glucose tolerance; (2) attenuate disease progression by increasing β-cell cAMP concentrations; and (3) induce weight loss possibly through GLP- 1 's ability to reduce food intake.

International Patent Applications WO 2005/061489, WO 2006/070208,

WO 2006/067532, WO 2006/067531, WO 2007/003960, WO 2007/003961,

WO 2007/003962, WO 2007/003964, WO 2007/116229, WO 2007/116230,

WO 2008/081204, WO 2008/081205, WO 2008/081206, WO 2008/081207,

WO 2008/081208, WO 2009/050522, WO 2009/050523, WO 2010/001166,

WO 2010/004343, WO 2010/004344, WO 2010/004345, WO 2010/004346,

WO 2010/004347 and WO 2010/004348 disclose GPR119 receptor agonists.

Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous, yet highly specific, serine protease that cleaves N-terminal dipeptides from polypeptides with L-proline or L-alanine at the penultimate position. Studies with DPP-IV inhibitors show the principle role of DPP-IV is in the inactivation GLP-1. By extending the duration of action of GLP-1, insulin secretion is stimulated, glucagon release inhibited, and gastric emptying slowed. DPP-IV inhibitors are of use for the treatment of type II diabetes, examples of DPP-IV inhibitors include vildagliptin, sitagliptin, alogliptin and saxagliptin.

The possibility of using a combination of a GPR119 agonist and a DPP-IV has been suggested, however this requires the administration of two separately formulated products to the patient or the co -formulation of two active ingredients with the inherent problems of achieving compatability in the physicochemical and pharmacokinetic and pharmacodynamic properties of the two active ingredients. WO 2009/034388 discloses dual GPR119 agonists and DPP-IV inhibitors. The compounds of the invention may also have dual activity as agonists of GPR119 and inhibitors of DPP-IV. SUMMARY OF THE INVENTION

According to the present invention there are provided compounds of formula (I) and pharmaceutically acceptable salts thereof:

(I)

wherein A is a para-substituted phenyl or a para-substituted 6-membered heteroaryl ring containing one to three nitrogen atoms;

R1 is hydrogen, halo, cyano, C\ _4alkyl, C\ .4 haloalkyl, C\ .4 alkoxy or C2. galkoxyalkyl;

2 is:

_s phenyl optionally substituted by one or more halo, methyl, halomethyl or methoxy groups, or pyridyl, N-pyridonyl or N-pyrazolyl, optionally substituted by one or more halo, Ci _2 alkyl or halomethyl groups,

R^ is independently halo, methyl or halomethyl;

Z is -C(0)OR⁴, -C(0)R⁴ , -S(0)₂R⁴ , -S(0)₂N(Ci_3alkyl)R⁴, heteroaryl or

-CH2-heteroaryl, and when p and q are both 0, Z can also be -CH₂-phenyl, which phenyl is optionally substituted by one or two groups independently selected from C\ .4 alkyl, C\ .4 haloalkyl and halo;

R⁴ is aryl, heteroaryl, C2-6^alkyl, C3_6cycloalkyl, C4_6heterocyclyl, heterocyclylCi . 4alkyl, C2_6^alkoxyalkyl, arylCj _4alkyl, heteroarylC^ .4 alkyl or C4_ cycloalkylCi _4alkyl, which cycloalkylCj .4 alkyl is optionally substituted by C\ .4 alkyl;

wherein when Z is or includes heteroaryl or when R⁴ is or includes aryl or heteroaryl, said aryl or heteroaryl may optionally be substituted by one or two groups selected from halo, cyano, SF5, C\ .4 alkyl, C\ _4haloalkyl, C\ .5 hydroxyalkyl, Ci _4alkoxy, C2.

4alkoxyalkyl, heterocyclyl, heterocyclylCi _4alkyl, heteroarylC 1.4 alkyl, Ci _4alkylamino,

Ci _4alkylaminoC 1.4 alkyl, C3_6cycloalkyl and -(C 1.3 alkyl)-(C3_6 cycloalkyl), wherein the cycloalkyl and alkyl groups are each optionally substituted by one or two groups

independently selected from Ci .4 alkyl, hydroxy or halo;

X is selected from CR⁵H, O, and NR⁶ in which R⁵ and R⁶ are independently hydrogen or C\ _2alkyl;

Y is or W-Υΐ, where W is a 5 membered heteroaryl ring containing one or more heteroatoms selected from N, O and S, and γΐ is selected from CR⁷H, O and NR⁸, in which R^ is hydrogen, Ci _2alkyl,C2-6^alkoxyalkyl or heterocyclyl; wherein said Ci _2alkyl can be optionally substituted by cyano, hydroxy or halo and R⁸ is C\ _4alkyl or C\ _4cycloalkyl, provided that when Y is W-Y¹, X is O and Y¹ is CR⁷H, when Y¹ is O or NR⁸, X is CR⁵H and when X is O or NR⁶, Y¹ is CR⁷H;

each of R^ and R^ is independently H, halo, C\ _2alky, C\ _2haloalkyl,

C\ _3alkoxy or hydroxy; or R9 and are joined to form an azabicyclo[3.3.1]nonane, a 3- oxa-7-azabicyclo[3.3.1]nonane or an azabicyclo[3.2.1]octane;

R11 is H, halo, Ci _2alkyl, C\ _2haloalkyl or Ci _3alkoxy;

m is 0, 1 or 2;

n is 0 or 1 ;

p and q are each 0, 1 or 2, provided that 0 < p+q < 2; and

r is 1 or 2.

The compounds of the invention have activity as agonists of GPRl 19 and may also be inhibitors of DPP-IV and are therefore useful for the treatment of metabolic disorders including type II diabetes.

DETAILED DESCRIPTION OF THE INVENTION

R^ is suitably hydrogen or methyl.

R⁶ is suitably hydrogen.

R⁸ is suitably methyl. Suitably R^{1 1} may be H. In some embodiments, R11 may be alkoxy, e.g., methoxy.

Alternatively, R11 may be halo, including F.

In some embodiments, the compounds of the invention may suitably have the stereochemistry defined below (compounds of formula (la)); such compounds may demonstrate DPP-IV inhibitory activity:

(la)

p and q are independently 0, 1 or 2 provided that p+q does not exceed 2, i.e., forming a 4-, 5- or 6-membered ring. In some embodiments, p and q may be the same, i.e., forming a 4- or 6-membered ring. Suitably p and q are both 1.

R9 and R¹⁰ may be the same or different from one another. Suitably R9 and RIO are both H. Where p (or q) is 2, the two R^ (or RIO) groups may be the same as or different from one another. Suitably where one of R^ (or RIO) is other than H, the other one may be H.

A may be a para linked 6-membered heteroaromatic ring containing one or two nitrogen atoms. A is suitably pyridine, pyrimidine, pyrazine or pyridazine, typically pyridine or pyrimidine, e.g., 2- or 3-pyridyl or 2- or 5-pyrimidinyl, where the 2-, 3- or 5- refers to the point of attachment of the pyrrolidine or piperidine ring.

In one sub-class of compounds according to the invention, Y is γΐ.

Within this sub-class, suitably γΐ may be O and X may be CR⁵H.

Alternatively, X may be O and γΐ may suitably be CR^H. In such embodiments, th refore, the compounds of the invention may have the formula:

(lb).

In another alternative, Y¹ may be NR⁸ and X may be CR⁵H.

In yet another alternative X may be NR^ and γΐ may be CR⁷H.

In another sub-class of the compounds of the invention, Y may be W-Υΐ, where γΐ is CR^H bonded directly to X and X is O.

W is typically oxadiazolyl. In such embodiments, therefore, the compounds of the invention may suitably have the formula:

(Ic) In each case A may be selected from:

In some embodiments, Z may suitably be -C(0)OR⁴, -C(0)R⁴ or -S(0)2R⁴.

R⁴ may suitably be alkyl, C4.5 alkoxyalkyl, cycloalkyl or cycloalkylalkyl, wherein said cycloalkylalkyl is optionally substituted by C \ .4 alkyl. Typically, R⁴ may be propyl, especially isopropyl.

Alternatively, Z may be a heteroaryl group that may optionally be substituted by one or two groups selected from C i .4 alkyl, C i .4 haloalkyl, C i .5 hydroxyalkyl,

C2.4 alkoxyalkyl, C3. cycloalkyl optionally substituted by C\ .4 alkyl or halo, C\ .4 alkoxy, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, alkylamino, alkylaminoalkyl, cyano and halogen.

When Z is heteroaryl, suitable heteroaryl groups are oxadiazole, pyrimidine, pyridazine, thiazole, tetrazole, benzothiazole and thiadiazole, e.g., oxadiazole and

pyrimidine.

In some embodiments Z may suitably comprise l ,2,4-oxadiazol-3-yl, 1 ,2,4- oxadiazol-5-yl or pyrimidin-2-yl, which may be substituted by any of the aforementioned substituents.

Typically, said l ,2,4-oxadiazol-3-yl or l ,2,4-oxadiazol-5-yl may be substituted by C\ .4 alkyl, such as propyl (e.g., 3-isopropyl or 5-isopropyl), C \ .4 haloalkyl,

Cl-5 hydroxyalkyl (e.g. 1 -hydroxyethyl), C2-4 alkoxyalkyl or heterocyclyl.

Suitably said C i .5 hydroxyalkyl group may be C i .3 hydroxyalkyl, e.g. hydroxyethyl.

Pyrimidin-2-yl may be unsubstituted or substituted with one or more halo groups, e.g. 5-chloropyrimidin-2-yl.

In a further alternative, Z may suitably be -CH2-phenyl, wherein the phenyl is optionally substituted by one or two groups independently selected from C i .4 alkyl, C i .4 haloalkyl and halo. In some embodiments R1 may suitably be H or Ci _2alkyl, e.g., methyl. Generally, compounds in which R1 is H may be preferred.

R^ may suitably be optionally substituted phenyl, pyridyl, N-pyrazolyl or N- pyridonyl,

e.g., 2-pyridyl.

In some embodiments, R^ may suitably be phenyl substituted by one, two or three halo groups; the halo groups are suitably fluoro.

Alternatively, R^ may be pyridyl, N-pyrazolyl or N-pyridonyl substituted by one, two or three halo, methyl or methoxy groups, typically one or two methyl groups.

When W is a 5 membered heteroaryl ring, such as oxadiazolyl, R^ may suitably be phenyl optionally substituted by one or more halo, methyl or halomethyl groups.

In som mbodiments, when Y is W-Y^, R^ may be selected from:

_s phenyl optionally substituted by one or more halo, methyl, halomethyl or methoxy groups, or pyridyl, optionally substituted by one or more halo, C\ _2 alkyl or halomethyl groups, wherein the lactam, phenyl and pyridyl groups are the same as they are above.

R^ is suitably H or C\ _2alkyl, typically methyl. When Z is -C(0)OR4, R^ may be

C\ _2alkyl and R^ may be phenyl, optionally substituted by one or more halo, methyl or halomethyl groups. When Z is -CH2-phenyl, R^ may be phenyl optionally substituted by one or more halo, methyl or halomethyl groups.

The molecular weight of the compounds of the invention is suitably less than about 800, typically less than about 600. When Z is heteroaryl, particularly oxadiazolyl, the compounds of the invention may be metabolized in vivo by a ring-opening mechanism to form compounds of formula (Id):

d)

wherein A, R1 to R11, X, Y, m, n, p, q and r are as defined for any of formulae (I), (lb) or (Ic) above;

Z is -C(0)R¹²; and

R¹² is -NHC(0)R¹³ or -NHC(NH)R¹³, in which R¹³ is selected from C 1.4 alkyl, Ci _4haloalkyl, C1.5 hydroxyalkyl, Ci _4alkoxy, C2_4alkoxyalkyl, heterocyclyl,

heterocyclylC 1.4 alkyl, heteroarylCi _4alkyl, C3_6cycloalkyl and

~(Ci .3 alkyl)-(C3_ cycloalkyl), wherein the cycloalkyl and alkyl groups are each optionally substituted by one or two groups independently selected from C\ .4 alkyl, hydroxy or halo.

Said compounds of formula (Id) may have the stereochemistry of formula (la).

It has been found that these metabolites may have some GPR119 agonist activity and accordingly they are included in the present invention, together with their pharmaceutically acceptable salts.

In some embodiments, R^³ may be C\ .4 alkyl, for instance propyl or isopropyl.

Suitably, Y¹ may be CR⁷H, where R⁷ is Ci _2 alkyl as defined above.

While suitable groups for each variable have generally been listed above separately for each variable, the compounds of the present invention include those in which several or each variable in formula (I) is selected from the groups mentioned particularly for each variable. Therefore, this invention is intended to include all combinations of listed groups, especially those indicated to be suitable or typical.

The invention also comprehends isotopically-labeled compounds, which are identical to those recited in formulae (I), (lb), (Ic) and (Id) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, such as ^C, and l ^F.

Compounds of the present invention and salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ¾, are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ¾, and carbon-14, i.e., l^C, isotopes are particularly preferred for their ease of preparation and detectability. 1 lC and l ^F isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ¾, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, isotopically labeled compounds of formula (I), (lb), (Ic) and (Id) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In one embodiment, the compounds of formula (I), (lb), (Ic) and (Id) or salts thereof are not isotopically labelled.

As used herein, unless stated otherwise, "alkyl" means carbon chains which may be linear or branched. Examples of alkyl groups include ethyl, propyl, isopropyl, butyl, sec- and tert-butyl. Such alkyl groups may in some embodiments be substituted with one or more halo groups, particularly fluoro. Generally a CF3 group may be replaced by SF5 without departing from the present invention.

The term "heteroaryl" rings means 5- or 6-membered N-containing heteroaryl rings optionally containing one or more, e.g. 1 , 2 or 3, additional heteroatoms selected from N, O and S, or fused bicyclic systems optionally containing one or more, e.g., 1 , 2, 3, 4 or 5, heteroatoms selected from N, O and S. Examples of such heteroaryl rings are pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl C4. cycloalkylalkyl wherein the cycloalkylalkyl is optionally substituted by C\ .4 alkyl, triazinyl, tetrazolyl and

benzothiazolyl.

Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The present invention includes all stereoisomers of the compounds of the invention and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

When a tautomer of the compound of the invention exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically drawn or stated otherwise.

When the compound of the invention and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.

The term "pharmaceutically acceptable salts" refers to salts prepared from

pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from

pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethyl amine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound of the invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, trifluoroacetic acid and the like.

Since the compounds of the invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98%> pure (% are on a weight for weight basis).

The compounds of formula (I) can be prepared as described below, wherein R1, R^, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^{1 1}, A, X, Y, Z, m, n, p, q and r are as defined for formula (I). PG is a protecting group, LG is a leaving group, Hal is halogen.

Compounds of formula (I) can be prepared as outlined in Scheme 1. Compounds of formula (IV) can be prepared by SN_AT displacement of suitable haloaromatic compounds of formula (II) with amines of formula (III) under standard conditions, for example, DBU and DMSO at 80 - 100°C. Alternatively, compounds of formula (IV) can be prepared by reaction of suitable haloaromatic compounds of formula (II) with amines of formula (III) under Buchwald-Hartwig conditions, such as, Pd₂(dba)₃ and XANTPHOS or

triisobutylphosphatrane in a suitable solvent, such as toluene at 120°C in a microwave reactor. Removal of the protecting group PG from the amine functionality to yield compound (I), can be achieved using standard conditions well known to those skilled in the art.

Scheme 1

I

Compounds of formula (II), where X is O, can be prepared as outlined in Scheme 2. Alcohols of formula (V) can be treated with hydroxyaryl compounds of formula (VI) under standard Mitsonobu conditions, for example, using diisopropylazodicarboxylate and triphenylphosphine in a suitable solvent such as toluene. Alternatively, compounds of formula (II) where X is O can be prepared from alcohols of formula (V) via formation of a suitable leaving group. Suitable leaving groups, such as mesylates of formula (VII), can be prepared using standard conditions, such as, methanesulfonyl chloride and triethylamine in DCM. Compounds of formula (II) can be prepared from mesylates of formula (VII) and hydroxyaryls of formula (VI) under standard conditions, for example, using a base such as CsF or K₂C0₃ in a suitable solvent such as DMA or DMF at 60 - 80°C.

Compounds of formula (IV), where X is NR⁶, and R⁶ is hydrogen, can be prepared as outlined in Scheme 3. Carbonyl compounds of formula (VIII) can be prepared from alcohols of formula (V) using standard oxidizing conditions, such as DMSO and oxalyl chloride with a base such as triethylamine, or Dess-Martin Periodinane in a solvent such as DCM.

Compounds of formula (IV) can be prepared from carbonyl compounds of formula (VIII) and amines of formula (IX) by reductive amination under standard conditions, using, for example, a reducing agent such as NaBH(OAc)3 and a catalyst such as AcOH in a suitable solvent such as DCM. Scheme 3

Further reaction of compounds of formula (IV) with readily available aldehydes under standard conditions, as outlined above, can be used to prepare compounds of formula

(IV) where R⁶ is an alkyl group.

Compounds of formula (IX) can be prepared as outlined in Scheme 4. Compounds of formula (XI) can be prepared by SNA_T displacement of suitable haloaromatic compounds of formula (X) with amines of formula (III) under the standard conditions outlined above. Compounds of formula (IX) can be prepared from compounds of formula (XI) by reduction under standard conditions using a catalyst such as 10% palladium on carbon under an atmosphere of hydrogen in a suitable solvent such as methanol or ethanol.

Scheme 4

XI

Compounds of formula (II), where X is CR^H and γΐ is O, can be prepared as outlined in Scheme 5. Alkylating agents such as halides of formula (XIII), which are either readily available or can be synthesised by known methods, can be reacted with Alcohols of formula (XII) under standard conditions using, for example, a base such as Sodium hydride or tBuOK in a suitable solvent such as THF or DMF. Scheme 5

XII XIII

Compounds of formula (IV), where X is CR^H and γΐ is NR^, and where R^ is hydrogen, can be prepared as outlined in Scheme 6. Compounds of formula (XIV) can be prepared from alcohols of formula (XII) under standard Mitsonobu conditions using, for example, diisopropylazodicarboxylate and triphenylphosphine in a suitable solvent such as toluene. Compounds of formula (XIV) can be converted to the amine by reaction with hydrazine hydrate in a solvent such as EtOH to afford amines of formula (XV). Compounds of formula (IV) can be prepared by reacting amines of formula (XV) with carbonyl compounds of formula (XVI), under standard reductive amination conditions as outlined above.

Scheme 6

XII XIV

IV

Further reaction of compounds of formula (IV) with readily available aldehydes under standard conditions, using a reducing agent such as NaBH(OAc)3 and catalyst such as AcOH in a suitable solvent such as DCM, can be used to prepare compounds of formula (IV) where R^ is an alkyl group.

Carbonyl compounds of formula (XVI) can be prepared as outlined in Scheme 7. Compounds of formula (XVIII) can be prepared by SN^r displacement of suitable, readily available haloaromatic compounds of formula (XVII) by amines of formula (III) under the standard conditions outlined above. Compounds of formula (XVIII) can be reduced to alcohols of formula (XIX) using, for example, a standard reducing agent such as DIBAL-H in a solvent such as THF. Carbonyl compounds of formula (XVI) can be prepared from alcohols of formula (XIX) by oxidation under standard conditions using a reagent such as Dess-Martin Periodinane in a solvent such as DCM. Alternatively, carbonyl compounds of formula (XVI) can be prepared by SN^r displacement of suitable readily available haloaromatic compounds of formula (XX) by amines of formula (III) under the standard conditions outlined above.

Scheme 7

XVII XVIII

x^x

Examples and syntheses of compounds of formula (III) have been described elsewhere: Benbow et.al, WO2007148185; Brackes et.al, Bioorg. Med. Chem. Lett., 2007, 17 (7), 2005-2012; Pei et.al, J. Med. Chem., 2007, 50 (8), 1983-1987; Cox et.al, Bioorg. Med. Chem. Lett., 2007, 17 (16), 4579-4583; Wright et.al, Bioorg. Med. Chem. Lett., 2007, 17 (20), 5638-5642. The syntheses of building blocks of formulae (V) and (XIII) have been described elsewhere: Fang et. al, WO2008070692; Walmsley et. al, WO2008038011; Chen et. al, WO2008083238; Wilson et. al, WO2009123992; Loso et. al, WO2008030266. Other compounds of formula (I) may be prepared by methods analogous to those described above or by methods known per se. Further details for the preparation of the compounds of formula (I) are found in the examples.

The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000, compounds and more preferably 10 to 100 compounds of formula (I). Compound libraries may be prepared by a combinatorial "split and mix" approach or by multiple parallel syntheses using either solution or solid phase chemistry, using procedures known to those skilled in the art.

Any novel intermediates as defined in the Schemes above or in the Examples, are also included within the scope of the invention. Therefore according to a further aspect of the invention there is provided a compound of any one of formulae (II), (IV), (IX) and (XVI) as defined above. The preferred groups for variables recited above in relation to the compounds of formula (I) also apply to the intermediate compounds.

As indicated above the compounds of the invention are useful as GPR119 agonists, e.g. for the treatment and/or prophylaxis of diabetes. For such use the compounds of the invention will generally be administered in the form of a pharmaceutical composition.

The compounds of the invention may also be useful as dual GPR119 agonists/DPP- IV inhibitors, e.g. for the treatment and/or prophylaxis of diabetes. For such use the compounds of the invention will generally be administered in the form of a pharmaceutical composition.

The invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

The invention also provides a pharmaceutical composition comprising a compound of the invention, in combination with a pharmaceutically acceptable carrier.

Preferably the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of the invention, or a

pharmaceutically acceptable salt thereof.

Moreover, the invention also provides a pharmaceutical composition for the treatment of disease by modulating GPR119 and optionally DPP-IV, resulting in the prophylactic or therapeutic treatment of diabetes, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of the invention, or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions may optionally comprise other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous)

administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practice, the compounds of the invention, or pharmaceutically acceptable salts thereof, can be combined as the active ingredient in intimate admixture with a

pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous).

Thus, the pharmaceutical compositions can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil -in- water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound of the invention, or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.

A tablet containing the composition of this invention may be prepared by

compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5 g of the active ingredient.

For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg.

Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms .

Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, using a compound of the invention, or a

pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.

Compositions containing a compound of the invention, or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

Generally, dosage levels on the order of O.Olmg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above -indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, obesity may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.

It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The compounds of the invention may be used in the treatment of diseases or conditions in which GPR119 and optionally DPP-IV play a role. Thus the invention also provides a method for the treatment of a disease or condition in which GPR119 and optionally DPP-IV play a role comprising a step of administering to a subject in need thereof an effective amount of a compound of the invention, or a

pharmaceutically acceptable salt thereof. Such diseases or conditions diabetes, obesity, impaired glucose tolerance, insulin resistance and diabetic complications such as neuropathy, nephropathy, retinopathy, cataracts, cardiovascular complications and dyslipidaemia). And the treatment of patients who have an abnormal sensitivity to ingested fats leading to functional dyspepsia. The compounds of the invention may also be used for treating metabolic diseases such as metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels and

hypertension.

The invention also provides a method for the treatment of type II diabetes, comprising a step of administering to a patient in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

The invention also provides a method for the treatment of obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension comprising a step of administering to a patient in need thereof an effective amount of a compound of the invention, or a

pharmaceutically acceptable salt thereof.

The invention also provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition as defined above.

The invention also provides the use of a compound of the invention, or a

pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition as defined above.

In the methods of the invention the term "treatment" includes both therapeutic and prophylactic treatment.

The compounds of the invention may exhibit advantageous properties compared to known compounds or combination therapies for the treatment of diabetes.

The compounds of the invention, or pharmaceutically acceptable salts thereof, may be administered alone or in combination with one or more other therapeutically active compounds. The other therapeutically active compounds may be for the treatment of the same disease or condition as the compounds of the invention or a different disease or condition. The therapeutically active compounds may be administered simultaneously, sequentially or separately. The compounds of the invention may be administered with other active compounds for the treatment of obesity and/or diabetes, for example insulin and insulin analogs, gastric lipase inhibitors, pancreatic lipase inhibitors, sulfonyl ureas and analogs, biguanides, a2 agonists, glitazones, PPAR-γ agonists, mixed PPAR-α/γ agonists, RXR agonists, fatty acid oxidation inhibitors, a-glucosidase inhibitors, β-agonists, phosphodiesterase inhibitors, lipid lowering agents, glycogen phosphorylase inhibitors, antiobesity agents e.g. pancreatic lipase inhibitors, MCH-1 antagonists and CB-1 antagonists (or inverse agonists), amylin antagonists, lipoxygenase inhibitors, somostatin analogs, glucokinase activators, glucagon antagonists, insulin signalling agonists, PTP1B inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic/dopaminergic antiobesity drugs, reuptake inhibitors e.g. sibutramine, CRF antagonists, CRF binding proteins, thyromimetic compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-1 inhibitors or sorbitol dehydrogenase inhibitors.

Combination therapy comprising the administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one other agent represents a further aspect of the invention.

The present invention also provides a method for the treatment of diabetes in a mammal, such as a human, which method comprises administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another agent, to a mammal in need thereof.

The invention also provides the use of a compound of the invention, or a

pharmaceutically acceptable salt thereof, and another agent for the treatment of diabetes.

The invention also provides the use of a compound of the invention, or a

pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in combination with another agent, for the treatment of diabetes.

The compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s) may be co-administered or administered sequentially or separately.

Co-administration includes administration of a formulation which includes both the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s), or the simultaneous or separate administration of different formulations of each agent. Where the pharmacological profiles of the compound of the invention, or a pharmaceutically acceptable salt thereof, and the other agent(s) allow it, coadministration of the two agents may be preferred.

The invention also provides the use of a compound of the invention, or a

pharmaceutically acceptable salt thereof, and another agent in the manufacture of a medicament for the treatment of diabetes.

The invention also provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and another antiobesity agent, and a pharmaceutically acceptable carrier. The invention also encompasses the use of such compositions in the methods described above.

All publications, including, but not limited to, patents and patent application cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as fully set forth.

The invention will now be described by reference to the following examples which are for illustrative purposes and are not to be construed as a limitation of the scope of the present invention.

EXAMPLES

Materials and methods

Column chromatography was carried out on Si0₂ (40-63 mesh) unless specified otherwise. LCMS data were obtained as follows: Atlantis 3μ C₁₈ column (3.0 x 20.0mm, flow rate = 0.85mL/min) eluting with a H₂0-MeCN solution containing 0.1% HC0₂H over 6 min with UV detection at 220 nm. Gradient information: 0.0-0.3 min 100% H₂0; 0.3-4.25 min: Ramp up to 10% H₂O-90% MeCN; 4.25-4.4 min: Ramp up to 100% MeCN; 4.4-4.9 min: Hold at 100% MeCN; 4.9-6.0 min: Return to 100% H₂0. The mass spectra were obtained using an electrospray ionisation source in either the positive (ES⁺) or negative (ES^~) ion modes.

LCMS -method 2 data were obtained as follows: Xbridge C₁₈ column (2.1 x 50mm, 2.5μΜ, flow rate 0.8mL/min) eluting with an MeCN-lOmM NH₄HCO₃ solution over 1.5 min with UV detection at 215 - 350nm. Gradient information: 0-0.8 min: 98% MeCN 2%

NH₄HCO₃ to 98% NH₄HCO₃ 2% MeCN; 0.8-1.2min: hold at 98% NH₄HCO₃ 2% MeCN. The mass spectra were obtained using an electrospray ionisation source in the positive (ES⁺) mode. LCMS-method 3 data were obtained as follows: Xbridge C₁₈ column (2.1 x 5.0mm, 2.55μΜ, flow rate 0.8mL/min) eluting with an MeCN-lOmM NH₄HCO₃ solution over 5 min with UV detection at 215 - 350nm. Gradient information: 0-4 min: 98% MeCN 2%

NH₄HCO₃ to 98% NH₄HCO₃ 2% MeCN; 4-4.6min: hold at 98% NH₄HCO₃ 2% MeCN. The mass spectra were obtained using an electrospray ionisation source in the positive (ES⁺) mode.

LCMS-method 4 data were obtained as follows: Xbridge CI 8 column (3.0 x 150mm,

5μΜ, flow rate l .OmL/min) eluting with an MeCN-lOmM NH₄HCO₃ solution over 5 min with UV detection at 215 - 350nm. Gradient information: 0-0.1 min: hold at 5% MeCN 95% NH₄HCO₃; 0.1-3.0 min: 5% MeCN 95%NH₄HC0₃ to 5% NH₄HCO₃ 95% MeCN; 3.0-

3.9min: hold at 5% NH₄HCO₃ 95% MeCN. The mass spectra were obtained using an electrospray ionisation source in the positive (ES⁺) mode.

LCMS-method 5 data were obtained as follows: Xbridge C₁₈ column (3.0 x 150mm,

5μΜ, flow rate 0.5mL/min) eluting with an MeCN-lOmM NH₄HCO₃ solution over 25 min with UV detection at 215 - 350nm. Gradient information: 0-15 min: 5% MeCN

95%NH₄HC0₃ to 5% NH₄HCO₃ 95% MeCN; 15-25min: hold at 5% NH₄HCO₃ 95% MeCN.

The mass spectra were obtained using an electrospray ionisation source in the positive (ES⁺) mode.

LCMS-method 6 data were obtained as follows: Phenomenex Kinetex CI 8 column (3.0x30mm, 2.6μΜ, flow rate l .OmL/min) eluting with a H₂0-MeCN solution containing 0.1% HC0₂H over 2 min with UV detection at 220 nm. Gradient information: 0.0-0.1 min 2% MeCN 98% H₂0 to 5% MeCN 95% H₂0; 0.1-1.50 min: Ramp up to 100% MeCN; 1.5- 1.75min: Hold at 100% MeCN; 1.75-1.8min: 100% MeCN to 2% MeCN 98% H₂0; 1.8-2.0 min: Hold at 2% MeCN 98% H₂0. The mass spectra were obtained using an electrospray ionisation source in either the positive (ES⁺) or negative (ES^~) ion modes.

LCMS-method 7 data were obtained as follows: Waters Atlantis CI 8 column (3.0 x 20mm, 3μΜ, flow rate l .OmL/min) eluting with H₂0-MeCN solution containing 0.1% HC0₂H over 6 min with UV detection at 220 nm. Gradient information: 0.00-0.30 min: 100% H₂0; 0.30-4.25 min: 100% H₂0 to 90% MeCN 10% H₂0; 4.25-4.40 min: 90% H₂0 to 10% MeCN to 100% MeCN; 4.40-4.90 min: hold at 100% MeCN; 4.90-5.00 min: 100% MeCN to 100% H₂0; 5.00-6.00 min: hold at 100% H₂0 for re-equilibration. The mass spectra were obtained using an electrospray ionisation source in the positive (ES⁺) mode.

LCMS-method 8 data were obtained as follows: Waters Xbridge C18 column (4.6 x 50mm, 3.5μΜ, flow rate 1.5 mL/min) eluting with H₂0-MeCN solution containing 0.2% NH₃OH over 5.5 min with UV detection at 220 nm. Gradient information: 0.00-0.30 min: 95% H₂0, 5% MeCN; 0.30-3.90 min: 100% H₂0 to 100% MeCN; 3.90-4.90 min: hold at 100% MeCN; 4.90-5.00 min: 100% MeCN to 5% MeCN 95% H₂0; 5.00-5.50 min: hold at 95% H₂0, 5%) MeCN for re-equilibration. The mass spectra were obtained using an electrospray ionisation source in the positive (ES⁺) mode.

Unless otherwise stated LCMS-method 1 was employed for analysis.

Preparative HPLC purification was carried out using either a standard or basic method.

Standard method: Gemini-NX C₁₈ column (21.2 x 100mm, 5μΜ, flow rate 20mL/min) eluting with a H₂0-MeCN solution containing 0.1% HC0₂H using a 10 minute gradient with UV detection at 220 nm.

Basic method: XBridge Prep C₁₈ column (19 x 100mm, 5μΜ, flow rate 20mL/min) eluting with a H₂0-MeCN solution containing 0.2% NH₄OH using a 10 minute gradient with UV detection at 220 nm. Unless otherwise stated, the standard method was employed for purification.

MDP (Mass-directed purification) was carried out using either an acidic or basic method. Acidic method: XBridge Prep C₁₈ column (19 x 50mm, 5μΜ, flow rate 20mL/min) eluting with a H₂0-MeCN solution containing 0.1% HC0₂H using an 8 minute gradient with

UV detection at 220 nm and additional mass ion detection.

Basic method: XBridge Prep C₁₈ column (19 x 50mm, 5μΜ, flow rate 20mL/min) eluting with a H₂0-MeCN solution containing 0.2% NH₄OH using an 8 minute gradient with UV detection at 220 nm and additional mass ion detection. Both the acidic and basic methods were employed for purification.

Chiral-HPLC was performed on a Daicel chiralpak IA 250 x 20 mm, 5 μΜ column. Abbreviations and acronyms: AcOH: Acetic acid; ADDP: Azodicarboxylic

dipiperidide; BA: n-butylamine; BOP: (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; n-BuLi: n-Butyl Lithium; ^lBuOK: tertiary Butanol; ^lBuOK: Potassium tertiary butoxide; C: Carbon; CsF: Cesium fluoride; DAST: Diethylaminosulfur trifluoride; DBU: l ,8-Diazabicyclo[5.4.0]undec-7-ene;

DCM: Dichloromethane; DCE: 1 ,2-dichloroethane; DEA: Diethylamine; DEAD:

Diethylazodicarboxylate; DIAD: Diisopropylazodicarboxylate; DMA: Dimethylacetamide;

DME: 1 ,2-Dimethoxyethane; DMF: Dimethylformamide; DIPEA: Diisopropylethylamine;

DMAP: Dimethylpyridin-4-ylamine; DMSO: Dimethylsulfoxide; EDCI: (3-

Dimethylaminopropyl)ethylcarbodiimide hydrochloride; Et₂0: Diethyl ether; EtOH: Ethanol;

EtOAc: Ethyl Acetate; h: hour(s); HBTU: 0-(benzotriazol-l-yl)N,N,N'N'- tetramethyluronium hexafluorophosphate; HC1: Hydrochloric acid; HC0₂H: Formic acid; H₂0: Water; HOAT: l-Hydroxy-7-azabenzotriazole; HOBt: 1 -Hydro xybenzotriazole monohydrate; HPLC: High performance liquid chromatography; H₂S0₄: Sulfuric acid; IH: Isohexane; IMS: Industrial methylated spirit; IPA: Isopropyl alcohol; M: Molar; MDP:

Mass-directed purification; MeCN: Acetonitrile; MeOH: Methanol; MgS0₄: Magnesium sulphate; min: minute/s; MTBE: Methyl tert-butyl ether; NaHC0₃: Sodium hydrogen carbonate; NaOH: Sodium hydroxide; Na₂S0₄: Sodium sulphate; n-BuLi: n-Butyl lithium; NH₃: Ammonia; NH₄HC0₃: Ammonium carbamate; NH₄OH: Ammonium hydroxide; NMP: N-methyl-2-pyrrolidone; Pd: Palladium; PE-AX: Anion exchange resin; POH: Phosphonic acid resin; PPh₃: Triphenylphosphine; PS: Polymer supported; RT: Retention time; r.t.: Room temperature; sat: Saturated; SCX: Strong Cation Exchange resin; Si0₂: Silica gel; STMAd: Succinic acid resin; TBAD: tert-butylazodicarboxylate; TBAI:

Tetrabutylammonium iodide; TBME: tert-Butyl methyl ether; THF: Tetrahydrofuran; TFA: Trifluoroacetic acid; TFAA: Trifluoroacetic anhydride; TsOH: /?-Toluenesulfonic acid monohydrate; wt: Weight

The syntheses of the following compounds have been described elsewhere: (1- Benzyl-5-fluoro-l,2,3,6-tetrahydro-pyridin-4-yl)-methanol: Nelson, T.D., et. al., WO

2006069287;

(3S,4S)-3,4-diazido-l-benzylpyrrolidine: Benbow et. al, WO2007148185; N-hydroxy-2- methoxyacetamidine: Allen, et. al., WO2004056823; 4-hydroxypiperidine-l-carbonitrile: Bertram, L., et. al., WO2007116229; (i?)-N-hydroxy-tetrahydro-furan-2-carboxamidine: Rikimaru, K., et. al., WO2010095663; (i?)-3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin- 4-yl]butan-l-ol: Fyfe et. al, WO2008081204; 3-isopropyl-5-trichloromethyl- [l,2,4]oxadiazole: Smith, N., et. al., WO2009117421; methanesulfonic acid l-(3-isopropyl- [1 ,2,4]oxadiazol-5-yl)-piperidin-4-ylmethyl ester: Fang et al, WO2008070692; 4-((R)-l- methanesulfonyloxy-ethyl)-piperidine-l-carboxylic acid isopropyl ester: Fang et al., WO2008070692; (i?)-l-piperidin-4-yl-ethanol acetate: Fang, J. et al., WO2008070692;

(35',45)-3-tert-butoxycarbonylamino-4-hydroxy-pyrrolidine- 1 -carboxylic acid tert-butyl ester: Johnson, J. et al., WO2009153554.

All other compounds were available from commercial sources. Preparation 1: [(l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol

A solution of 4-piperidinemethanol (3.45g, 30mmol) in DCM (25mL) was cooled to 0°C and sodium hydrogen carbonate (24.72g, 120mmol) was added. To the mixture was added a solution of cyanogen bromide (3.82g, 36mmol) in water (lOmL), dropwise over 15 min, and the mixture was stirred at 0°C for 2 h before being stirred at r.t. for 16 h. The organic phase was separated, and the aqueous phase extracted with DCM (4 x 50mL).

Organic fractions were combined and concentrated in vacuo to afford 4- hydroxymethylpiperidine-l-carbonitrile: RT = 1.71 min, m/z (ES ) = 141.1 [M+ H]⁺.

To a solution of the intermediate and N-hydroxyisobutyramidine (2.80g, 27.43mmol) in EtOH (30mL) was added a solution of zinc chloride (3.73g, 27.43mmol) in EtOH (20mL) over 15 min. The reaction was stirred at r.t. for 2 h and then 12M HCl (13.33mL) was added before heating the mixture to 50°C for 18 h. After cooling to r.t., the crude mixture was filtered and the filtrate concentrated in vacuo. The resulting residue was diluted with water (lOOmL), then solid NaHC0₃ was added to bring the pH to 7. The mixture was extracted with EtOAc (3 x 200mL), then organic fractions were combined, washed with brine (2 x 200mL) and dried (MgSC^). Removal of the solvent in vacuo afforded the title compound R- T = 2.57 min, m/z (ES⁺) = 226.2 [M+ H]⁺.

Preparation 2 : 2-Chloro-5- [ l-(3-isopropyl- [1 ,2,4] oxadiazol-5-yl)piperidin-4- ylmethoxy] pyrimidine

To a solution of [(l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation 1, 1.13g, 5.0mmol) and triethylamine (0.77mL, 5.5mmol) in DCM (30mL), cooled to 0°C, was added methanesulfonyl chloride (0.39mL, 5.0mmol), dropwise, before allowing the reaction to warm to r.t. for 30 min. The reaction mixture was partitioned between DCM (lOOmL) and 1M HCl (150mL), then the organic phase was separated and concentrated in vacuo to afford the intermediate product methanesulfonic acid l-(3- isopropyl[ 1 ,2,4]oxadiazol-5-yl)piperidin-4-ylmethyl ester.

To a solution of the intermediate in DMF (50mL) was added 2-chloropyrimidin-5-ol (0.78g, 6.0mmol) and potassium carbonate (1.38g, lO.Ommol), and the reaction was heated to 80°C for 16 h. The reaction solvent was concentrated in vacuo and the resulting residue was re-dissolved in EtOAc (300mL). The solution was washed with 1M NaOH solution (2 x 300mL), brine, then dried (MgSC^), and the solvent was removed in vacuo to afford the title compound: RT = 3.55 min, m/z (ES⁺) = 338.1 [M+ H]⁺.

Preparation 3: 2-Bromo-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy] pyridine

A solution of [(l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol

(Preparation 1, 1.13g, 5.0mmol) and 6-bromopyridin-3-ol (0.87g, 5.0mmol) in toluene (lOOmL), under argon, was cooled to 0°C. ADDP (2.52g, lO.Ommol) was added, followed by portion- wise addition of tri-n-butyl phosphine (2.46mL, lO.Ommol). The resulting mixture was allowed to reach r.t., then stirred for 112 h before concentration of the reaction solvent in vacuo. The residue was re-dissolved in EtOAc, washed with 1M NaOH solution (2 x 200mL), then brine (2 x 150mL), and dried (MgSC^). Purification by column

chromatography (IH:EtOAc, 60:40) afforded the title compound: RT = 2.37 min; m/z (ES ) =

Preparation 4: 2-Bromo-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrazine

[(l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation 1) was reacted with 5-bromopyrazin-2-ol employing the procedure outlined in Preparation 2. Further purification by column chromatography (IH:EtOAc, 2:1) afforded the title compound: RT = 2.37 min; m/z (ES⁺) =382.1, 384.0 [M+ H]⁺.

Preparation 5: 3-(2,5-Difluorophenyl)-4-nitrobutyric acid methyl ester

To a solution of (2E)-3-(2,5-difluorophenyl)acrylic acid (21.10g, 114.7mmol) in a mixture of DCM and MeOH (DCM:MeOH, 4: 1, 250mL) was added a solution of trimethylsilyldiazomethane (2M in Et₂0, 57.34mL, 114.7mmol) over 15 min and the resulting mixture was stirred at r.t. until complete. AcOH was added, dropwise, until the reaction turned colourless, and the solvent was removed in vacuo. The residue was re- dissolved in MeCN (114mL), then nitromethane (7.45mL, 137.6mmol) was added. The mixture was cooled to 0°C before adding DBU (17.49mL, 117.0mmol), dropwise, over 30 min. The reaction was allowed to warm to r.t. and stirred for 16 h. Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 95:5, 90: 10) afforded the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 7.18 - 7.00 (m, 3H), 4.91 - 4.77 (m, 2H), 4.27 - 4.17 (m, 1H), 3.75 (s, 3H), 2.91 (m, 2H).

Preparation 6: (frans)-l-Benzyl-4-(2, -difluorophenyl)-5-nitropiperidin

A combination of 3-(2,5-difluorophenyl)-4-nitrobutyric acid methyl ester

(Preparation 5, 16.27g, 62.81mmol), paraformaldehyde (1.94g, 64.63mmol) and benzylamine (13.7mL, 125.62mmol) in EtOH was heated to 90°C in a sealed tube for 16 h. After complete reaction the mixture was partitioned between EtOAc (400mL) and 2M HCl (600mL). The organic fraction was separated, washed with brine, dried (MgSC^), and the solvent removed in vacuo. Purification by column chromatography (IH:EtOAc, 70:30) afforded the title compound: RT = 3.72 min mlz (ES⁺) = 347.1 [M+ H]⁺.

Preparation 7: (frans)-l-Benzyl-4-(2,5-difluorophenyl)-3-nitropiperidine hydrochloride

To a solution of (trans)- l-benzyl-4-(2,5-difluorophenyl)-5-nitropiperidin-2 -one

(Preparation 6, 10.44g, 30.17mmol) in THF (90mL), under argon, was added borane dimethylsulfide complex (2.0M in DCM, 45.3mL, 90.60mmol) and the reaction was heated to 70°C for 3 h. After cooling to r.t. the mixture was diluted with MeOH (20mL), then 1M HCl (30mL) was added. The mixture was stirred for 10 min before removal of the solvent in vacuo. Further portions of MeOH (20mL) and 1M HCl (20mL) were added and the reaction was stirred for 10 min. Removal of the solvent in vacuo afforded the title compound: RT = 3.30 min mlz (ES⁺) = 333.1 [M+ H]⁺.

Preparation 8: [(3R,4R)-l-Benzyl-4-(2,5-difluorophenyl)piperidin-3-yl]carbamic acid tert-buty\ ester

A combination of (trans)- l-benzyl-4-(2,5-difluorophenyl)-3-nitropiperidine hydrochloride (Preparation 7, 11.12g, 30.17mmol) and zinc dust (15.69g, 241.36mmol) in a mixture of AcOH and EtOH (1 : 1, 1 lOmL) was heated to 80°C. After complete reaction the mixture was filtered and the solvent removed in vacuo. To a solution of the resulting residue in MeOH (30mL) was added HC1 in dioxane (4M, 30mL), and the solvent was removed in vacuo. The material was triturated with Et₂0 (x 2), then toluene (x 3) to afford the amine intermediate as the hydrochloride salt. To a solution of the intermediate in a mixture of THF (150mL) and water (75mL), cooled to 0°C, was added triethylamine (12.6mL, 90.51mmol), followed by di-tert-butyl dicarbonate (9.59g, 45.26mmol). The mixture was allowed to warm to r.t. and stirred for 16 h, until complete. The mixture was partitioned between EtOAc (750mL) and water (200mL) and the organic phase was separated. The aqueous phase was extracted with EtOAc (500mL), then organic fractions were combined, dried (MgS0₄) and the solvent removed in vacuo. Purification by column chromatography (IH:EtOAc, 80:20) followed by further purification by chiral HPLC (IH:IPA:DEA, 90: 10:0.1, 15ml/min, 270nm, RT = 9.8 min) afforded the title compound: RT = 2.68 min mlz (ES⁺) = 403.2 [M+ H]⁺.

Preparation 9: [(3R,4R)-4-(2,5-Difluorophenyl)piperidin-3-yl]carbamic acid tert-buty\ ester

A solution of [(3i?,4i?)-l-benzyl-4-(2,5-difluorophenyl)piperidin-3-yl]carbamic acid tert-butyl ester (Preparation 8, 1.89g, 4.70mmol) in MeOH (94mL) was passed through an H-Cube apparatus (10% pd/C Catcart 70, 30bar, 80°C) at a flow rate of lmL per min. The solvent was removed in vacuo to afford the title compound: RT = 2.37 min; mlz (ES⁺) = 313.2[ + H]⁺. Preparation 10: l-Piperidin-4-yl ethanol

To a solution of a-methyl-4-pyridine methanol (3.7g, 30mmol) in EtOH (lOOmL) was added AcOH (1.9mL, 33mmol) and platinum oxide (0.5g, 2.2mmol), and the resulting mixture was allowed to stir under an atmosphere of hydrogen at r.t. for 16h. The mixture was filtered and the filtrate was concentrated in vacuo. To a solution of the residue, dissolved in MeOH, was added a solution of NaOH (1.6g, 40mmol) and water (1.6mL) in MeOH. The reaction was stirred for 30 min before removing the solvent in vacuo, and the resulting residue was suspended in Et₂0 for 30 min. The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound: 1H NMR 5_H (400MHZ, CDCI3): 3.63 - 3.55 (m, 1H), 3.39 - 3.31 (m, 2H), 2.7 - 2.6 (m, 2H), 2.01 - 1.92 (m, 2H), 1.76 - 1.69 (m, 1H), 1.67 - 1.54 (m, 2H), 1.51 - 1.42 (m, 1H), 1.1 - 1.14 (m, 3H).

Preparation 11: (S)-l-Piperidin-4-yl ethanol

The title compound was prepared from (5)-(-)-a-methyl-4-pyridinemethanol employing the procedure outlined in Preparation 10: 1H NMR δ_Η (400MHz, CDC1₃): 3.63 - 3.55 (m, 1H), 3.39 - 3.31 (m, 2H), 2.7 - 2.6 (m, 2H), 2.01 - 1.92 (m, 2H), 1.76 - 1.69 (m, 1H), 1.67 - 1.54 (m, 2H), 1.51 - 1.42 (m, 1H), 1.1 - 1.14 (m, 3H).

Preparation 12: 4-Hydroxymethylpiperidine-l-carboxylic acid isopropyl ester

To a solution of 4-piperidine methanol (12. Og, 104.12mmol) in DCM (200mL) in a 3- necked flask, under argon, was added DIPEA (23.6mL, 135.42mmol) and the reaction was cooled to 0°C. A solution of isopropylchloroformate in toluene (1M, 120mL, 119.79mmol) was added, dropwise, over 1.5h, then the reaction was brought to r.t. and stirred for a further 2.5 h. The mixture was partitioned with 1M HC1 solution (200mL) then the organic layer was separated, washed with 1M HC1 solution (200mL), brine (200mL) and dried (MgSC^). Removal of the solvent in vacuo afforded the title compound: 1H NMR δ_Η (400MHz,

CDCI3): 4.96 - 4.86 (m, 1H), 4.09 - 4.25 (m, 2H), 3.51 (d, J = 6.2 Hz, 2H), 2.80 - 2.68 (m, 2H), 1.78 - 1.62 (m, 3H), 1.49 - 1.41 (m, 1H), 1.29 - 1.09 (m, 8H). The following compounds were prepared from the appropriate piperidine starting material employing the procedure outlined in Preparation 12:

Preparation 15: 4-(6-Bromopyridin-3-yloxymethyl)piperidine-l-carboxylic acid isopropyl ester

To a dry solution of ADDP (5.01g, 19.87mmol) in toluene (200mL) was added tri n- butylphosphine (4.95mL, 19.87mmol) followed by 6-bromopyridin-3-ol (1.73g, 9.94mmol) and the reaction was cooled to 0°C for 5 min. A solution of 4-hydroxymethylpiperidine-l- carboxylic acid isopropyl ester (Preparation 12, 2.0g, 9.94mmol) in toluene (50mL) was added to the solution, dropwise, over 5 min, and the reaction was allowed to stir at 0°C for 16h. IH (200mL) was added and the reaction was stirred for 10 min before filtering the mixture to remove the precipitate. The filtrate was washed with 2M NaOH solution (2 x 150mL), water (150mL), 1M HC1 solution (2 x 150mL), and brine (150mL), then dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 4: 1, 3:1) afforded the title compound: RT = 3.87 min; mlz (ES⁺) = 359.1 [M + H]⁺.

Preparation 16: (3S,4S)-4-Azido-l-benz lpyrrolidin-3-ylamine

To a solution of (SS^^-S^-diazido-l-benzylpyrrolidine (15.6g, 64.10mmol) in THF (500mL), cooled to 0°C, was added a solution of triphenylphosphine (16.5g, 62.81mmol) in THF (lOOmL), dropwise over 4 h. The resulting mixture was allowed to reach r.t., and stirred for 16h. The reaction solvent was removed in vacuo and the resulting residue was re- dissolved in THF (500mL) and water (1.3mL). The mixture was heated to reflux for 4h, then stirred at r.t. for 16h. The reaction solvent was removed in vacuo and the resulting residue was triturated with Et₂0. The precipitate was filtered and the filtrate was concentrated in vacuo. The residue was taken into Et₂0 again and filtered. Removal of the filtrate in vacuo followed by purification by column chromatography (IH:EtOAc, 90: 10, 80:20, 50:50, 0: 100 then MeOH:NH₄OH, 9: 1) afforded the title compound: RT = 0.77 min; mlz (ES⁺) = 218.1 [M + H]⁺.

Preparation 17: ((3S,4S)-4-Azido-l-benzylpyrrolidin-3-yl)carbamic acid tert-buty\ ester

To a solution of (35',45)-4-azido-l-benzylpyrrolidin-3-ylamine (Preparation 16,

6.0g, 27.74mmol) and triethylamine (4.6mL, 33.29mmol) in DCM (lOOmL), cooled to 0°C, was added a solution of di tert-butyldicarbonate (7.3g, 33.29mmol) in DCM (lOmL), dropwise over 20 min. The resulting mixture was allowed to reach r.t., and stirred for 72h. The reaction solvent was washed with sat. NaHC0₃ solution, then brine, and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (DCM:MeOH) afforded the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 7.37 - 7.26 (m, 5H), 4.09 - 4.02 (m, 1H), 3.84 - 3.76 (m, 1H), 3.68 - 3.59 (m, 2H), 3.12 - 3.01 (m, 1H), 2.91 - 2.82 (m, 1H), 2.55 - 2.35 (m, 2H), 1.46 (s, 9H). Preparation 18: ((3S,4S)-4-Amino-l-benzylpyrrolidin-3-yl)carbamic acid tert-butyl ester

The title compound was prepared from ((35',45)-4-azido-l-benzylpyrrolidin-3- yl)carbamic acid tert-butyl ester (Preparation 17) employing the procedure outlined in WO2007/148185

Preparation 19: [(3S,4S)-l-Benzyl-4-(2-oxopiperidin-l-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

The title compound was prepared in 2 steps from ((3S,4S)-4-amino-l- benzylpyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 18) employing the procedures outlined in WO2007/148185. Preparation 20: [(3S,4S)-4-(2-Oxopiperidin-l-yl)pyrrolidin-3-yl]carbamic acid tert- butyl ester

A solution of [(35',45)-l-benzyl-4-(2-oxopiperidin-l-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 19, 2.6g, 7.07mmol) in MeOH (140mL) was passed through an H-Cube apparatus (10% pd/C Catcart 70, lObar, 90°C) at a flow rate of ImL per min. The solvent was removed in vacuo to afford the title compound: 1H NMR 5_H (400MHZ, CDCI3): 5.25 - 5.07 (m, 1H), 4.85 - 4.62 (m, 1H), 4.34 - 4.07 (m, 1H), 3.49 - 3.28 (m, 3H), 3.24 (s, 1H), 2.99 (s, 1H), 2.87 - 2.73 (m, 1H), 2.52 - 2.39 (m, 2H), 2.38 - 2.22 (m, 2H), 1.91 - 1.74 (m, 1H), 1.54 - 1.38 (m, 9H). Preparation 21: 4-Methanesulfonyloxymethylpiperidine-l-carboxylic acid isopropyl ester

To a dry solution of 4-hydroxymethylpiperidine-l-carboxylic acid isopropyl ester (Preparation 12, 2.5g, 12.42mmol) in DCM (30mL), under argon, was added triethylamine (2.08mL, 14.9mmol) and the mixture was cooled to 0°C. Methanesulfonyl chloride (1.06mL, 13.66mmol) was added, dropwise over 4 minutes, then the reaction was stirred at 0°C for 30 min. The mixture was diluted with DCM (50mL) and the organic layer was washed with water (2 x 50mL), 0.5M HC1 solution (2 x 50mL), brine (50mL) then dried (MgS0₄).

Removal of the solvent in vacuo afforded the title compound: 1H NMR δ_Η (400MHz, DMSO-de): 4.95 - 4.85 (m, 1H), 4.25-4.18 (m, 2H), 4.17 - 4.07 (m, 2H), 3.31 (s, 3H), 2.98 - 2.79 (m, 2H), 2.08 - 1.96 (m, 1H), 1.85 - 1.75 (m, 2H), 1.35 - 1.17 (m, 8H)

Preparation 22: 4-(4-Bromophenoxymethyl)piperidine-l-carboxylic acid isopropyl ester

To a solution of 4-methanesulfonyloxymethylpiperidine-l-carboxylic acid isopropyl ester (Preparation 21, 3.40g, 12.17mmol) and 4-bromophenol (2.32g, 13.39mmol) in DMF (70mL), under argon, was added potassium carbonate (3.36g, 24.34mmol) and the reaction was heated to 90°C for 16h. The reaction solvent was removed in vacuo, then the crude residue was dissolved in EtOAc (200mL) before being washed with water (3 x lOOmL). The aqueous layers were combined and extracted with EtOAc (50mL). The organic fractions were then combined, washed with sat. NaHC0₃ solution (2 x 150mL), brine (150mL), then dried (MgS0₄). Removal of the solvent in vacuo afforded the title compound: RT = 4.36 min; mlz (ES⁺) = 536.2 [M+ H]⁺.

Preparation 23: 4-Methanesulfonyloxymethylpiperidine-l-carboxylic acid tert-butyl ester

To a solution of 4-hydroxymethylpiperidine-l-carboxylic acid tert-butyl ester (5.0g, 23.2mmol) in DCM (lOOmL), cooled to 0°C, was added triethylamine (5.0 mL, 35.9 mmol). To the mixture was added methanesulfonyl chloride, dropwise, over 5 min, and the resulting reaction was stirred at 0°C for 30 min. The mixture was washed with water, then brine, and dried (MgS0₄). Removal of the solvent in vacuo afforded the title compound: 1H NMR 5H (400MHz, CDC1₃): 4.24 - 4.09 (m, 2H), 4.08 (d, J= 6.6 Hz, 2H), 3.02 (s, 3H), 2.77 - 2.65 (m, 2H), 1.97 - 1.87 (m, 1H), 1.77 - 1.71 (m, 2H), 1.46 (s, 9 H), 1.29 - 1.15 (m, 2H)

Preparation 24: 4-(2-Chloropyrimidin-5-yloxymethyl)piperidine-l-carboxylic acid tert- butyl ester

To a solution of 4-methanesulfonyloxymethylpiperidine-l-carboxylic acid tert-butyl ester (Preparation 23, 1.47g, 5.0mmol) and 2-chloropyrimidin-5-ol (0.65g, 5.0mmol) in DMF (80mL) was added potassium carbonate (0.83g, 6.0mmol) and the reaction was heated to 80°C until complete. The solvent was removed in vacuo, and the resulting residue was re- dissolved in EtOAc (300mL). The solution was washed with 1M NaOH solution (200mL), brine (200mL), then dried (MgS0₄) and the solvent was removed in vacuo. Purification by column chromatography (IH:EtOAc, 70:30) afforded the title compound: ^lH NMR δπ

(400MHz, CDCI3): 8.30 (s, 1H), 4.18 (br. s., 2H), 3.92 (dd, J=6.25, 3.51 Hz, 2H), 2.78 (t, J=12.30 Hz, 2H), 2.09 - 1.95 (m, 1H), 1.84 (d, J=12.89 Hz, 2H), 1.49 (s, 9H), 1.41 - 1.24 (m,

2H).

Preparation 25: 4-(2-Chloropyrimidin-5-yloxymethyl)piperidine-l-carboxylic acid isopropyl ester

To a solution of 4-(2-chloropyrimidin-5-yloxymethyl)piperidine-l-carboxylic acid tert-butyl ester (Preparation 24, 820mg, 2.51mmol) in DCM (25mL) was added a solution of HC1 in dioxane (4M, 2.5 lmL, 10.04mmol) and the reaction was stirred at r.t. until complete. The reaction solvent was removed in vacuo and the resulting residue was re- dissolved in THF. The mixture was cooled to 0°C and triethylamine (0.75mL, 5.52mmol) was added, dropwise, followed by a solution of isopropyl chloro formate in toluene (1M, 3.02mL, 3.02mmol). The mixture was stirred at r.t. for 2 h before concentrating the solvent in vacuo. The residue was dissolved in DCM, washed with sat. NaHC0₃ solution, then 1M HC1 solution, and the organic phase was passed through a phase separator. Removal of the solvent in vacuo afforded the title compound: RT = 3.65 min; m/z (ES⁺) = 314.0 [M+ H]⁺. Preparation 26: 4-(l-Methanesulfonyloxyethyl)piperidine-l-carboxylic acid isopropyl ester

To a dry solution of 4-(l-hydroxyethyl)piperidine-l-carboxylic acid isopropyl ester (Preparation 13, 3.02g, 14.1mmol) in DCM (150mL), under argon, was added triethylamine (2.28mL, 16.9mmol) and the mixture was cooled to 0°C. Methanesulfonyl chloride (1.20mL, 15.5mmol) was added, dropwise over 5 min, and the reaction was allowed to warm to r.t. with stirring until complete. The crude mixture was partitioned between DCM (150mL) and 1M HC1 (500mL), then the organic phase was separated, washed with further 1M HC1 (400mL), dried (MgS0₄), and the solvent removed in vacuo to afford the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 4.94 (spt, J=6.25 Hz, 1H), 4.68 (quin, J=6.25 Hz, 1H), 4.38 - 4.19 (m, 2H), 3.04 (s, 3H), 2.80 - 2.67 (m, 2H), 1.86 - 1.66 (m, 3H), 1.42 (d, J=6.25Hz, 3H), 1.39 - 1.24 (m, 8H).

Preparation 27: 4-[l-(2-Chloropyrimidin-5-yloxy)ethyl]piperidine-l-carboxylic acid isopropyl ester

The title compound was prepared by reacting 4-(l- methanesulfonyloxyethyl)piperidine-l-carboxylic acid isopropyl ester (Preparation 26) with 2-chloropyrimidin-5-ol employing a similar method to that outlined in Preparation 24, but in this case the reaction was heated to 100°C: RT = 3.75 min; mlz (ES⁺) = 328.1 [M+ H]⁺.

Preparation 28: 4-((S)-l-Methanesulfonyloxyethyl)piperidine-l-carboxylic acid isopropyl ester

4-((5)-l-Hydroxyethyl)piperidine-l-carboxylic acid isopropyl ester (Preparation 14) was reacted with methanesulfonyl chloride employing a similar method to that outlined in Preparation 21. The reaction mixture was diluted with EtOAc (50mL) and the organic layer was washed with water (2 x 50mL), 0.5M HC1 solution (2 x 50mL), brine (50mL) then dried (MgS0₄). Removal of the solvent in vacuo afforded the title compound: 1H NMR 5H

(400MHz , CDCI3): 5.01 - 4.82 (m, 1H), 4.70 - 4.58 (m, 1H), 4.33 - 4.08 (m, 2H), 3.01 (s,

3H), 2.82 -2.53 (m, 2H), 1.88 - 1.55 (m, 3H), 1.41 (d, J=6.25 Hz, 3H), 1.38 - 1.08 (m, 8H) Preparation 29: 4-[(R)-l-(2-Chloropyrimidin-5-yloxy)ethyl]piperidine-l-carboxylic acid isopropyl ester

To a solution of 4-((5)-l-methanesulfonyloxyethyl)piperidine-l-carboxylic acid isopropyl ester (Preparation 28, 1.85g, 6.30mmol) and 2-chloropyrimidin-5-ol (0.69g, 5.25mmol) in DMF (40mL) was added potassium carbonate (1.45g, 10.50mmol) and the reaction was heated to 100°C until complete. The mixture was poured into a combination of water (300mL) and brine (300mL), then the aqueous mixture was extracted with EtOAc (4 x lOOmL). The organic fractions were combined, washed with brine (lOOmL), dried (MgS0₄) and the solvent removed in vacuo. Purification by column chromatography (IH:EtOAc, 2: 1) afforded the title compound: RT = 3.75 min; m/z (ES⁺) = 328.1 [M+ H]⁺.

Preparation 30: 2,4-Difluoro-l-((E)-2-nitr inyl)benzene

A solution of 2,4-difluorobenzaldehyde (25. Og, 0.18mol) and nitromethane (11.4mL,

0.21mol) in MeOH (53mL), under argon, was cooled to -15°C. A solution of NaOH (7.4g, 0.19mol) in water (26mL) was added, dropwise, over 20 min. The resulting mixture was stirred at -15°C and a precipitate formed after 30 min. More MeOH was added to form a slurry and stirring continued for 15 min before allowing the reaction to warm to 0°C. Ice water was added and the mixture was stirred for 15 min before adding 4M HC1 (lOOmL). The organic fraction was extracted with DCM (3 x 300mL), dried (Na₂S0₄) and the solvent removed in vacuo. A portion of the residue (10. Og, 50mmol) was dissolved in acetic anhydride (8.1mL, 90mol) and cooled to 0°C under argon. DMAP (0.4g, 3mmol) was added and the reaction was stirred at this temperature for 20 min before warming the mixture to r.t. and allowing it to stir for a further 16 h. The reaction solvent was removed in vacuo and the resulting residue re-dissolved in DCM. Any remaining acetic anhydride was destroyed by the addition of a small volume of 1M NaOH solution, and the resulting solution was dried (MgS0₄) and concentrated in vacuo. Purification by column chromatography (DCM) afforded the title compound: RT = 3.60 min; m/z (ES⁺) = 186.1 [M+ H]⁺. Preparation 31: (frans)-l-Benzyl-3-(2 4-difluorophenyl)-4-nitropyrrolidine

A solution of 2,4-difluoro-l-((E)-2-nitrovinyl)benzene (Preparation 30, 8.0g, 43.0mmol) in DCM (250mL), under argon, was cooled to -30°C, and N-(methoxymethyl)-N- (trimethylsilylmethyl)benzylamine (11.7mL, 45.0mmol) was added so as to maintain the temperature. The reaction was stirred for 10 min before the dropwise addition of TFA (0.3mL, 4.3mmol), and the resulting mixture was allowed to stir at r.t. over 16 h. The reaction mixture was washed with water, then brine, and dried (Na₂S0₄). Removal of the solvent in vacuo afforded the title compound: RT = 3.05 min; mlz (ES⁺) = 319.1 [M+ H]⁺.

Preparation 32: [(irans)-l-Benzyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbamic acid terf-butyl ester

A combination of (trans)- l-benzyl-3-(2,4-difluorophenyl)-4-nitropyrrolidine

(Preparation 31, 25. Og, 0.08mol) and zinc dust (17.8g, 0.28mol) in a mixture of AcOH and EtOH (1 : 1, 500mL) was heated to 70°C. After 45 h a further portion of zinc dust (12.0g, 0.18mol) was added and heating continued for 20 min. After complete reaction the solvent was removed in vacuo. The resulting residue was re-dissolved in EtOAc, washed with sat. NaHCC"3 solution, then brine, and dried (Na₂S0₄). Removal of the solvent in vacuo afforded the intermediate product (tra/75)-l-benzyl-4-(2,4-difluorophenyl)pyrrolidin-3-ylamine: RT = 1.82 min; mlz (ES⁺) = 289.1 [M+ H]⁺.

To a solution of the product in THF (400mL), under argon, was added triethylamine (20.4mL, 0.15mol) and the solution was cooled to 0°C. Di-tert-butyl dicarbonate (19.0g, 0.09mol) was added over 5 min and the reaction was allowed to reach r.t. over 16 h. The solvent was removed in vacuo, then the resulting residue was re-dissolved in EtOAc, washed with brine, dried (Na₂S0₄), and the solvent removed in vacuo. To the product was added heptane (lOOmL), and the suspension was sonicated until fully dissolved. The solution was allowed to stand for 60 h, allowing formation of a prepipitate. The solvent was decanted and the solids washed with a fresh portion of heptane (50mL) to afford the title compound: RT = 2.74 min; mlz (ES⁺) = 389.3 [M+ H]⁺.

Preparation 33: [(3R,4S)-l-Benzyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

The title compound was afforded via chiral HPLC separation of [(trans)- l-benzyl-4- (2,4-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 32):

IH:IPA:DEA 96:4:0.1, 15ml/min, 270nm, RT = 9.8 min.

Preparation 34: [(3R,4S)-4-(2,4-Difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

The title compound was prepared from [(3i?,45)-l-benzyl-4-(2,4- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 33) employing the procedure outlined in Preparation 20, but at a temperature of 50°C: RT = 2.38 min; mlz

Preparation 35: 2,4,5-Trifluoro-l-((E)-2-nitr inyl)benzene

The title compound was prepared from 2,4,5-trifluorobenzaldehyde employing a similar method to that outlined in Preparation 30. After reaction with DMAP the crude mixture was diluted with sat. NaHC0₃ solution. The precipitate that formed was stirred for 30 min, filtered, and dried under vacuum to afford the title compound: 1H NMR 5_H (300MHZ , CDC1₃): 7.97 - 7.93 (m, 1H), 7.66 - 7.62 (m, 1H), 7.42 - 7.26 (m, 1H), 7.16 - 6.96 (m, 1H)

Preparation 36: (frans)-l-Benzyl-3-(2,4,5-trifluorophenyl)-4-nitropyrrolidine

The title compound was prepared from 2,4,5-trifluoro-l-((E)-2-nitrovinyl)benzene (Preparation 35) employing the method outlined in Preparation 31, but the reaction was carried out at 0°C. Purification by column chromatography (Hexane:EtOAc, 100:0, 98:2, 95:5, 90:10) afforded the title compound. LCMS Method 2: RT = 0.94 min; mlz (ES⁺) = 337.2 [M+ H]⁺.

Preparation 37: [(irans)-l-Benzyl-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-buty\ ester

A combination of (tra/75)-l-benzyl-3-(2,4,5-trifluorophenyl)-4-nitropyrrolidine

(Preparation 36, 11.5g, 0.03mol) and zinc dust (18.0g, 0.28mol) in a mixture of AcOH and IMS (1 :1, 210mL) was heated to 65°C. After complete reaction the mixture was filtered, washing with AcOH, and the filtrate was concentrated in vacuo. The resulting residue was re-dissolved in EtOAc, washed with sat. NaHC0₃ solution, then brine, and dried (Na₂S0₄). Removal of the solvent in vacuo and purification by column chromatography (DCM:MeOH, 100:0, 80:20) afforded the intermediate product (tra/?s)-l-benzyl-4-(2,4,5- trifluorophenyl)pyrrolidin-3-ylamine. LCMS Method 2: RT = 0.82 min; mlz (ES⁺) = 307.2 [M+ H]⁺.

To a solution of the product in THF (1 lOmL), under argon, was added triethylamine (3.9mL, 0.04mol) and the mixture was cooled to 0°C. Di-tert-butyl dicarbonate (4.7g, 0.02mol) was added over 5 min, then the reaction was allowed to reach r.t. and stirred for 16 h. The solvent was removed in vacuo, then the resulting residue was re-dissolved in EtOAc, washed with brine, dried (Na₂S0₄), and the solvent was removed in vacuo. The product was triturated several times with heptane to afford the title compound. LCMS Method 3 : RT = 3.10 min; mlz (ES⁺) = 407.3 [M+ H]⁺.

Preparation 38: [(frans)-4-(2,4,5-Trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert- butyl ester

A solution of [(tra/75)-l-benzyl-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 37, 40. lg, 98.8mmol) in a combination of IMS (325mL) and EtOAc (50mL), in an autoclave, was placed under an atmosphere of argon. Palladium on carbon (5%, 4.0g, 1.9mmol) was added as a slurry in the minimum volume of toluene, then the reaction mixture was placed under an atmosphere of hydrogen (50atm) and stirred for 72 h. The crude mixture was filtered through celite, washing with EtOAc, and the filtrate was concentrated in vacuo to afford the title compound. LCMS Method 4: RT = 2.42 min; mlz

Preparation 39: [(3R,4S)-4-(2,4,5-Trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert- butyl ester

[(tra/75)-4-(2,4,5-Trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 38, 30. Og, 95mmol) was suspended in EtOH (lOOmL) and heated to 70°C. To the suspension was added a warm solution of (S)-(+)-naproxen (10.9g, 47mmol) in EtOH (lOOmL) and the mixture was heated to reflux. The heat was removed and the mixture was slowly allowed to cool to r.t., with stirring, for 16 h. The resulting precipitate was filtered, washing with EtOH, and the solid product was partitioned between DCM (2400mL) and 1M NaOH (600mL). The organic phase was separated, washed with 1M NaOH, brine, then dried (MgS0₄), and the solvent was removed in vacuo.

A second portion of [(tra/75)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-bvXy\ ester (Preparation 38, 29.5g, 93mmol), suspended in EtOH (lOOmL), was heated to 70°C. Treatment with a warm solution of (5)-(+)-naproxen (10.6g, 46mmol) in EtOH (lOOmL), employing the procedure outlined above, afforded a second batch of the enantiomerically enriched product.

The two products were combined, and suspended in EtOH (200mL) before being treated with a hot solution of (5)-(+)-naproxen (16g, 69mmol) in EtOH (150mL). The mixture was heated to reflux, employing the procedure outlined above, and work-up was repeated to afford the title compound: 1H NMR δ_Η (400MHz , CD₃OD): 7.38 - 7.25 (m, 1H), 7.14 - 7.01 (m, 1H), 4.20 - 4.09 (m,l H), 3.30 - 3.21 (m, 3H), 2.90 - 2.81 (m, 1H), 2.77 - 2.68 (m, 1H), 1.34 (br. s., 9H) Preparation 40: [(irans)-l-Benzyl-4-(2,3-difluorophenyl)pyrrolidin-3-yl]carbamic acid terf-butyl ester

The title compound was prepared in 3 steps from 2,3-difluorobenzaldehyde employing the procedures outlined in the synthesis of Preparation 37. LCMS Method 3: RT = 3.04 min; mlz (ES⁺) = 389.3 [M+ H]⁺.

Preparation 41: [(3R,4S)-l-Benzyl-4-(2,3-difluorophenyl)pyrrolidin-3-yl]carbamic acid terf-butyl ester

The title compound was afforded via chiral HPLC separation of [(trans)- l-benzyl-4- (2,3-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 40):

IH:IPA:DEA 96.5:3.5:0.1, 15ml/min, 270nm, RT = 10.6 min. Preparation 42: [(3R,4S)-4-(2,3-Difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

The title compound was prepared from [(3i?,45)-l-benzyl-4-(2,3- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 41) employing the procedure outlined in Preparation 20, but at a pressure of 30 bar: 1H NMR δ_Η (400MHz , CDCI3): 7.17 - 6.93 (m, 3H), 4.31 - 4.08 (m, 1H), 3.57 - 3.39 (m, 2H), 3.38 - 3.17 (m, 1H), 3.06 - 2.81 (m, 2H), 1.40 (br. s., 9H).

Preparation 43: [(irans)-l-Benzyl-4-(4-chloro-2-fluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

The title compound was prepared in 3 steps from 4-chloro-2-fluorobenzaldehyde employing the procedures outlined in the synthesis of Preparation 37. LCMS Method 3: RT = 3.25 min; m/z (ES⁺) = 405.4 [M+ H]⁺.

Preparation 44: [(frans)-3-terf-Butoxycarbonylamino-4-(4-chloro-2- fluorophenyl)pyrrolidine-l-carboxylic acid tert-butyl ester

To a solution of [(tra/75)-l-benzyl-4-(4-chloro-2-fiuorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 43, 2.03g, 5.01mmol) in DCE was added 1,8- bis(dimethylamino)naphthalene (1.02g, 4.76mmol) and 1-chloroethyl chloroformate (1.60mL, 14.70mmol), and the reaction was heated to reflux for 1 h before being stirred at r.t. for 16 h. The crude mixture was passed through a silica plug (DCM:MeOH, 100:0, 10: 1, 4: 1) and the polar fractions were combined and concentrated in vacuo. The resulting residue was dissolved in MeOH (lOOmL) and heated to reflux for 3 h before being allowed to cool to r.t.. To the solution was added DIPEA (5mL, 28.7mmol) followed by άι-tert- butyldicarbonate (3.02g, 13.8mmol), and the mixture was stirred at r.t. for 45 min before removal of the solvent in vacuo. The residue was taken up in EtOAc (300mL), washed with water, then brine, and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 3: 1) afforded the title compound: RT = 3.34 min; mlz

Preparation 45: [(irans)-4-(4-Chloro-2-fluorophenyl)pyrrolidin-3-yl]carbamic acid tert- butyl ester

A suspension of zinc bromide (5.00g, 19.6mmol) in DCM (50mL), under argon, was stirred at r.t. for 16 h. An aliquot of the suspension (3.50mL) was added to [(trans)-3-tert- butoxycarbonylamino-4-(4-chloro-2-fiuorophenyl)pyrrolidine-l-carboxylic acid tert-butyl ester (Preparation 44, 0.25g, 0.6mmol) and the mixture was stirred for a further 4 h. 1M NaOH solution (lOOmL), was added, followed by EtOAc (lOOmL), and the mixture was stirred for 10 min before being filtered. The filtrate was extracted with EtOAc then the organic phase was washed with brine, dried (MgS0₄) and concentrated in vacuo. Purification by column chromatography (DCM:MeOH, 10:1, 8:2) afforded the title compound: RT = 2.53 min; mlz (ES⁺) = 315.1 [M+ H]⁺. Preparation 46: [(irans)-l-Benzyl-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-buty\ ester

The title compound was prepared in 3 steps from 2,5-difluorobenzaldehyde employing the procedures outlined in the synthesis of Preparation 37. LCMS Method 3: RT = 3.04 min; m/z (ES⁺) = 389.3 [M+ H]⁺.

Preparation 47: [(3R,4S)-l-Benzyl-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-buty\ ester

The title compound was afforded via chiral HPLC separation of [(trans)- l-benzyl-4- (2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 46):

IH:IPA:DEA 96:4:0.1, 15ml/min, 270nm, RT = 10.9 min.

Preparation 48: [(3R,4S)-4-(2,5-Difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

The title compound was prepared from [(3i?,45)-l-benzyl-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 47) employing the procedure outlined in Preparation 20, but the reaction was carried out under 30 bar pressure. RT = 2.35 min; m/z (ES⁺) = 299.2 [M+ H]⁺. Preparation 49: (R)-3-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]butyric acid

To a stirring solution of concentrated H₂SO₄ (5mL) was added chromium (VI) oxide (5g) and a thick brown paste resulted. The paste was added to water (15mL), cooled to 0°C with stirring, and a bright red/orange solution formed.

To a separate solution of (i?)-3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]butan-l-ol (250mg, 0.94mmol) in acetone (lOOmL), cooled to 0°C, was added the red Jones' reagent, dropwise, until no change from the yellow colour was observed. The reaction was quenched by the addition of a few drops of IP A, and the mixture was concentrated in vacuo. The resulting residue was partitioned between EtOAc (lOOmL) and water (50mL), and the organic phase was separated. The aqueous fraction was extracted with EtOAc (lOOmL), then the organic fractions were combined, washed with brine, dried (MgS0₄), and the solvent removed in vacuo to afford the title compound: RT = 3.12 min; mlz (ES ) = 282.1 [M+ H]⁺.

Preparation 50: 4-Hydroxymethylpiperidine-l-carbonitrile

To a solution of 4-piperidinemethanol (15g, 0.13mol) in DCM (60mL) was added a slurry of NaHC0₃ (44. Og) in water (60mL), and the mixture was cooled to 0°C. A solution of cyanogen bromide in DCM (3M, 48.5mL, 0.15mol) was added, dropwise, over 40 min, and the reaction was warmed to r.t. over 90 min. The mixture was filtered and the organic phase was separated. The aqueous phase was extracted with DCM, then organic fractions were combined, washed with sat. NaHC0₃ solution, brine, and dried (MgS0₄). The solvent was removed in vacuo to afford the title compound: 1H NMR δ_Η (300MHz , CDC1 ): 3.56 - 3.35 (m, 4H), 3.10 - 2.91 (m, 2H), 1.85 - 1.51 (m, 4H), 1.46 - 1.25 (m, 2H).

Preparation 51 : [(1 -(3-Ethyl- [ 1 ,2,4] oxadiazol-5-yl)piperidin-4-yl] methanol

4-Hydroxymethylpiperidine-l-carbonitrile (Preparation 50, 7.5g, 0.05mol) was combined with N-hydroxypropionamidine (5.7g, 0.06mol) in EtOH (150mL). To the mixture was added a solution of zinc(II)chloride (8.8g, 0.06mol) in EtOH (lOmL) over 15 min, and the reaction was stirred at r.t. for 2 h. To the mixture was then added concentrated HC1 (25mL), over 5 min, and the reaction was heated to reflux for 4 h. The reaction solvent was concentrated in vacuo, and water was added. The mixture was brought the pH7 with

NaHC0₃ and extracted with EtOAc. The organic fraction was washed with brine, dried (MgS0₄), and the solvent removed in vacuo. Purification by column chromatography afforded the title compound. LCMS Method 3: RT = 1.12 min; mlz (ES⁺) = 212.1 [M+ H]⁺.

Preparation 52: Methanesulfonic acid-l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethyl ester

To a dry solution of [(l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol

(Preparation 51, 3.50g, 16.57mmol) in DCM (95mL) was added triethylamine (4.60mL, 33.13mmol) and the mixture was cooled to 5°C. Methanesulfonyl chloride (1.30mL, 16.57mmol) was added, dropwise, over 5 min and the reaction was allowed to warm to r.t., with stirring, until complete. The crude mixture was partitioned between DCM and 1M HCl, then the organic phase was separated, dried (Na₂S0₄) and the solvent removed in vacuo to afford the title compound. LCMS Method 2: RT = 0.65 min; mlz (ES⁺) = 290.1 [M+ H]⁺.

Preparation 53 : 2-Chloro-5- [ l-(3-ethyl- [ 1 ,2,4] oxadiazol-5-yl)piperidin-4- ylmethoxy] pyrimidine

A combination of methanesulfonic acid-l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethyl ester (Preparation 52, 440mg, 1.51mmol), 2-chloropyrimidin-5-ol (270mg, 1.81mmol) and potassium carbonate (417mg, 3.02mmol) in DMF (20mL) was heated to 100°C in a microwave reactor for 2 h. The reaction solvent was concentrated in vacuo and the resulting residue was dissolved in EtOAc. The solution was washed with 1M NaOH solution (x 2), brine, then dried (MgS0₄), before removal of the solvent in vacuo.

Purification by column chromatography (DCM:MeOH, 95:5) afforded the title compound: 1H NMR δ_Η (400MHz , CDC1₃): 8.27 (s, 1H), 8.25 (s, 1H), 4.26 - 4.15 (m, 2H), 3.95 - 3.85 (m, 2H), 3.15 - 3.00 (m, 2H), 2.62 - 2.50 (m, 2H), 2.15 - 2.01 (m, 1H), 1.97 - 1.85 (m, 2H), 1.52 - 1.38 (m, 2H), 1.30 - 1.19 (m, 3H). Preparation 54: 4-[l-(6-Bromopyridin-3-yloxy)ethyl]piperidine-l-carboxylic acid isopropyl ester

To a solution of 4-(l-methanesulfonyloxyethyl)piperidine-l-carboxylic acid isopropyl ester (Preparation 26, 967mg, 3.30mmol) and 6-bromopyridin-3-ol (632mg, 3.63mmol) in DMF (lOmL) was added potassium carbonate (1366mg, 9.90mmol) and the reaction was heated to 100°C for 16 h. The solvent was concentrated in vacuo and the residue purified by column chromatography (IH:EtOAc, 2: 1). The product was dissolved in a small volume of MeOH and crystals were allowed to form. The crystals were removed by filtration, and the filtrate concentrated in vacuo to afford the title compound: RT = 2.45 min; mlz (ES⁺) = 371.0, 373.0 [M+ H]⁺.

Preparation 55: 2-Chloro-5-methoxy-4-methylpyrimidine

To a solution of 2,4-dichloro-5-methoxypyrimidine (1.5g, 8.38mmol) in THF (15mL), under argon, was added trimethylboroxine (1.2g, 9.22mmol),

dichlorobis(triphenylphosphine)palladium (0.6g, 0.84mmol) and potassium phosphate (3.6g, 16.76mmol) and the mixture was heated to reflux for 16 h. The reaction was diluted with EtOAc, washed with water, then dried (Na₂S0₄). Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 100:0, 90: 10, 80:20, 70:30) afforded the title compound: RT = 2.45 min; mlz (ES⁺) = 159.0 [M+ H]⁺.

Preparation 56: 2-Chloro-4-methylpyrimidin-5-ol

A dry solution of 2-chloro-5-methoxy-4-methylpyrimidine (Preparation 55, l . lg, 6.94mmol) in DCM (20mL), under argon, was cooled to -78°C. Boron tribromide (2.63mL, 27.82mmol) was added, dropwise over 15 min, then the reaction was allowed to stir at -78°C for 20 min before being stirred at r.t. for a further 16 h. The mixture was cooled down to - 78°C and quenched by the dropwise addition of MeOH. The reaction was allowed to reach r.t. then NaHCCb was carefully added to adjust the pH to 5. The mixture was extracted with EtOAc and the organic phase was washed with brine, then dried (Na₂S0₄). Removal of the solvent in vacuo and trituration with DCM afforded the title compound: RT = 2.13 min; mlz (ES⁺) = 145.0 [Μ+ ηγ. Preparation 57: 2-Chloro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy] -4-methylpyrimidine

To a solution of [(l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation 1, 1.40g, 5.84mmol) and triethylamine (0.98mL, 7.01mmol) in DCM (20mL), cooled to 0°C, was added methanesulfonyl chloride (0.50mL, 6.43mmol), dropwise, before removing the ice bath and allowing the reaction to stir at r.t. for 1 h. 1M HCl was added and the organic phase was separated, dried (Na₂S0₄), and concentrated in vacuo to afford the intermediate product methanesulfonic acid l-(3-isopropyl[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethyl ester.

To a solution of the intermediate (0.79g, 2.61mmol) in DMF (lOmL) was added 2- chloro-4-methylpyrimidin-5-ol (Preparation 56, 0.38g, 2.61mmol) and potassium carbonate (0.72g, 5.21mmol), and the reaction was heated to 80°C in a sealed tube for 48 h. The reaction solvent was diluted with EtOAc, washed with brine, dried (Na₂S0₄), and concentrated in vacuo. Purification by column chromatography (DCM:MeOH, 98:2) afforded the title compound: RT = 3.68 min, m/z (ES⁺) = 352.1 [M+ H]⁺.

Preparation 58: [l-(5-Isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4-yl]methanol

To a solution of 4-hydroxymethylpiperidine-l-carbonitrile (Preparation 50, 7.00g, 50mmol) in IMS (lOOmL) was added hydroxylamine (50% in water, 6.06mL, lOOmmol) and the reaction was stirred at r.t. for 30 min. The solvent was concentrated in vacuo and the residue azeotroped three times from toluene to afford the amidoxime intermediate.

To a solution of the amidoxime (8.66g, 50mmol) and DIPEA (36.9mL, 120mmol) in DMF (80mL) was added isobutyric acid (4.87mL, 53mmol) followed by HBTU (22.70g, 60mmol), portionwise, and the reaction was stirred at r.t. for 16 h. The mixture was diluted with water and extracted with EtOAc (x 3). The organic fractions were combined, washed with sat. NaHCCb solution, brine, and the solvent removed in vacuo. The resulting residue was dissolved in toluene (50mL) and heated to reflux for 3 h before removing the solvent in vacuo. Purification by column chromatography (DCM:MeOH, 100:0, 95:5, 90:10) afforded the title compound. LCMS Method 4: RT = 2.25 min; m/z (ES⁺) = 226.2 [M + H]⁺. Preparation 59: Methanesulfonic acid l-(5-isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4- ylmethyl ester

The title compound was prepared from [l-(5-isopropyl-[l,2,4]oxadiazol-3- yl)piperidin-4-yl]methanol (Preparation 58) employing the procedure outlined in

Preparation 52. LCMS Method 3 : RT = 1.73 min; mlz (ES⁺) = 304.2 [M+ H]⁺.

Preparation 60 : 2-Chloro-5- [ l-(5-Isopr opyl- [ 1 ,2,4] oxadiazol-3-yl)piperidin-4- ylmethoxy] pyrimidine

Methanesulfonic acid l-(5-isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4-ylmethyl ester

(Preparation 59) was reacted with 2-chloropyrimidin-5-ol employing the procedure outlined in Preparation 53. Purification by column chromatography (heptane:EtOAc, 100:0, 50:50) afforded the title compound: 1H NMR δ_Η (300MHz , CDC1₃): 8.29 (s, 2H), 4.15 - 4.05 (m, 2H), 3.94 - 3.87 (m, 2H), 3.12 - 3.01 (m, 1H), 2.99 - 2.86 (m, 2H), 2.13 - 1.97 (m, 1H), 1.94 - 1.83 (m, 2H), 1.51 - 1.39 (m, 2H), 1.35 (d, J= 7.3 Hz, 6H).

Preparation 61: (R)-l-Piperidin-4-yl ethanol

The title compound was prepared from (i?)-(+)-a-Methyl-4-pyridinemethanol employing the procedure outlined in Preparation 10, but carrying out the reaction over 64 h: 1H NMR δ_Η (400MHz, CDC1₃): 3.63 - 3.55 (m, 1H), 3.39 - 3.31 (m, 2H), 2.7 - 2.6 (m, 2H), 2.01 - 1.92 (m, 2H), 1.76 - 1.69 (m, 1H), 1.67 - 1.54 (m, 2H), 1.51 - 1.42 (m, 1H), 1.14 - 1.10 (m, 3H).

Preparation 62 : (R)- 1- [ l-(3-Isopr opyl- 1 ,2,4] oxadiazol-5-yl)piperidin-4-yl] ethanol

To a solution of (i?)-l-piperidin-4-yl ethanol (Preparation 61, 519mg, 4.02mmol) in DCM (40mL), under argon, was added NaHC0₃ (1350mg, 10.08mmol) and water (20mL), and the reaction was cooled to 0°C. A solution of cyanogen bromide (51 lmg, 4.83mmol) in DCM (20mL) was added, dropwise over 5 min, then the reaction was stirred at 0°C for 30 min before being allowed to warm to r.t.. The mixture was diluted with DCM, and the organic phase was separated, washed with sat. NaHC0₃ solution (2 x lOOmL), brine, then dried (MgS0₄). Removal of the solvent in vacuo afforded the cyano intermediate.

To a solution of the intermediate in EtOH (30mL) was added N- hydroxyisobutyramidine (367mg, 3.60mmol), followed by zinc(II)chloride, and the reaction was stirred at r.t. for 2 h. Concentrated HCl (629mL, 17.25mmol) was added and the reaction was heated to 50°C for 16 h, before concentrating the solvent in vacuo. To the residue was added sat. NaHC0₃ solution, and the mixture was washed with EtOAc (4 x 250mL). The organic fractions were combined, washed with brine, dried (MgS0₄), and the solvent removed in vacuo to afford the title compound: RT = 2.72 min; mlz (ES ) = 240.1 [M+ H]⁺.

Preparation 63: 2-Chloro-5-{(S)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl] ethoxy}pyrimidine

To a solution of (i?)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation 62, 570mg, 2.38mmol) and triethylamine (390μΕ, 2.86mmol) in DCM

(42mL), cooled to 0°C, was added methanesulfonyl chloride (204μΕ, 2.86mmol) and the reaction was allowed to warm to r.t. over 1 h. Further portions of methanesulfonyl chloride (92μΕ, 1.19mmol) and triethylamine (199μΕ, 1.43mmol) were added and stirring continued for 16 h. The mixture was partitioned between DCM (lOOmL) and 1M HCl (250mL), then the organic phase was separated and concentrated in vacuo. To a solution of the residue in DMF (15mL) was added 2-chloropyrimidin-5-ol (373mg, 2.86mmol) and potassium carbonate (985mg, 7.34mmol), and the mixture was heated to 80°C for 48 h. The reaction solvent was concentrated in vacuo, then azeotroped once from toluene. The residue was dissolved in EtOAc, washed with brine, dried (MgS0₄), and the solvent removed in vacuo. Recrystallisation from MeOH, followed by column chromatography (IH:EtOAc, 70:30) afforded the title compound: RT = 3.82 min; mlz (ES⁺) = 352.1 [M+ H]⁺. Preparation 64: (3R,4S)-4-(2,5-Difluorophenyl)-l-[5-(piperidin-4-ylmethoxy)pyrimidin- 2-yl] pyr rolidin-3-ylamine

To a combination of 4-(2-chloropyrimidin-5-yloxymethyl)piperidine-l-carboxylic acid tert-butyl ester (Preparation 24, 165mg, 0.5mmol) and [(3R,4S)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, lOOmg, 0.33mmol) in DMSO (lmL) was added DBU (T4uL, 0.5mmol) and the reaction was heated to 100°C for 225 min before being cooled to r.t.. The mixture was diluted with water, and extracted with DCM. The organic fraction was washed with brine, concentrated in vacuo, and purified by column chromatography (DCM:MeOH, 95:5) to afford the intermediate product 4-{2-[(3i?,45)-3-tert-butoxycarbonylamino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyrimidin-5-yloxymethyl}piperidine-l-carboxylic acid tert-butyl ester: RT = 4.67 min; m/z (ES⁺) = 590.3 [M+ H]

To a solution of the product in DCM (5mL) was added TFA (lmL) and the reaction was stirred at r.t. for 1 h. The crude mixture was passed directly down an SCX cartridge, eluting with MeOH followed by NH₄OH in MeOH, and the basic fraction was collected. Removal of the solvent in vacuo afforded the title compound: RT = 1.82 min; m/z (ES ) =

Preparation 65: 4-Cyanopiperidine-l-carboxylic acid isopropyl ester

To a solution of 4-cyanopiperidine (29.74g, 0.27mol) in toluene (300mL), under argon, was added triethylamine (57mL, 0.41mol) and the reaction was cooled to 0°C. A solution of isopropyl chloroformate in toluene (1M, 297mL, 0.30mol) was added, dropwise, then the resulting mixture was allowed to warm to r.t., and stirred for 1 h. The crude reaction mixture was filtered and the filtrate concentrated in vacuo. The resulting residue was dissolved in EtOAc, washed with water, then brine, and dried (MgSC^). Removal of the solvent in vacuo and purification by column chromatography (hexane:EtOAc, 70:30) afforded the title compound: 1H NMR δ_Η (400MHz , CDC1₃): 4.93 - 4.83 (m, 1H), 3.72 - 3.61 (m, 2H), 3.40 - 3.31 (m, 2H), 2.83 - 2.74 (m, 1H), 1.90 - 1.71 (m, 4H), 1.21 (d, 6H). Preparation 66: 4-(N-Hydroxycarbamimidoyl)piperidine-l-carboxylic acid isopropyl ester

To a mixture of 4-cyanopiperidine-l-carboxylic acid isopropyl ester (Preparation 65, 47.17g, 0.24mol), potassium carbonate in water (35.38g, 0.26mol, 400mL) and EtOH (225mL) was added hydroxylamine hydrochloride (35.58g, 0.51 mo 1) and the mixture was heated to reflux for 16 h. After cooling to r.t. the EtOH was removed in vacuo, and the aqueous layer was extracted with EtOAc (x 2). The organic fractions were combined, washed with water (x 2), then brine, and dried (MgSC^). Removal of the sovent in vacuo afforded the title compound: 1H NMR δ_Η (400MHz , CDC1₃): 4.94 - 4.84 (m, 1H), 4.56 (br s, 2H), 4.26 - 4.10 (m, 2H), 2.81 - 2.69 (m, 2H), 2.31 - 2.22 (m, 1H), 1.86 - 1.78 (m, 2H), 1.61 - 1.49 (m, 2H), 1.22 (d, 6H).

Preparation 67: 4-(5-Hydroxymethyl-[l,2,4]oxadiazol-3-yl)piperidine-l-carboxylic acid isopropyl ester

To a suspension of glycolic acid (l .OOg, 13.15mmol) in DCM (15mL) was added carbonyldiimidazole (2.13g, 13.15mmol) and the reaction was stirred at r.t. for 16 h. To the mixture was added 4-(N-hydroxycarbamimidoyl)piperidine-l-carboxylic acid isopropyl ester (Preparation 66, 3.01g, 13.15mmol) and stirring continued for 3 h. The reaction was then heated to 35°C for 2 h before stirring at r.t. for 16 h. The reaction was heated to 35°C for a further 16 h before concentrating the reaction mixture in vacuo. The crude residue was partitioned between EtOAc (150mL) and water (lOOmL). The organic layer was separated, washed with brine, and dried (MgS0₄). Removal of the solvent in vacuo afforded an oil, which was dissolved in toluene and heated to 105°C for 16 h. Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 40:60) afforded the title compound: RT = 2.67 min; mlz (ES⁺) = 270.1 [M+ H]⁺. Preparation 68: 4-[5-(2-Chloropyrimidin-5-yloxymethyl)-[l,2,4]oxadiazol-3- yl]piperidine-l-carboxylic acid iso ropyl ester

To a solution of 4-(5-hydroxyrnethyl-[l,2,4]oxadiazol-3-yl)piperidine-l-carboxylic acid isopropyl ester (Preparation 67, 103mg, 0.38mmol) in THF (5mL), in an oven-dried flask, under argon, was added 2-chloro-pyrimidin-5-ol (50mg, 0.38mmol), followed by triphenylphosphine (150mg, 0.57mmol), and the mixture was cooled to 0°C. DIAD (112μΙ,, 0.57mmol) was added, dropwise, and the resulting mixture was stirred at r.t. for 2.5 h. The reaction solvent was removed in vacuo, and the residue was re-dissolved in EtOAc (lOOmL). The solution was washed with water (50mL), then brine, and dried (MgS0₄), before removal of the solvent in vacuo. IH was added, followed by a minimal volume of Et₂0, and a precipitate formed. The solvent was decanted and concentrated in vacuo. Purification of the resulting residue by column chromatography (IH:EtOAc, 50:50, 40:60) afforded the title compound: RT = 3.43 min; mlz (ES⁺) = 382.1 [M+ H]⁺.

Preparation 69: 4-(5-{2-[(3R,4R)-3-teri-Butoxycarbonylamino-4-(2,5- difluorophenyl)piperidin-l-yl]pyrimidin-5-yloxymethyl}-[l,2,4]oxadiazol-3- yl)piperidine-l-carboxylic acid isopropyl ester

A combination of 4-[5-(2-chloropyrimidin-5-yloxymethyl)-[l,2,4]oxadiazol-3- yl]piperidine-l-carboxylic acid isopropyl ester (Preparation 68, 38mg, O. lOmmol),

[(3i?,4i?)-4-(2,5-difluorophenyl)piperidin-3-yl]carbamic acid tert-butyl ester (Preparation 9, 31mg, O. lOmmol) and DIPEA (19μΕ, 0.1 lmmol), in tert-butanol (lmL), was heated to 80°C for 40 h. The reaction mixture was partitioned between EtOAc (50mL) and brine (50mL), then the organic layer was separated, dried (MgS0₄), and the solvent removed in vacuo. The crude residue was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected to afford the title compound: RT = 4.47 min; mlz (ES⁺) = 658.2[ + H]⁺.

Preparation 70 : (frans)-3-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-(2- fluorophenyl)pyrrolidine-l-carbox lic acid terf-butyl ester

To a solution of (tra/75)-3-amino-4-(2-fluorophenyl)pyrrolidine-l-carboxylic acid tert- butyl ester (2.00g, 7.13mmol) and triethylamine (1.59mL, 11.40mmol) in a combination of dioxane and water (2: 1, 75mL), cooled to 0°C, was added 9-fluorenylmethyl chloro formate (2.3 lg, 8.92mmol), then the reaction was allowed to reach r.t. before stirring for 16 h. The mixture was diluted with EtOAc, washed with water, 1M HC1, sat. NaHC0₃ solution, then brine, and dried (MgSC^). Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 90: 10, 80:20, 70:30) afforded the title compound: RT = 4.28 min mlz (ES⁺) = 503.3 [M+ H]⁺.

Preparation 71: [(frans)-4-(2-Fluorophenyl)pyrrolidin-3-yl]carbamic acid-9H-fluoren- 9-ylmethyl ester hydrochloride

To a solution of (tra/?5)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-(2- fluorophenyl)pyrrolidine-l-carboxylic acid tert-butyl ester (Preparation 70, 1.50g,

2.98mmol) in dioxane (30mL) was added a solution of HC1 in dioxane (4M, 30mL) and the reaction was stirred at r.t. for 16 h, after which time a precipitate had formed. Et₂0 was added to the mixture until no further precipitation was observed, and the solvent was decanted. The residue was suspended in a further volume of Et₂0 and stirred for 5 min before decanting the solvent. This process was repeated twice more and the resulting residue was concentrated in vacuo to afford the title compound: RT = 2.82 min mlz (ES ) = 403.1 [M

+ H]⁺.

Preparation 72: (l-Cyanopiperidin-4-yl)carbamic acid tert-butyl ester

To a solution of piperidin-4-ylcarbamic acid tert-butyl ester (10. Og, 49.9mmol) in DCM (130mL) was added a slurry of NaHC0₃ (12.6g, 149.8mmol) in water (30mL) and the resulting mixture was cooled to 0°C. A solution of cyanogen bromide (6.4g, 59.9mmol) in DCM (15mL) was added, dropwise, over 10 min then the mixture was warmed to r.t and stirred for 3 h. The reaction mixture was diluted with water, then the layers were separated. The aqueous phase was extracted with DCM, then the organic fractions were combined, washed with sat. NaHC0₃ solution, then brine, and dried (MgS0₄). Removal of the solvent in vacuo afforded the title compound: RT = 2.93 min; mlz (ES ) = 226.1 [M+ H]⁺.

Preparation 73 : l-(3-Isopropyl- [ 1 ,2,4 oxadiazol-5-yl)piperidin-4-ylamine

To a solution of (l-cyanopiperidin-4-yl)carbamic acid tert-butyl ester (Preparation 72, 4.04g, 17.9mmol) and N-hydroxyisobutyramidine (2.20g, 21.5mmol) in EtOH (50mL) was added a solution of Zinc(II)chloride (2.93g, 21.5mmol) in EtOH (30mL), and the resulting solution was stirred at RT for 2.25h. Concentrated HC1 (4.58mL, 53.8mmol) was then added and the reaction heated to 50°C for 16 h. The solvent was removed in vacuo and the resulting residue was triturated with MeCN. The white solid was collected by filtration and washed with EtOAc (x 3), then dissolved in water and basified to pH12 with 2M NaOH solution. EtOAc was added and the resulting emulsion was filtered through celite. The aqueous phase was extracted with EtOAc (x 4), then the organic fractions were combined, washed with brine, dried (MgS0₄), and the solvent removed in vacuo to afford the title compound: RT = 1.71 min; mlz (ES⁺) = 211.1 [M+ H]⁺.

Preparation 74: (2-Chloropyrimidin-5-yl)methanol

A solution of 2-chloropyrimidine-5-carboxylic acid methyl ester (l .Og, 5.8mmol) in THF (30mL), under argon, was cooled to -78°C. To the solution was added a solution of DIBAL-H in DCM (1.0M, 20.3mL, 20.3mmol), slowly over 40min. The reaction was allowed to warm to r. t. before continuing to stir for a further 16 h. A solution of sat. sodium potassium tartrate (lOOmL) was slowly added, followed by EtOAc, and the mixture was stirred vigorously for 2 h. The organic phase was separated then a further portion of EtOAc was added to the aquoues phase before stirring vigorously for lh. The organic phase was removed and the aqueous phase was washed with a mixture of EtOAc and THF (1 :1). All organic fractions were combined and washed with sat. sodium potassium tartrate solution, water, then brine, and dried (MgS0₄). The solvent was removed in vacuo to afford the title compound: RT = 1.62 min; mlz (ES⁺) = 145.0 [M+ H]⁺.

Preparation 75: [(3R,4S)-4-(2,5-Difluorophenyl)-l-(5-hydroxymethylpyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-but l ester

To a dry solution of (2-chloropyrimidin-5-yl)methanol (Preparation 74, 253mg, 1.75mmol) and [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 574mg, 1.93mmol) in DMSO (1.6mL) was added DBU (262μΕ,

1.75mmol) and the reaction was heated to 70°C for 21 h. The mixture was diluted with water and extracted with EtOAc (x 2). The organic fractions were combined, washed with sat. NaHC0₃ solution, then brine, and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (DCM:MeOH, 97:3) afforded the title compound: RT = 3.23 min; mlz (ES⁺) = 407.1 [M+ H]⁺.

Preparation 76: [(3R,4S)-4-(2,5-Difluorophenyl)-l-(5-formylpyrimidin-2-yl)pyrrolidin- 3-yl]carbamic acid tert-butyl ester

To a solution of [(3i?,45)-4-(2,5-difluorophenyl)-l-(5-hydroxymethylpyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 75, 413mg, 1.02mmol) and pyridine (243 μί, 3.00mmol) in DCM (16mL) at 0°C was added Dess-Martin periodinane (517mg, 1.22mmol), and the resulting mixture was stirred at r.t. for 16 h. The solvent was removed in vacuo, then the remaining residue was dissolved in EtOAc, washed with 2M NaOH solution (x 6) then brine, and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (HLEtOAc, 1 : 1) afforded the title compound: RT = 3.73 min; mlz (ES⁺) = 405.1 [M+ H]⁺.

Preparation 77: [(3R,45)-4-(2,5-Difluorophenyl)-l-(5-{[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)piperidin-4-ylamino]methyl}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert- butyl ester

To a solution of [(3i?,45)-4-(2,5-difluorophenyl)-l-(5-formylpyrimidin-2-yl)pyrrolidin- 3-yl]carbamic acid tert-butyl ester (Preparation 76, lOlmg, 0.25mmol) and l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-ylamine (Preparation 73, 63mg, 0.30mmol) in DCE (3mL) was added oven dried molecular sieves (550mg), and the reaction mixture was heated to 100°C for 48 h. Further DCE (5mL) was added, followed by sodium

triacetoxyborohydride (85mg, 0.40mmol), and the mixture was stirred at r.t. for 96 h. The reaction mixture was filtered through celite, washing with DCM, then the combined organics were washed with water, dried (MgS0₄), and the solvent removed in vacuo. Purification by column chromatography (EtOAc:MeOH, 100:0, 90: 10) afforded the title compound. LCMS: RT = 2.87 min; mlz (ES⁺) = 599.4 [M+ H]⁺.

Preparation 78: {(3R,45)-4-(2,5-Difluorophenyl)-l-[5-({[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)piperidin-4-yl] methylamino} methyl)pyrimidin-2-yl] pyr rolidin-3-yl} carbamic acid terf-butyl ester

A combination of [(3i?,4S)-4-(2,5-difluorophenyl)-l-(5-{[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-ylamino]methyl}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 77, 75mg, 0.12mmol), formaldehyde (4mg, 0.14mmol) and sodium triacetoxyborohydride (37mg, 0.18mmol) in DCE (2mL), under argon, was stirred at r.t. for 66 h. The solvent was removed in vacuo and the resulting residue was dissolved in EtOAc, washed with 2M NaOH solution, then brine, and dried (MgS0₄).

Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 95:5) afforded the title compound: RT = 2.93 min; m/z (ES⁺) = 612.7 [M+ H]⁺.

Preparation 79 : 1- [3-(Pr opan-2-yl)- 1 ,2 4-oxadiazol-5-yl] piperidine-4-carbaldehyde

To a solution [(l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol

(Preparation 1, 5.44g, 24.13mmol) in DCM (150mL), cooled to 0°C, was added dess-martin periodinane (12.28g, 28.95mmol), portionwise over 5min. The reaction mixture was warmed to r.t. and stirred for 2 h. The solvent was removed in vacuo and the resulting residue dissolved in EtOAc. The solution was washed with 2M NaOH solution (x 7), then brine, and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 60:40) afforded the title compound: RT = 2.37 min; m/z (ES⁺) = 224.1 [M +

H]⁺.

Preparation 80: [(3R,4S)-4-(2,5-Difluorophenyl)-l-(5-nitropyrimidin-2-yl)pyrrolidin-3- yl]carbamic acid tert-butyl ester

To a solution of 2-chloro-5-nitropyrimidine (2.00g, 12.5mmol) and [(3R,4S)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 4.1 lg,

13.8mmol) in anhydrous DMSO (16mL), under argon, was added DBU (1.87mL, 12.5mmol) and the mixture was heated to 60°C for 16 h. Upon cooling, the mixture was poured into water (150mL) and the resulting scum was extracted into EtOAc (lOOmL then 50mL). The combined organic fractions were washed with sat. NaHC0₃ solution (50mL), then brine (50mL) and dried (MgS0₄), before removal of the solvent in vacuo. Recrystallisation from EtOAc:IH (2:3) (x 2), followed by recrystallisation from EtOH, afforded the title compound: RT = 4.12 min; mlz (ES⁺) = 422.1 [M+ H]⁺.

Preparation 81 : [(3R,4S)-l-(5-Aminopyrimidin-2-yl)-4-(2,5-difluorophenyl)pyrrolidin- 3-yl]carbamic acid tert-butyl ester

A solution of [(3i?,45)-4-(2,5-difluorophenyl)-l-(5-nitropyrimidin-2-yl)pyrrolidin-3- yljcarbamic acid tert-butyl ester (Preparation 80, 1.04g, 2.47mmol) in a combination of THF (20mL) and MeOH (30mL) was passed through an H-Cube apparatus (10% pd/C, atmospheric pressure, r.t.) at a flow rate of ImL per min. The solvent was removed in vacuo to afford the title compound: RT = 2.84 min; mlz (ES⁺) = 391.2 [M+ H]⁺. Preparation 82: [(3R,45)-4-(2,5-Difluorophenyl)-l-(5-{[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)piperidin-4-ylmethyl] amino}pyrimidin-2-yl)pyrrolidin-3-yl] carbamic acid tert- butyl ester

To a solution of [(3 ?,45)-l-(5-aminopyrimidin-2-yl)-4-(2,5- difluorophenyl)pyrrolidin-3-yl] carbamic acid tert-butyl ester (Preparation 81, 300mg, 0.77mmol) and l-[3-(propan-2-yl)-l,2,4-oxadiazol-5-yl]piperidine-4-carbaldehyde

(Preparation 79, 220mg, 0.99mmol) in DCE (20mL), under argon, was added sodium triacetoxyborohydride (276mg, 1.30mmol), followed by AcOH (199μΕ, 3.50mmol). After stirring at r.t for 16 h, the reaction mixture was washed with sat. NaHC0₃ solution (2 x 20mL). The organic phase was dried (MgS0₄) and the solvent removed in vacuo.

Purification by column chromatography (IH:EtOAc, 30:70) followed by recrystallisation from EtOAc/IH afforded the title compound: RT = 3.87 min; mlz (ES ) = 599.4 [M+ H] .

Preparation 83 : l-(3-Isopropyl- [ 1 ,2,4] oxadiazol-5-yl)piperidin-4-ol

To a solution of 4-hydroxypiperidine-l-carbonitrile (1.08g, 8.6mmol) and N- hydroxyisobutyramidine (1.05g, 10.3mmol) in EtOH (20mL) was added Zinc(II)chloride (1.40g, 10.3mmol) in EtOH (15mL), and the mixture was stirred at r.t. for 2 h. Cone. HC1 (4.19mL, 49.2mmol) was added, and the resulting mixture was heated to 50°C for 16 h. The solvent was removed in vacuo and water was added to the residue before neutralising with solid NaHC0₃. The mixture was filtered, extracted with EtOAc (x 3), and the combined organic fractions were washed with brine, then dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromotography (EtOAc) afforded the title compound: RT = 2.44 min; mlz (ES⁺) = 212.1 [M+ H]⁺.

Preparation 84: 2-Chloro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yloxym ethyl] pyrimidine

To a dry solution of l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-ol

(Preparation 83, 432mg, 2.04mmol) in THF (4mL) was added NaH (60% suspension in mineral oil, 98mg, 2.44mmol), and the mixture was stirred at r.t. for 25 min. To the mixture was added a solution of 2-chloro-5-chloromethylpyrimidine (332mg, 2.04mmol) in THF (3mL) and stirring continued at r.t. for 16 h. The reaction was heated to 30°C for 1.5 h then a further portion of NaH (49mg, 1.02mmol) was added, along with TBAI (7mg, 0.02mmol). The reaction was then heated to 35°C for 16 h.

The solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with water, then brine, and dried (MgS0₄). Removal of the solvent in vacuo and purification by Preparative HPLC afforded the title compound: RT = 3.27 min; mlz (ES ) = 338.2 [M +

H]⁺. Preparation 85: ((3R,4S)-4-(2,5-Difluorophenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yloxymethyl] pyrimidin-2-yl}pyrr olidin-3-yl)carbamic acid tert-butyl ester

To a solution of 2-chloro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yloxymethyljpyrimidine (Preparation 84, 24mg, 0.07mmol) and [(3i?,45)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 23mg, 0.08mmol) in DMSO (0.05mL) was added DBU (1 Ι μΙ,, 0.07mmol), and the reaction was heated to 70°C for 16 h. The mixture was diluted with EtOAc, washed with water (x 2), then brine, and dried (MgS0₄). Solvent was removed in vacuo then the residue was purified by column chromotography (IH:EtOAc, 3:7). The resulting product was passed down an SCX cartridge, eluting with EtOH then NH₄OH in MeOH, and the basic fraction collected and concentrated. Removal of the solvent in vacuo afforded the title compound: RT = 4.15 min; m/z (ES⁺) = 600.3 [M+ H]

Preparation 86: 5-Benzyloxy-2-chloropyrimidine

A solution of 2-chloropyrimidin-5-ol (70% purity, 7.5g, 40mmol) in DMF (15mL, 190mmol), under argon, was cooled to 0°C. Cesium Carbonate (14. Og, 43mmol) was added, portionwise, and the mixture was stirred for 5min at 0°C then lOmin at r.t.. The mixture was cooled back back down to 0°C and benzyl bromide (5.1mL, 43mmol) was added, portionwise. The reaction was stirred at 0°C for 15min, then allowed to warm to r.t. and stirred for a further 90min. The solvent was removed in vacuo and the residue partitoned between EtOAc and water. The organic phase was separated, washed with water:brine(l : 1), dried (MgS0₄), and the solvent removed in vacuo. Trituration from a combination of Et₂0 and IH, and further trituration of the motherliquer after concentration in vacuo, afforded the title compound in two crops: RT = 3.54 min; m/z (ES ) = 221.0 [M+ H]⁺. Preparation 87: [(3R,4S)-l-(5-Benzyloxypyrimidin-2-yl)-4-(2,4,5- trifluorophenyl)pyrrolidin-3-yl carbamic acid tert-but l ester

A combination of 5-benzyloxy-2-chloropyrimidine (Preparation 86, 4.4g, 20mmol), [(3i?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 6.0g, 19mmol) and DIPEA (4.4mL, 25mmol) in MeCN (56mL, 1 lOOmmol) was heated in a microwave reactor at 150°C for 4 x 60 min. The solvent was removed in vacuo and the resulting residue partitioned between DCM and water. The organic phase was separated and the aqueous layer was washed with DCM. Organic fractions were combined, dried (MgS0₄), and the solvent removed in vacuo. The crude material was triturated from Et₂0. The precipitate was filtered, washing with Et₂0 (x 2) and Et₂0/IH (x 2), and dried under vacuum to afford the title compound: RT = 4.50 min; m/z (ES⁺) = 501.1 [M+ H]⁺.

Preparation 88: [(3R,4S)-4-(2,4,5-Trifluorophenyl)-l-(5-hydroxypyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid ter -buty\ ester

To a combination of [(3 ?,45)-l-(5-benzyloxypyrimidin-2-yl)-4-(2,4,5- trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 87, 4.5g, 9.0mmol) and 10% Pd/C (O.lg, O. lmmol), purged with argon, was added EtOH (lOOmL) and the reaction was placed under an atmosphere of hydrogen for 60 min. The mixture was filtered through celite, washing with EtOH (2 x 50mL) and the solvent removed in vacuo. The crude material was triturated with Et₂0, filtered, then triturated with DCM, filtered and dried under vacuum to afford the title compound: RT = 3.53 min; m/z (ES ) = 411.3 [M +

H]⁺. Preparation 89: [l-(5-Chloropyrimidin-2- l)-4-methoxypiperidin-4-yl] methanol

2,5-Dichloropyrimidine (471mg, 3.2mmol) and triethylamine (1030μί, 7.4mmol) were added to a solution of (4-methoxypiperidin-4-yl)methanol hydrochloride (1 :1) (400mg, 2.0mmol) in t-BuOH (3mL), and the reaction was heated in a microwave reactor at 80°C for 30min. The mixture was partitioned between DCM and water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and concentrated in vacuo. Purification by column chromatography (IH:EtOAc, 100:0 - 0: 100) afforded the title compound: RT = 2.80 min; mlz (ES⁺) = 258.0 [M+ H]⁺.

Preparation 90: [(3R,4S)-l-{5-[l-(5-Chloropyrimidin-2-yl)-4-methoxypiperidin-4- ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl] carbamic acid tert- butyl ester

To a solution of [(3i?,45)-4-(2,4,5-trifluorophenyl)-l-(5-hydroxypyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 88, 50mg, O. lmmol) in THF (lmL) was added PS-triphenylphosphine (1.52 mmol/g loading; 120mg, 0.18mmol) and the mixture was allowed to stand at r.t. for 5 min. A solution of TBAD (31mg, 0.13mmol) in THF (0.5mL) was added and the mixture was stirred at r.t. for 5 min. A solution of [l-(5- chloropyrimidin-2-yl)-4-methoxypiperidin-4-yl]methanol (Preparation 89, 31mg,

0.12mmol) in THF (0.5mL) was added and the mixture stirred at r.t. for 2h. Further portions of TBAD (31mg, 0.13mmol) and PS-triphenylphosphine (1.52 mmol/g loading; 120mg, 0.18mmol) were added and the reaction was heated to 40°C for 2 h, before being stirred at r.t. for 60 h. The reaction mixture was filtered and the resin washed with DCM and methanol. The filtrate was concentrated in vacuo before being purified by preparative HPLC. Removal of the solvent in vacuo afforded the title compound: RT = 4.80 min; mlz (ES ) = 650.5 [ + H]⁺. Preparation 91 : [(3S,4S)-l-Benzyl-4-(5-bromo-4,4-difluoropentanoylamino)pyrrolidin- 3-yl]carbamic acid tert-butyl ester

A combination of 5-bromo-4,4-difluoropentanoic acid (containing 25% 5-chloro-4,4- difluoropentanoic acid, 3.46g, 16.82mmol), EDCI (3.87g, 20.18mmol), HOAT (2.75g,

20.18mmol) and triethylamine (7.00mL, 50.45mmol) in DMF (35mL) was stirred at r.t. for 1 h. To the reaction was added a solution of ((35',45)-4-amino-l-benzylpyrrolidin-3- yl)carbamic acid tert-butyl ester (Preparation 18, 4.90g, 16.82mmol) in DMF (35mL) and the reaction was heated to 50°C for 16h. DMF was removed in vacuo and the crude residue was taken into water. The mixture was extracted with EtOAc (x 3) then the organic fractions were combined, washed with brine (1 : 1) and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (DCM:MeOH:NH₄OH, 99: 1 :0.1, 96:4:0.1) afforded the title compound: RT = 2.92 min; m/z (ES⁺) = 490.1, 492.1 [M+ H]⁺. Preparation 92: [(3S,4S)-l-Benzyl-4-(5,5-difluoro-2-oxopiperidin-l-yl)pyrrolidin-3- yl]carbamic acid tert-butyl ester

A solution of [(35^,,45)-l-benzyl-4-(5-bromo-4,4-difluoropentanoylamino) pyrrolidin- 3-yl]carbamic acid tert-butyl ester (containing 25% [(35',45)-l-benzyl-4-(5-chloro-4,4- difluoropentanoylamino) pyrrolidin-3-yl]carbamic acid tert-butyl ester, Preparation 91, 5.60g, 11.7mmol) in DMF (30mL) was cooled to 0°C. Sodium hydride (60%> mineral oil, 0.94g, 23.4mmol) was added and the reaction allowed to stir, gradually warming to r.t. over 2 h. The DMF was removed in vacuo, azeotroping with toluene (x 3) then the crude residue was partitioned between DCM and water. The aqueous phase was separated and extracted with DCM, then the organic layers were combined, washed with brine and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (DCM:MeOH:NH₄OH, 99: 1 :0.1, 98:2:0.2 then IH:EtOAc, 50:50, 0: 100) afforded the title compound. LCMS Method 4: RT = 2.90 min; mlz (ES⁺) = 410.2 [M+ H]⁺.

Preparation 93 : [(3S,4S)-4-(5,5-Difluoro-2-oxopiperidin-l-yl)pyrrolidin-3-yl] carbamic acid tert-buty\ ester

The title compound was prepared from [(35',45)-l-benzyl-4-(5,5-difluoro-2- oxopiperidin-l-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 92) employing the procedure outlined in Preparation 20: RT = 2.04 min; mlz (ES⁺) = 320.2 [M+ H]⁺.

Preparation 94: 2-bromo-5-{(S)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl] ethoxy} pyridine

To a solution of (i?)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation 62, 1.02g, 4.24mmol) in THF (12.5mL), under argon, was added

triphenylphosphine (1.66g, 6.32mmol) and the reaction was cooled to 0°C. TBAD (1.46g, 6.32mmol) was added and the reaction was allowed to warm to r.t. before being stirred for 20 h. The reaction solvent was reduced to a volume of 5mL, then purification by column chromatography (TEA doped Si0₂, Heptane:EtOAc, 4: 1, 3:1) afforded the title compound. LCMS method 5: RT = 14.07 min; mlz (ES⁺) = 395.0, 397.0 [M+ H]⁺.

Preparation 95 : 2-Bromo-5-{(5)- 1- [ l-(3-isopropyl- [ 1 ,2,4] oxadiazol-5-yl)piperidin-4- yl] ethoxy} pyrazine

To a solution of (i?)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation 62, 1.10g, 4.58mmol) in THF (14mL), under argon, was added triphenylphosphine (1.80g, 6.89mmol) and the reaction was cooled to 0°C. DIAD (1.35mL, 6.86mmol) was added, in two portions, and the reaction was allowed to warm to r.t. before being stirred for 16 h. The reaction solvent was reduced in vacuo and the thick slurry was purified by column chromatography (Heptane:EtOAc, 4: 1, 3: 1 then TEA doped Si0₂, Heptane:EtOAc, 4: 1, 3:1). The purification method was repeated to afford the title compound. LCMS method 5: RT = 14.99 min; mlz (ES⁺) = 396.0, 398.0 [M+ H]⁺.

Preparation 96: (R)-l-Pyridin-4-yl-ethanol

To a solution of diphenyl-(5)-pyrrolidin-2-ylmethanol (10.5g, 41.3mmol) in THF (800mL) was added trimethoxyborane (5.52mL, 49.5mmol) and the reaction was stirred at r.t. for 1 h. The mixture was cooled to 0°C and borane dimethylsulfide (78mL, 825.5mmol) was added, followed by a solution of 4-acetylpyridine (50g, 410.7mmol) in THF (200mL), over 1 h. The reaction was stirred for a further 1 h before being quenched with 2M HC1. After stirring for 10 min the reaction mixture was basified with sat. NaHCC"3 solution. The precipitate that formed was filtered, and the remaining filtrate was extracted with EtOAc (x 10). The organic fractions were combined, dried (MgS0₄) and the solvent removed in vacuo. Purification by column chromatography (DCM:MeOH, 9: 1) afforded the title compound: 1H NMR δ_Η (300MHz , CDC1₃): 8.49 (s, 2H), 7.30 (s, 1H), 4.93 - 4.84 (m, 1H), 3.08 - 2.86 (m, 1H), 1.51 - 1.48 (m, 3H).

Preparation 97: (R)-l-Piperidin-4- lethanol acetate

To a solution of (i?)-l-pyridin-4-yl-ethanol (Preparation 96, 31.6g, 0.29mol) in MeOH (650mL) was added AcOH (16.2mL), and the vessel was flushed with argon.

Platinum oxide (4.0g) was added and the reaction was stirred under an atmosphere of hydrogen at 50atm for 18 h. The mixture was filtered through celite, washing with MeOH, then the filtrate was concentrated in vacuo. The residue was triturated with EtOAc, then filtered to afford the title compound: 1H NMR δ_Η (400MHz , CDC1₃): 5.82 - 5.46 (m, 3H), 3.65 - 3.60 (m, 1H), 3.38 - 3.30 (m, 2H), 2.77 - 2.65 (m, 2H), 2.00 - 1.92 (m, 4H), 1.76 - 1.69 (m, 1H), 1.65 - 1.40 (m, 3H), 1.20 - 1.16 (m, 3H). Preparation 98: 4-((R)-l-hydroxyeth l)piperidine-l-carbonitrile

To a solution of (i?)-l-piperidin-4-ylethanol acetate (Preparation 97, 60. Og, 0.32mol) in DCM (175mL) was added a slurry of NaHC0₃ (106.5g) in water (175mL), and the mixture was cooled to 0°C. A solution of cyanogen bromide in DCM (3M, 116.0mL,

0.35mol) was added, drop-wise, over 50 min, then the reaction was warmed to r.t. and stirred for 2 h. The mixture was partitioned between DCM and water, and the organic phase was separated. The aqueous phase was extracted with DCM, then organic fractions were combined, washed with sat. NaHC0₃ solution, and dried (MgS0₄). The solvent was removed in vacuo to afford the title compound: 1H NMR δ_Η (400MHz , CDC1₃): 3.64 - 3.53 (m, 1H), 3.50 - 3.40 (m, 2H), 3.05 - 2.90 (m, 2H), 1.92 - 1.80 (m, 1H), 1.72 - 1.30 (m, 4H), 1.20 - 1.11 (m, 3H).

Preparation 99: N-Hydroxypropionamidine

To a solution of hydroxylamine (15mL, 0.45mol) in IMS (210mL) was added propionitrile (38mL, 0.54mol) and the reaction was heated to 100°C for 16 h. The reaction solvent was concentrated in vacuo to afford the title compound: 1H NMR δ_Η (400MHz , CDC1₃): 4.75 - 4.38 (s (br), 2H), 2.20 - 2.09 (m, 2H), 1.19 - 1.06 (m, 3H). Preparation 100: (R)-l-[l-(3-Ethyl- l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol

4-((i?)-l-hydroxyethyl)piperidine-l-carbonitrile (Preparation 98, 28.4g, 183mmol) was combined with N-hydroxypropionamidine (Preparation 99, 19.4g, 220mol) in EtOH (570mL). To the mixture was added a solution of zinc(II)chloride (309g, 220mol) in EtOH (40mL) over 15 min, and the reaction was stirred at r.t. for 2 h. To the mixture was then added concentrated HC1 (25mL), over 5 min, and the reaction was heated to reflux for 4 h. The reaction solvent was concentrated in vacuo, and water was added. The mixture was brought the pH7 with NaHC0₃ and extracted with EtOAc, then the organic fraction was dried (MgS0₄), and the solvent removed in vacuo. Purification by column chromatography

(DCM:MeOH, 95:5) afforded the title compound. LCMS Method 3: RT

(ES⁺) = 226.1 [Μ+ ηγ. Preparation 101: Methanesulfonic acid (R)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl] ethyl ester

To a dry solution of (i?)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation 100, 2.0g, 8.9mmol) in DCM (30mL) was added triethylamine (1.5mL, 10.6mmol) and the mixture was cooled to 0°C. Methanesulfonyl chloride (0.8mL, 9.8mmol) was added by syringe and the reaction was stirred until complete. The reaction mixture was diluted with DCM (50mL), washed with 1M HC1 (x 3) and brine, then dried using a phase separator. Removal of the solvent in vacuo afforded the title compound: RT = 3.02 min; mlz

Preparation 102: 2-Chloro-5-{(5)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl] ethoxy}pyrimidine

The title compound was prepared from methanesulfonic acid (R)-l-[l-(3-ethyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethyl ester (Preparation 101) employing the method outlined in Preparation 29. Purification by column chromatography (IH:EtOAc, 40:60) afforded the title compound: RT = 3.50 min; mlz (ES⁺) = 338.1 [M+ H]⁺.

Preparation 103 : l-(3-Isopropyl- [ 1 ,2,4] oxadiazol-5-yl)-4-oxiranylpiperidine

To a solution of trimethylsulfoxonium iodide (1.18g, 5.37mmol) in DMSO (lOmL) was added sodium hydride (0.22g, 5.37mmol). The resulting solution was stirred at r.t. for 30 min before the addition of a solution of l-[3-(propan-2-yl)-l,2,4-oxadiazol-5-yl]piperidine-4- carbaldehyde (Preparation 79, 1.20g, 5.37mmol) in DMSO (8mL), via cannula. The reaction was stirred at r.t. for 16 h before being poured into ice-water (400mL). The mixture was extracted with EtOAc (x 3), and the combined organic fractions were washed with water, then brine, and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 65:35) afforded the title compound: RT = 2.99 min; mlz (ES⁺) = 238.2 [M+ H] .

Preparation 104 : 1- [ l-(3-Isopr opyl- [ 1 ,2,4] oxadiazol-5-yl)piperidin-4-yl] -2- methoxyethanol

To a solution of l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-4-oxiranylpiperidine

(Preparation 103, 356mg, 1.50mmol) in anhydrous MeOH (6mL) was added sodium methoxide (85mg, 1.50mmol) and the resulting mixture was stirred under reflux for 16 h. The solvent was removed in vacuo and the resulting residue partitioned between water and EtOAc. The aqueous phase was separated, extracted with EtOAc (x 2), and the combined organic fractions were dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 30:70) afforded the title compound: RT = 2.64 min; m/z

Preparation 105: Methanesulfonic acid l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl] -2-methox ethyl ester

To a solution of l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]-2- methoxyethanol (Preparation 104, 217mg, 0.8mmol) in DCM (5mL), cooled to 0°C, was added triethylamine (190μΕ, 1.4mmol), followed by methanesulfonyl chloride (81 μΕ, l.Ommol), and the reaction was stirred at 0°C for 2.5 h. The reaction was quenched with water, and the organic phase was separated, washed with sat. NH₄C1 solution, then brine, and dried (MgS0₄). Removal of the solvent in vacuo afforded the title compound: RT =

3.24 min; m/z (ES⁺) = 348.1 [M+ H]⁺. Preparation 106: [(3R,4S)-l-(5-Benzyloxypyrimidin-2-yl)-4-(2,5- difluorophenyl)pyrrolidin-3- l]carbamic acid tert-butyl ester

A combination of 5-benzyloxy-2-chloropyrimidine (Preparation 86, 350mg, 1.6mmol), [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 570g, 1.9mmol) and DIPEA (550μΕ, 3.2mmol) in MeCN (lOmL) was heated in a microwave reactor at 160°C for 30 min. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (IH:EtOAc, 100:0, 75:25) to afford the title compound: RT = 4.42 min; m/z (ES⁺) = 483.2 [M+ H]⁺.

Preparation 107: [(3R,4S)-4-(2,5-Difluorophenyl)-l-(5-hydroxypyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-but l ester

A combination of [(3i?,45)-l-(5-benzyloxypyrimidin-2-yl)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 106, 300mg, 0.6mmol) and palladium on carbon (10% wt., 66mg, 0.06mmol) in EtOH (30mL) was purged with argon and then placed under an atmosphere of hydrogen for 60min. The mixture was filtered through celite and the solvent removed in vacuo to afford the title compound: RT = 3.35 min; m/z (ES⁺) = 393.2 [M+ H]⁺.

Preparation 108: [(3R,45)-4-(2,5-Difluorophenyl)-l-(5-{l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-2-methoxyethoxy}pyrimidin-2-yl)pyrrolidin-3- yl]carbamic acid tert-butyl ester

To a solution of methanesulfonic acid l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-2-methoxyethyl ester (Preparation 105, 80.5mg, 0.23mmol) and [(3R,4S)- 4-(2,5-difluorophenyl)-l-(5-hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 107, 82.7mg, 0.21mmol) in DMA (2.0mL) was added CsF (35.2mg, 0.23mmol), and the reaction was stirred at 65°C for 120 h. A further portion of CsF (35.0mg, 0.23mmol) was added, along with TBAI (15.6mg, 0.04mmol), and the reaction was heated to 75°C for 16 h. Further portions of CsF (35mg, 0.23mmol) and methanesulfonic acid l-[l-(3- isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]-2-methoxyethyl ester (Preparation 105, 40mg, 0.12mmol) in DMA (0.4mL) were added and the reaction continued heating at 75°C for 16 h. Further CsF (35mg, 0.23mmol) was added and the reaction was heated to 85°C for 120 h. On cooling, the reaction mixture was diluted with EtOAc, washed with water (x 3), then brine, and dried (MgS0₄), before removal of the solvent in vacuo. Purification by column chromatography (IH:EtOAc, (70:30, 70:35, 60:40, 50:50, 0: 100) and further purification by preparative HPLC afforded the title compound: RT = 4.33 min; m/z (ES ) =

Preparation 109: [ l-(5-Ethyl-2-meth l-2H- [ 1 ,2,4] triazol-3-yl)piperidin-4-yl] methanol

To a solution of [l-(5-ethyl-2H-[l,2,4]triazol-3-yl)piperidin-4-yl]methanol (510mg, 2.4mmol) in MeOH (lOmL) was added KOH (140mg, 2.4mmol), portion-wise, and the reaction was stirred at r.t. for 1 h. Methyl iodide (ΠΟμί, 2.7mmol) was added, drop-wise, and the reaction mixture was heated to 60°C for 16 h. The mixture was cooled, a further portion of methyl iodide (Πμί, O.leq) was added, and the reaction was heated to 60°C for 30 min. The mixture was cooled again, another portion of methyl iodide (35μί, 0.2eq.) was added, and the reaction was heated to 60°C for 60 min. The mixture was cooled once more, a further portion of methyl iodide (35μί, 0.2eq) was added, followed by KOH (70mg, 0.5eq), and the reaction was heated to 60°C for 60 min. The mixture was partitioned between DCM and water. The aqueous phase was separated, extracted with DCM, then the combined organic fractions were dried (MgS0₄) and concentrated in vacuo to afford an oil. The aqueous layer was then extracted with ethyl acetate (x 3). The combined organic fractions were dried (MgS0₄) and the solvent removed in vacuo to afford an oil.

A small aliquot of the aqueous phase (3mL) was acidified with citric acid, extracted with DCM (5mL), filtered through a phase separator, and the solvent removed in vacuo to afford an oil. The remaining aqueous phase was concentrated in vacuo, and the residue was dissolved in a solution of DCM and MeOH (DCM:MeOH, 95:5). The mixture was passed through a silica cartridge and desired fractions concentrated in vacuo to afford an oil. All oil products were combined and dissolved in MeOH. Purification by preparative HPLC (basic method) afforded the title compound: RT = 1.90 min; mlz (ES⁺) = 225.2 [M+ H]⁺.

Preparation 110: [ l-(3-Ethyl- [1 ,2,4] triazolo [4,3-c] pyrimidin-7-yl)piperidin-4- yl] methanol

A combination of 7-chloro-3-ethyl-[l,2,4]triazolo[4,3-c]pyrimidine (50mg, 0.3mmol) and 4-(hydroxymethyl)piperidine (1 lOmg, l .Ommol) in NMP (250μί) was heated in a microwave reactor at 100°C for 15min. The reaction mixture was diluted with DCM and washed with water, before filtering through a phase separator. The organic layer was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. Removal of the solvent in vacuo afforded the title compound: RT = 2.09 min; mlz (ES⁺) = 262.2 [M+ H]⁺.

Preparation 111: [l-(3-Isopropyl-[l 2,4] oxadiazol-5-yl)piperidin-3-yl] methanol

A combination of 3-isopropyl-5-trichloromethyl-[l,2,4]oxadiazole (600mg,

2.61mmol) and 3-piperidinemethanol (137mg, 3.90mmol) was heated in a microwave reactor at 80°C for 60 min. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The material was then passed down an STMAd cartridge, eluting with a mixture of DCM and MeOH, and the filtrate was concentrated in vacuo to afford the title compound: RT = 2.65 min; mlz (ES⁺) = 226.1 [M+ H]⁺. Preparation 112: (3R,4S)-4-(2,5-Difluoro henyl)pyrrolidin-3-ylamine

To a solution of [(3 ?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert- butyl ester (Preparation 48, 2.5g, 8.4mmol) in DCM (25mL) was added TFA (5mL) and the reaction was stirred at r.t. for 3 h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected. Removal of the solvent in vacuo afforded the title compound: 1H NMR δ_Η (400MHz, CDCI3): 7.04 - 6.95 (m, 2H), 6.92 - 6.85 (m, 1H), 3.57 - 3.49 (m, 2H), 3.37 - 3.31 (m, 1H), 3.15 - 3.07 (m, 1H), 3.04 - 2.98 (m, 1H), 2.82 - 2.75 (m, 1H).

Preparation 113: 4-((R)-l-Hydroxy thyl)piperidine-l-carboxylic acid terf-butyl ester

To a solution of ( ?)-l-piperidin-4-ylethanol acetate (Preparation 97, 20g, 69mmol) in 1,4-dioxane (150mL) was added a solution of Na₂C0₃ (28g, 265mmol) in water (lOOmL) and the mixture was cooled to 0°C. Di-tert-butyldicarbonate (24g, 11 lmmol) was added portion- wise, over 10 min, and the reaction was allowed to stir at r.t for 22 h. The crude mixture was poured into water and extracted with DCM (x 3) then the combined organic fractions were dried (MgS0₄), and the solvent removed in vacuo. Purification by column chromatography (DCM:EtOAc, 100:0, 80:20, 60:40, 40:60, 20:80, 0: 100) afforded the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 4.23 - 4.10 (m, 2H), 3.62 - 3.53 (m, 1H), 2.70 - 2.58 (m, 2H), 1.85 - 1.78 (m, 1H), 1.64 - 1.50 (m, 3H), 1.48 - 1.33 (m, 10H), 1.20 - 1.15 (m, 3H).

Preparation 114: 4-((R)-l-Methanesulfonyloxyethyl)piperidine-l-carboxylic acid terf- butyl ester

The title compound was prepared from 4-((i?)-l-hydroxyethyl)piperidine-l-carboxylic acid fert-butyl ester (Preparation 113) employing the procedure outlined in Preparation 101 : H NMR δ_Η (400MHz , CDC1₃) δ = 4.69 - 4.60 (m, 1H), 4.29 - 4.08 (m, 2H), 3.01 (s, 3H), 2.73 - 2.60 (m, 2H), 1.83 - 1.61 (m, 3H), 1.46 (s, 9H), 1.41 (d, J = 6.2Hz, 3H), 1.35 - 1.18 (m, 2H)

Preparation 115: 4- [(5)- l-(2-Chloropyrimidin-5-yloxy)ethyl] piperidine- 1-carboxylic acid tert-buty\ ester

To a solution of 4-((i?)-l-methanesulfonyloxyethyl)piperidine- 1-carboxylic acid tert- butyl ester (Preparation 114, 1.77g, 5.76mmol) and 2-chloropyrimidin-5-ol (0.75g, 5.75mmol) in NMP (20mL) was added potassium carbonate (l .lg, 8.10mmol) and the reaction was heated to 80°C for 16 h. The reaction mixture was partitioned between TBME and water, and the aqueous layer was separated and washed with further TBME. The organic fractions were combined, washed with water, then brine, and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 100:0 - 70:30) afforded the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 8.26 (s, 2H), 4.25 - 4.19 (m, 3H), 2.74 - 2.64 (m, 2H), 1.90 - 1.65 (m, 3H), 1.47 (s, 9H), 1.39 - 1.25 (m, 5H).

Preparation 116: 4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyrimidin-5-yloxy}eth l)piperidine-l-carboxylic acid terf-butyl ester

To a combination of 4-[(5)-l-(2-chloropyrimidin-5-yloxy)ethyl]piperidine-l- carboxylic acid tert-butyl ester (Preparation 115, 1.98g, 5.79mmol) and (3R,4S)-4-(2,5- difluorophenyl)pyrrolidin-3-ylamine (Preparation 112, (1.67g, 8.42mmol)) in DMSO (1 lmL) was added DBU (1.30mL, 8.70mmol) and the reaction was heated to 80°C in a sealed vial for 64 h. The reaction mixture was partitioned between DCM and water. The organic phase was separated, washed with water, then brine, and dried (MgS0₄). Removal of the solvent in vacuo afforded the title compound: RT = 2.92 min; mlz (ES ) = 504.2 [M +

H]⁺. Preparation 117: 4-((S)-l-{2-[(3S,4R)-3-(2,5-Difluorophenyl)-4-(9H-fluoren-9- ylmethoxycarbonylamino)pyrrolidin-l-yl]pyrimidin-5-yloxy}ethyl)piperidine-l- carboxylic acid tert-buty\ ester

A combination of 4-((5)-l-{2-[(3i?,45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyrimidin-5-yloxy}ethyl)piperidine-l-carboxylic acid tert-butyl ester (Preparation 116, 2.59g, 5.14mmol) 9-fluorenylmethyl chloroformate (1.60g, 6.17mmol) and NaHC0₃ (1.73g, 20.60mmol) in 1,4-Dioxane (40mL), water (50mL) and toluene (20mL) was stirred at r.t. for 16 h. A further portion of 9-fluorenylmethyl chloroformate (0.16g, 0.62mmol) was added and stirring continued for 30 min. The bi-phasic reaction mixture was separated and the aqueous layer washed with EtOAc. The organic fractions were combined, dried (MgS0₄) and the solvent removed in vacuo. Purification by column chromatography (IH:EtOAc, 100:0 - 60:40) afforded the title compound: RT = 5.12 min; m/z (ES⁺) = 726.3 [M+ H]⁺.

Preparation 118: {(3R,45)-4-(2,5-Difluorophenyl)-l-[5-((S)-l-piperidin-4- ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid 9H-fluoren-9-ylmethyl ester acetate

To a solution of 4-((5)-l-{2-[(3^,4i?)-3-(2,5-difluorophenyl)-4-(9H-fluoren-9- ylmethoxycarbonylamino)pyrrolidin- 1 -yl]pyrimidin-5 -yloxy } ethyl)piperidine- 1 -carboxylic acid tert-butyl ester (Preparation 117, 2.29g, 3.16mmol) in DCM (38mL) was added TFA (8mL) and the reaction was stirred at r.t. for 16 h. The reaction solvent was removed in vacuo and the residue re-dissolved in DCM. The solution was passed through a PE-AX column, washing with methanol, and the filtrate was concentrated in vacuo to afford the title compound: RT = 3.18 min; m/z (ES⁺) = 626.2 [M + H]⁺. Preparation 119: {(3R,45)-4-(2,5-Difluorophenyl)-l-[5-((S)-l-piperidin-4- ylethoxy)pyrimidin-2-yl]pyrrolidin-3- l}carbamic acid 9H-fluoren-9-ylmethyl ester

{(3i?,45)-4-(2,5-Difluorophenyl)-l-[5-((5)-l-piperidin-4-ylethoxy)pyrimidin-2- yl]pyrrolidin-3-yl}carbamic acid 9H-fluoren-9-ylmethyl ester acetate (Preparation 118, 0.8 lg, 1.2mmol) was partitioned between DCM (20mL) and sat. NaHC0₃ solution (20mL), and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and concentrated in vacuo to afford the title compound: RT = 3.18 min; m/z (ES⁺) = 626.2 [M + H]⁺. Preparation 120: 4-((5)-l-{2-[(3R,4S)-3-te^Butoxycarbonylamino-4-(2,5- difluorophenyl)pyrrolidin-l-yl]pyrimidin-5-yloxy}ethyl)piperidine-l-carboxylic acid tert-butyl ester

To a combination of 4-[(5)-l-(2-chloropyrimidin-5-yloxy)ethyl]piperidine-l- carboxylic acid tert-butyl ester (Preparation 115, 190mg, 0.55mmol) and [(3R,4S)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 160mg, 0.55mmol) in DMSO (2mL) was added DBU (124μΕ, 0.83mmol) and the reaction was heated in a sealed vial at 100°C for 16 h. The mixture was partitioned between DCM and water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and concentrated in vacuo. Purification by column chromatography (IH:EtOAc, 80:20, 60:40) afforded the title compound: RT = 4.75 min; mlz (ES⁺) = 604.3 [M+ H]⁺. Preparation 121: (3R,45)-4-(2,5-Difluorophenyl)-l-[5-((S)-l-piperidin-4-yl- ethoxy)pyrimidin-2-yl]pyrrolidin-3- lamine

To a solution of 4-((5)-l-{2-[(3i?,45)-3-fert-butoxycarbonylamino-4-(2,5- difluorophenyl)pyrrolidin- 1 -yl]pyrimidin-5 -yloxy } ethyl)piperidine- 1 -carboxylic acid tert- butyl ester (Preparation 120, 150mg, 0.25mmol) in DCM (2.5mL) was added TFA (0.5mL) and the reaction was shaken at r.t. for 16 h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo to afford the title compound: RT = 1.99 min; mlz (ES ) = 404.1 [M+ H]⁺.

Preparation 122: (5'-Fluoro-3,4,5,6-tetrah dro-2H-[l,2']bipyridinyl-4-yl)methanol

A combination of 2,5-difluoropyridine (0.5g, 4mmol) and 4- (hydroxymethyl)piperidine (1.5g, 13mmol), in a microwave vial, was warmed gently with a heat gun to achieve a melt. The reaction was heated in a microwave reactor at 60°C for 15min, and then at 100°C for 30min. The mixture was partitioned between EtOAc and water and the organic phase separated. The aqueous phase was extracted with EtOAc, then the combined organic fractions were dried (MgS0₄) and the solvent removed in vacuo.

Purification by column chromatography afforded the title compound: RT = 1.87 min; mlz (ES ) = 211.1 [ + H] .

Preparation 123: [l-(4-Methylthiazol-2-yl)piperidin-4-yl]methanol ^N f OH

A combination of 2-chloro-4-methylthiazole (0.25g, 2mmol) and 4- (hydroxymethyl)piperidine (0.50g, 4mmol), in a microwave vial, was warmed gently with a heat gun to achieve a melt. The reaction was heated in a microwave reactor at 100°C for 15min, and then at 100°C for a further 30min. The resulting gum was partitioned between DCM and water, and the organic phase was separated and concentrated in vacuo. The remaining aqueous phase was extracted with EtOAc, then the organic layer was washed with brine and concentrated in vacuo. The two organic residues were combined and triturated with EtOAc. The supernatant was separated and purified by column chromatography to afford the title compound: RT = 1.74 min; mlz (ES⁺) = 213.1 [M+ H]⁺. Preparation 124: [(3R,45)-l-{5-[l-(5-Ethyl-2-methyl-2H-[l,2,4]triazol-3-yl)piperidin-4- ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl] carbamic acid tert- butyl ester

To a solution of [(3i?,45)-4-(2,4,5-trifluorophenyl)-l-(5-hydroxypyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 88, 29.3mg, 0.07mmol) in THF (0.6mL) was added PS-triphenylphosphine (1.52 mmol/g loading; 70.4mg, 0.1 lmmol) and the mixture was allowed to stand at r.t. for 5 min. A solution of TBAD (18.1mg, 0.08mmol) in THF (0.3mL) was added and the mixture was stirred at r.t. for 5 min. A solution of [l-(5-ethyl-2-methyl-2H-[l,2,4]triazol-3-yl)piperidin-4-yl]methanol

(Preparation 109, 16mg, 0.07mmol) in THF (0.3mL) was added and the mixture was stirred at r.t. for 2h. Further portions of TBAD (18.1mg, 0.08mmol) and PS-triphenylphosphine (1.52 mmol/g loading; 70.4mg, 0.1 lmmol) were added and the mixture was heated to 40°C for 2 h. The reaction mixture was filtered and the resin washed with MeOH. The filtrate was concentrated in vacuo before being purified by preparative HPLC. Removal of the solvent in vacuo afforded the title compound: RT = 3.73 min; mlz (ES⁺) = 617.6 [M+ H]⁺. Preparation 125: [(3R,4S)-l-[5-(5'-Fluoro-3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-4- ylmethoxy)pyrimidin-2-yl] -4-(2,4,5-trifluorophenyl)pyr rolidin-3-yl] carbamic acid tert- butyl ester

To a solution of [(3 ?,4S)-4-(2,4,5-trifluorophenyl)- 1 -(5-hydroxypyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 88, 50mg, O. lOmmol) and (5'- fluoro-3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-4-yl)methanol (Preparation 122, 31mg, 0.15mmol), in a combination of DCM (2mL) and THF (2mL), was added PS- triphenylphosphine (1.94 mmol/g loading; 113mg, 0.22mmol) and the mixture was allowed to stir at r.t. for 5 min. TBAD (5 lmg, 0.22mmol) was added and the mixture was stirred at r.t. for 16 h. Further portions of TBAD (5 lmg, 0.22mmol) and PS-triphenylphosphine (1.94 mmol/g loading; 113mg, 0.22mmol) were added and the mixture was heated to 40°C for 2 h before being allowed to stir at r.t. for 60 h. The reaction mixture was filtered, the resin washed with MeOH, and the filtrate was concentrated in vacuo. The resulting residue was partitioned between DCM and water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and the solvent removed in vacuo. Trituration with MeOH afforded the title compound: RT = 4.50 min; mlz (ES⁺) = 603.3 [M+ H]⁺. Preparation 126: [(3R,45)-l-{5-[l-(4-Methylthiazol-2-yl)piperidin-4- ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl] carbamic acid tert- butyl ester

To a solution of [(3 ?,45)-4-(2,4,5-trifluorophenyl)-l-(5-hydroxypyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 88, 50mg, O.lOmmol) and [1- (4-methylthiazol-2-yl)piperidin-4-yl]methanol (Preparation 123, 31mg, 0.15mmol) in a combination of DCM (2mL) and THF (2mL) was added PS-triphenylphosphine (1.94 mmol/g loading; 113mg, 0.22mmol) and the reaction was stirred at r.t. for 5 min. TBAD (51mg, 0.22mmol) was added and the mixture was stirred at r.t. for 16 h. before being heated to 40 °C for 2 h. Further portions of PS-triphenylphosphine (1.94 mmol/g loading; 113mg, 0.22mmol) and TBAD (51mg, 0.22mmol) were added, then the reaction continued to heat at 40 °C for 2 h., before being allowed to stand at r.t. for 60 h. The reaction mixture was filtered, the resin washed with MeOH, and the filtrate was concentrated in vacuo. The resulting residue was partitioned between DCM and water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and the solvent removed in vacuo. Purification by preparative HPLC afforded the title compound: RT = 3.42 min; mlz (ES⁺) = 605.2 [M+ H]⁺.

Preparation 127: [(3R,45)-l-{5-[l-(3-Ethyl-[l,2,4]triazolo[4,3-c]pyrimidin-7- yl)piperidin-4-ylmethoxy] pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3- yl]carbamic acid terf-but l ester

Triethylamine (40μί, 0.3mmol) and methanesulfonyl chloride (20μΙ_^, 0.2mmol) were added to a solution of [l-(3-ethyl-[l,2,4]triazolo[4,3-c]pyrimidin-7-yl)piperidin-4- yljmethanol (Preparation 110, 37mg, 0.14mmol) in DCM (lmL) and the reaction was shaken at r.t. for 2 h. The mixture was washed with 1M HC1 (lmL) and passed through a phase separator. The aqueous phase was washed with DCM, then the organic fractions were combined and concentrated in vacuo.

A solution of [(3i?,45)-4-(2,4,5-trifluorophenyl)-l-(5-hydroxypyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 88, 50mg, 0.12mmol) in DMF (lmL) was added to the crude residue, followed by K₂CO₃ (50mg, 0.40mmol), and the reaction was heated to 80 °C for 16 h. The mixture was partitioned between DCM and water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 3.93 min; mlz (ES ) = 654.3 [M+ H]⁺.

Preparation 128: [(3R,45)-l-{5-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-3- ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl] carbamic acid tert- butyl ester

The title compound was prepared from [l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-3-yl]methanol (Preparation 111) by formation of the mesylate intermediate, followed by reaction with [(3i?,45)-4-(2,4,5-trifluorophenyl)-l-(5-hydroxypyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 88) employing the procedure outlined in Preparation 127: RT = 4.53 min; mlz (ES⁺) = 618.3 [M+ H]⁺.

Preparation 129: Methanesulfonic acid (R)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl] ethyl ester

To a solution of (i?)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation 62, 4.0g, 16.7mmol) in DCM (50mL) was added triethylamine (2.8mL, 20.0mmol) and the mixture was cooled to 0°C. Methanesulfonyl chloride (1.6mL,

20.0mmol) was added over 10 min and the reaction was allowed to stir at 0°C for 2 h, before being quenched with water. The mixture was washed with brine (x 2), dried (Na₂S04), and the solvent removed in vacuo to afford the title compound: : 1H NMR 5_H (400MHZ , CDCI3):

4.73 - 4.65 (m, 1H), 4.17 - 4.18 (m, 2H), 3.08 - 2.97 (m, 5H), 2.93 - 2.84 (m, 1H), 1.94 -

1.74 (m, 3H), 1.53 - 1.35 (m, 5H), 1.29 (d, J= 7.0 Hz, 6H). Preparation 130: [(3R,4S)-4-(2,5-Difluorophenyl)-l-(5-{(S)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethylamino}pyrimidin-2-yl)pyrrolidin-3- yl]carbamic acid tert-but \ ester

To [(3i?,45)-l-(5-aminopyrimidin-2-yl)-4-(2,5-difluorophenyl)pyrrolidin-3- yljcarbamic acid tert-butyl ester (preparation 81, 256mg, 0.65mmol) was added a solution of methanesulfonic acid (i?)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethyl ester (Preparation 129, 208mg, 0.65mmol) in MeCN (5.5mL). K₂C0₃ (99.4mg, 0.72mmol) was added and the reaction was heated at reflux for 16 h. The mixture was reduced in vacuo to a volume of 2mL, heated in a microwave reactor at 100°C for 3 h, and then heated at reflux for 144 h. The solvent was removed in vacuo, then the resulting residue was dissolved in EtOAc, washed with water, then brine, and dried (MgS0₄), before removal of the solvent in vacuo. Purification by column chromatography (IH:EtOAc, 5:4) and further purification by preparative HPLC afforded the title compound: RT = 3.95 min; m/z (ES ) = 613.3 [M +

H]⁺.

Preparation 131: [(3R,45)-l-{5-[l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl] carbamic acid tert- butyl ester

To a solution of 2-chloro-5-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidine (Preparation 53, 162mg, 0.5mmol) and [(3 ?,45)-4-(2,4,5- trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 158mg, 0.5mmol) in DMSO (lmL) was added DBU (75μΕ, 0.5mmol) and the reaction was heated to 100°C for 72 h. The mixture was diluted with DCM, washed with brine and passed through a phase separater. Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 40:60) afforded the title compound: RT = 4.25 min; mlz (ES ) =

Preparation 132: [(3R,45)-l-{5-[l-(5-Isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4- ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl] carbamic acid tert- butyl ester

The title compound was prepared by reacting 2-chloro-5-[l-(5-isopropyl- [l,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 60) with [(3R,4S)-4- (2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39) employing the procedure outlined in Preparation 131. Purification by column

chromatography (IH:EtOAc, 70:30) afforded the title compound: RT = 4.74 min; mlz (ES ) =

Preparation 133: 2-((E)-2-Nitrovinyl) ridine

A solution of pyridine-2-carbaldehyde (lO.Og, 93mmol) and nitromethane (8.3mL, 112mmol) in MeOH (85mL), under argon, was cooled to -15°C. A solution of NaOH (3.9g, 98mmol) in water (lOmL) was added, drop-wise, over 20 min. The pale yellow precipitate which resulted was stirred at 0°C for 10 min. Ice water (60mL) was added and the mixture was stirred for 15 min before the addition of sat. NH₄C1 solution (70mL). The organic fraction was extracted with DCM (x), dried (Na₂S0₄) and the solvent removed in vacuo.

The residue was dissolved in acetic anhydride (lOmL, 195mmol) and cooled to 0°C under argon. DMAP (0.8g, 6mmol) was added and the ice bath was removed, allowing the reaction to stir at r.t. for 16 h. The reaction solvent was extracted with DCM, washed with brine, and the solvent removed in vacuo. The resulting residue was re-dissolved in DCM and the solution was washed with 2M NaOH solution, then brine, before being dried (MgS0₄). Removal of the solvent in vacuo afforded the title compound: 1H NMR δ_Η (300MHz , CDCI₃): 8.74 - 8.60 (m, 1H), 8.07 - 7.85 (m, 2H), 7.82 - 7.72 (m, 1H), 7.50 - 7.43 (m, 1H), 7.40 - 7.32 (m, 1H).

Preparation 134: 2-((frans)-l-Benz l-4-nitropyrrolidin-3-yl)pyridine

The title compound was prepared from 2-((E)-2-Nitrovinyl)pyridine (Preparation 133) employing the method outlined in Preparation 31, but the reaction was carried out at 0°C. Purification by column chromatography (Hexane:EtOAc, 100:0, 90: 10, 80:20, 50:50) afforded the title compound. LCMS Method 2: RT = 0.84 min; mlz (ES⁺) = 284.2 [M+ H]⁺.

Preparation 135: ((irans)-l-Benzyl-4-pyridin-2-ylpyrrolidin-3-yl)carbamic acid tert- butyl ester

A combination of 2-((tra/?5)-l-benzyl-4-nitropyrrolidin-3-yl)pyridine (Preparation 134, 15.3g, 54mmol) and zinc dust (28. Og, 432mmol) in a mixture of AcOH and EtOH (1 : 1, 300mL) was heated to 60°C for 1 h. After complete reaction the mixture was cooled and filtered, washing with AcOH, and the filtrate was concentrated in vacuo. The resulting residue was re-dissolved in DCM, washed with brine, and dried (Na₂S0₄). Removal of the solvent in vacuo and purification by column chromatography (DCM:MeOH, 100:0, 98:2, 95:5) afforded the intermediate product (tra/75)-l-benzyl-4-pyridin-2-yl-pyrrolidin-3- ylamine. LCMS Method 2: RT = 0.63 min; mlz (ES⁺) = 254.3 [M+ H]⁺.

To a solution of the product in THF (lOOmL), under argon, was added triethylamine (5.5mL, 39mmol) and the mixture was cooled to 0°C. Di-tert-butyl dicarbonate (5.2g, 24mmol) was added, then the reaction was allowed to reach r.t. and stirred for 16 h. The solvent was removed in vacuo, and the resulting residue was re-dissolved in EtOAc, washed with brine, dried (Na₂S0₄), and the solvent removed in vacuo. The product was triturated several times with heptane to afford the title compound. LCMS Method 3: RT = 2.35 min; mlz (ES⁺) = 354.3 [M+ H]

Preparation 136: ((frans)-4-Pyridin-2- lpyrrolidin-3-yl)carbamic acid tert-buty\ ester

A solution of ((tra/75)-l-benzyl-4-pyridin-2-ylpyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 135, 500mg, 1.42mmol) in MeOH (28mL) was passed through an H- Cube apparatus (10% pd/C Catcart 30, 30bar, 90°C) at a flow rate of ImL per min. Removal of the solvent in vacuo and purification by column chromatography (DCM:MeOH, 90: 10) afforded the title compound: RT = 1.84 min; mlz (ES⁺) = 264.1 [M+ H]⁺.

Preparation 137: 4-Methanesulf nyloxymethylpiperidine-l-carboxylic acid benzyl ester

To a solution of 4-hydroxymethylpiperidine-l-carboxylic acid benzyl ester (16.2g, 65mmol) and methanesulfonyl chloride (8.2g, 71mmol) in DCM (80ml), cooled to 4°C, was added a solution of triethylamine (7.6g, 75mmol) in DCM (20ml), drop-wise, over 1 h. The resulting reaction was stirred for 30 min. The mixture was washed with water (x 2), dried (MgS0₄) and the solvent removed in vacuo to afford the title compound: 1H NMR 5H

(400MHz, CDCls): 7.43 - 7.32 (m, 5H), 5.16 (s, 2H), 4.28 (Br. s, 2H), 4.10 (m, 2H), 3.05 (s, 3H), 2.84 (t, 2H), 2.04 - 1.92 (m, 1H), 1.80 (m, 2H), 1.34 - 1.21 (m, 2H).

Preparation 138: 4-(2-Chloropyrimidin-5-yloxymethyl)piperidine-l-carboxylic acid benzyl ester

A combination of 4-methanesulfonyloxymethylpiperidine-l-carboxylic acid benzyl ester (Preparation 137, 20.2g, 61mmol), 2-chloropyrimidin-5-ol (containing 30% 2- bromopyrimidin-5-ol, 10.5g, 73mmol) and potassium carbonate (11.8g, 85mmol) in DMF (200mL) was heated to 80°C for 16 h. The reaction was cooled, diluted with water (500mL), and EtOAc (300mL) was added. Further water (lOOmL) and Brine (500mL) were added, and the organic phase was separated. The aqueous phase was extracted with EtOAc (x 3). All organic fractions were combined, washed with 1M NaOH solution (500mL), then brine (500mL), and dried (MgS0₄). Removal of the solvent in vacuo afforded a crude residue. The remaining aqueous phase was again extracted with EtOAc (x 2). The organic fractions were washed with 1M NaOH solution (250mL), then brine (250mL), and dried (MgS0₄).

Removal of the solvent in vacuo afforded a further amount of the crude residue. The two fractions of crude material were combined and purified by column chromatography

(DCM:EtOAc, 90: 10) to afford the title compound as a mixture of 4-(2-chloropyrimidin-5- yloxymethyl)piperidine-l-carboxylic acid benzyl ester and 4-(2-bromopyrimidin-5- yloxymethyl)piperidine-l-carboxylic acid benzyl ester (64:36): 1H NMR δπ (400MHz, CDC1₃): 8.30 (s, 1.4H), 8.26 (s, 0.6H), 7.41 - 7.31 (m, 5H), 5.17 (s, 2H), 4.28 (Br. s, 2H), 3.93 (d, J= 6.2Hz, 2H), 2.86 (m, 2H), 2.10 - 1.99 (m, 1H), 1.87 (d, J= 12.8Hz, 2H), 1.35 (m, 2H). Preparation 139: 4-{2-[(3R,4S)-3-tert-Butoxycarbonylamino-4-(2,5- difluorophenyl)pyrrolidin-l-yl]pyrimidin-5-yloxymethyl}piperidine-l-carboxylic acid benzyl ester

To a solution of 4-(2-chloropyrimidin-5-yloxymethyl)piperidine-l-carboxylic acid benzyl ester (containing 36% 4-(2-bromopyrimidin-5-yloxymethyl)piperidine-l-carboxylic acid benzyl ester, Preparation 138, 13.22g, 35mmol) and [(3i?,45)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 5.45g, 18.3mmol) in DMSO (150mL) was added DBU (3.60mL, 24.4mmol) and the reaction was heated to 100°C for 16 h. A second portion of [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3- yljcarbamic acid tert-butyl ester (Preparation 48, 0.55g, 1.8 mmol) was added and heating continued for 4 hours. A third portion of [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3- yljcarbamic acid tert-butyl ester (Preparation 48, 4.00g, 13.4mmol) was added, along with DBU (1.57mL, 1 lmmol), and the reaction continued for 16 h. On cooling, the mixture was diluted with water (600mL) and extracted with a mixture of EtOAc and Et₂0 (95:5, x 4). The combined organic fractions were washed with brine, and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (DCM:EtOAc, 80:20) afforded the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 8.13 (s, 2H), 7.41 - 7.31 (m, 5H), 7.02 - 7.21 (m, 2H), 7.0 - 6.93 (m, 1H), 4.71 (Br. s, 1H), 5.17 (s, 2H), 4.47 (Br.s, 1H), 4.28 (Br. s, 2H), 4.22 - 4.07 (m, 2H), 3.83 (d, J= 6.2Hz, 2H), 3.70 - 3.60 (m, 2H), 3.41 (m, 1H) 2.86 (m, 2H), 2.06 - 1.95 (m, 1H), 1.86 (d, J= 14Hz, 2H), 1.43 (s, 9H), 1.33 (m, 2H).

Preparation 140: {(3R,45)-4-(2,5-Difluorophenyl)-l-[5-(piperidin-4- ylmethoxy)pyrimidin-2-yl]p rrolidin-3-yl}carbamic acid terf-butyl ester

To a solution of 4-{2-[(3i?,45)-3-tert-butoxycarbonylamino-4-(2,5- difluorophenyl)pyrrolidin- 1 -yl]pyrimidin-5 -yloxymethyl} piperidine- 1 -carboxylic acid benzyl ester (Preparation 139, 13.7g, 22mmol) in ethanol (230mL) was added palladium carbon (10% wt., 4.1 g, 50% water) and the reaction was stirred under an atmosphere of hydrogen for 1 h. The mixture was filtered and the solvent removed in vacuo to afford the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 8.14 (s, 2H), 7.12 - 7.01 (m, 2H), 7.0 - 6.93 (m, 1H), 4.72 (Br. s, 1H), 4.47 (Br.s, 1H), 4.22 - 4.07 (m, 2H), 3.80 (d, J= 6.5Hz, 2H), 3.69 - 3.60 (m, 2H), 3.42 (m, 1H) 3.17 (m, 2H), 2.68 (m, 2H), 2.00 - 1.75 (m, 4H), 1.43 (s, 9H), 1.33 (m, 2H). Preparation 141: [(3R,4S)-l-[5-(l-Cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5- difluorophenyl)pyrrolidin-3- l]carbamic acid tert-butyl ester

{(3i?,45)-4-(2,5-Difluorophenyl)-l-[5-(piperidin-4-ylmethoxy)pyrimidin-2- yl]pyrrolidin-3-yl}carbamic acid tert-butyl ester (Preparation 140, 10.4g, 21.3mmol) and NaHC0₃ (5.37 g, 63.8mmol) were added to a combination of water (30mL) and DCM (30mL) and the mixture was cooled to 0°C. To the slurry that formed were added further volumes of water (20mL) and DCM (20mL). A solution of Cyanogen bromide (2.5g, 23.6mmol) in DCM (30mL) was added drop-wise, over 15 minutes, whilst maintaining the temperature below 5°C, then the reaction was stirred for 1 h at 0°C before being allowed to continue at r.t. for 16 h. The mixture was separated and the aqueous layer extracted with DCM (x 2). The organic fractions were combined, washed with sat. NaHC0₃ solution, then brine, and dried (MgS0₄). Removal of the solvent in vacuo and purification by column chromatography (DCM:MeOH, 95:5) afforded the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 8.13 (s, 2H), 7.10 - 7.02 (m, 2H), 7.0 - 6.93 (m, 1H), 4.71 (Br. S, 1H), 4.47 (Br.s, 1H), 4.22 - 4.07 (m, 2H), 3.83 (d, J= 6.1Hz, 2H), 3.69 - 3.60 (m, 2H), 3.53 (m, 2H), 3.42 (m, 1H) 3.10 (m, 2H), 2.0 - 1.85 (m, 3H), 1.55 (m, 2H), 1.43 (s, 9H).

Preparation 142: ((3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(2H-tetrazol-5-yl)piperidin-4- ylmethoxy]pyrimidin-2- l}pyrrolidin-3-yl)carbamic acid tert-butyl ester

To a solution of [(3 ?,45)-l-[5-(l-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4- (2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141, 300mg, 0.60mmol) in DMF (5mL), under argon, was added ammonium chloride (47mg, 0.87mmol), portion-wise. Sodium azide (57mg, 0.87mmol) was then added, portion-wise, and the reaction was allowed to stir at r.t. for 20min, before being heated to 100°C for 16 h. On cooling, the mixture was diluted with a combination of water and brine, and extracted into EtOAc (x 2). The combined organic fractions were washed with brine, dried (MgS0₄), and the solvent removed in vacuo. Trituration with DCM afforded the title compound: RT = 3.62 min; mlz (ES⁺) = 558.3 [M+ H]⁺.

Preparation 143: ((3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(2-isopropyl-2H-tetrazol-5- yl)piperidin-4-ylmethox ]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester

To a solution of ((3i?,45)-4-(2,5-difluorophenyl)-l-{5-[l-(2H-tetrazol-5-yl)piperidin- 4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 142, 196mg, 0.35mmol) and acetone (2.5mL) in DMF (0.5mL), under argon, was added K₂CO₃ (146mg, 1.05mmol), followed by isopropyl iodide (70uL, 0.70mmol). The reaction was heated to 50°C for 3.5 h, and then concentrated in vacuo. To the crude residue was added a combination of water and brine, and the mixture was extracted with EtOAc (x 2). The combined organic layers were washed with brine, dried (MgS04), and the solvent removed in vacuo. Purification by preparative HPLC (basic method) afforded the title compound: RT = 4.53 min; mlz (ES⁺) = 600.4 [M+ H]⁺.

Preparation 144: ((3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(5-isopropyl-[l,3,4]oxadiazol- 2-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester

To a solution of {(3i?,45)-4-(2,5-difluorophenyl)-l-[5-(piperidin-4- ylmethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid tert-butyl ester (Preparation 140, 70mg, O.lOmmol) in DMF (4mL) was added 5-isopropyl-3H-[l,3,4]oxadiazol-2-one (27mg, 0.21mmol), followed by BOP (95mg, 0.21mmol) and DIPEA (50μΙ, 0.28mmol), and the reaction was allowed to stir at r.t. for 16 h. The mixture was diluted with water and extracted into EtOAc (x 2). The combined organic fractions were passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The resulting residue was passed down an SCX(POH) cartridge, eluting with MeOH then NH₄OH in MeOH. Both fractions were collected and concentrated in vacuo. Further purification by preparative HPLC afforded the title compound: RT = 4.09 min; m/z (ES⁺) = 600.3 [M+ H]⁺.

Preparation 145: ((3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(N- hydroxycarbamimidoyl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3- yl)carbamic acid tert-but \ ester

A solution of [(3 ?,45)-l-[5-(l-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141, 4.0g, 7.8mmol), dissolved in EtOH (40 ml), was warmed to 50°C and further EtOH (35ml) was added until a solution was obtained. The solution was allowed to cool to 40°C and hydroxylamine (50% in water, 0.5mL, 7.8mmol) in EtOH (5ml) was added drop-wise, over 10 min. The reaction was stirred at this temperature for 16 h, after which time a white precipitate had formed. The mixture was filtered, and the resulting solid was triturated with EtOAc (x 2) to afford the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 8.13 (s, 2H), 7.10 - 7.02 (m, 2H), 7.0 - 6.93 (m, 1H), 4.80 (br. s, 1H), 4.64 (br. s, 1H), 4.47 (br. s, 1H), 4.22 - 4.07 (m, 2H,), 3.80 (m, 2H), 3.74 - 3.67 (m, 2H),3.67 - 3.59 (m, 2H), 3.42 (m, 1H), 2.79 - 2.69 (m, 2H), 2.00 - 1.80 (m, 3H), 1.48 - 1.34 (m, 11H).

Preparation 146: 3-Methoxy-2-methyl ropionic acid

To a solution of 3-methoxy-2-methylpropionic acid methyl ester (3.0g, 20mmol) in EtOH (30mL) was added a solution of NaOH (1.4g, 34mmol) in water (30mL) and the reaction was heated to 60°C for 2 h. On cooling, the EtOH was removed in vacuo, and the residue was partitioned between EtOAc and water. The mixture was acidified with 1M HC1 solution, extracted with EtOAc, and the organic layer dried (MgS0₄). Removal of the solvent in vacuo afforded the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 3.64-3.59 (m, 1H), 3.52-3.48 (m., 1H), 3.40 (s, 3H), 2.85-2.75 (m, 1H), 1.22 (d, J=7.01 Hz, 3H)

Preparation 147: [(3R,45)-l-(5-{l-[5-(l,l-Difluoroethyl)-[l,2,4]oxadiazol-3-yl]piperidin- 4-ylmethoxy}pyrimidin-2-yl)-4-(2,5-difluorophenyl)pyrrolidin-3-yl] carbamic acid tert- butyl ester

To a solution of ((3i?,45)-4-(2,5-difiuorophenyl)-l-{5-[l-(N- hydroxycarbamimidoyl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 145, 50mg, 0.09mmol) in DMF (3mL) was added 2,2- difluoropropionic acid (18mg, 0.16mmol), followed by HOBt (28mg, 0.18mmol), and finally EDCI (35mg, 0.18mmol), and the reaction was allowed to stir at r.t. for 90 min. The solvent was removed in vacuo and the resulting residue was purified by preparative HPLC (basic method) to afford the title compound: RT = 4.64 min; mlz (ES⁺) = 622.3 [M+ H]⁺.

Preparation 148: (S)-N-Hydroxy-2-methoxypropionamidine

To a solution of (5)-2-methoxypropionitrile (910mg, 10.69mmol) in IMS (lOmL) was added hydroxylamine (50% in water, 1.55mL, 23.52mmol) and the reaction was heated to 80°C for 16 h. On cooling, the solvent was removed in vacuo and the product recrystallised from heptane: EtOAc (1 :1). The mother liquor was concentrated in vacuo and crystallised for a second time. Both crops of material were combined and dried under vacuum to afford the title compound. LCMS method 2: RT = 0.33 min; mlz (ES⁺) = 119.0 [M+ H]⁺. Preparation 149: 2,2-Difluoro-N-hydrox ropionamidine

To a solution of 2,2-difluoropropionitrile (lOOOmg, 10.98mmol) in IMS (30mL) was added hydroxylamine (50% in water, 792μΕ, 13.18mmol) and the reaction was heated to 90°C for 16 h. On cooling, the solvent was removed in vacuo, azeotroping with toluene. The residue was purified by column chromatography (heptane :EtO Ac, 4:1) to afford the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 4.78 (br. s, 1H), 1.90 - 1.73 (m, 3H).

Preparation 150: ((3R,45)-4-(2,5-Difluor ophenyl)- 1-{5- [l-(5-ethyl- [ 1 ,2,4] oxadiazol-3- yl)piperidin-4-ylmethox ]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid terf-butyl ester

To a combination of methoxyacetic acid (lOmgg, 0.2mmol) and ((3i?,45)-4-(2,5- difluorophenyl)- 1 - {5 -[ 1 -(N-hydroxycarbamimidoyl)piperidin-4-ylmethoxy]pyrimidin-2- yl}pyrrolidin-3-yl)carbamic acid fert-butyl ester (Preparation 145, 50mg, O. lmmol) in DMF (3mL, 40) was added HOBt (28mg, 0.18mmol), followed by EDCI (35mg, 0.18mmol), and the reaction was stired at r.t. for 180 min, before being heated to 70°C for 90min. On cooling, the solvent was removed in vacuo. The resulting residue was purified by preparative HPLC (basic method) and fractions containing product were concentrated in vacuo to afford the title compound: RT = 4.47 min; mlz (ES⁺) = 586.2 [M+ H]⁺.

The following compounds were prepared by reacting ((3i?,45)-4-(2,5- difluorophenyl)- 1 - {5 -[ 1 -(N-hydroxycarbamimidoyl)piperidin-4-ylmethoxy]pyrimidin-2- yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 145) with the appropriate acid building block, employing the procedure outlined in Preparation 150: Prep

Structure Name LCMS No.

[(3R,4S)- 1 - {5-[l -(5-Difluoromethyl- [l,2,4]oxadiazol-3-yl)piperidin-4- RT = 4.52 min; mlz

151 ylmethoxy]pyrimidin-2-yl}-4-(2,5- (ES⁺) = 608.2 [M + difluorophenyl)pyrrolidin-3-yl]carbamic acid tert- H]⁺.

butyl ester

[(3R,4S)-4-(2,5-Difluorophenyl)-l-(5-{l-[5-(l- RT = 4.77 min; mlz methylcyclopropyl)-[l,2,4]oxadiazol-3- (ES⁺) = 612.3 [M +

152

yl]piperidin-4-ylmethoxy}pyrimidin-2- H]⁺.

yl)pyrrolidin-3-yl]carbamic acid fert-butyl ester

((3R,4S)-4-(2,5-Difluorophenyl)-l-{5-[l-(5- RT = 4.43 min; mlz ethoxymethyl-[ 1 ,2,4]oxadiazol-3-yl)piperidin-4- (ES⁺) = 616.3 [M +

153

ylmethoxy]pyrimidin-2-yl} pyrrolidin-3 - H]⁺.

yl)carbamic acid fert-butyl ester

Prep

Structure Name LCMS No.

[(3R,4S)-4-(2,5-Difluorophenyl)-l-(5-{l-[5-(3- RT = 4.32 min; mlz methylisoxazol-5-ylmethyl)-[ 1 ,2,4]oxadiazol-3- (ES⁺) = 653.3 [M +

157

yl]piperidin-4-ylmethoxy}pyrimidin-2- H]⁺.

yl)pyrrolidin-3-yl]carbamic acid fert-butyl ester

Preparation 158: 2-Chloro-5- [ l-(3-isopropyl- [1 ,2,4] oxadiazol-5-yl)piperidin-4- yloxy] pyrimidine

To a solution of l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-ol (Preparation 83, 422mg, 2.0mmol) in DCM was added triethylamine (324μΙ_^, 2.4mmol) and the mixture was cooled to 0°C. Methanesulfonyl chloride (171 μί, 2.2mmol) was added, and the reaction was allowed to reach r.t. over 15 min, before being stirred for a further 15 min. The mixture was partitioned between DCM and 1M HC1 solution, and dried using a phase separator. Removal of the solvent in vacuo afforded the intermediate product methanesulfonic acid l-(3- isopropyl-[l ,2,4]oxadiazol-5-yl)piperidin-4-yl ester.

To a combination of the intermediate and 2-chloropyrimidin-5-ol (containing 40% 2- bromopyrimidin-5-ol, 358mg, 2.4mmol) in DMF (20mL) was added K₂CO₃ (828mg, 6.0mmol) and the reaction was heated to reflux for 16 h. The solvent was removed in vacuo, then the resulting residue was taken into MeOH and filtered. The filtrate was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. Further purification by column chromatography

(IH:EtOAc, 1 :1) afforded the title compound (contains 40% 2-bromo-5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yloxy]pyrimidine): RT = 3.20 min; m/z (ES⁺) = 324.1 [M +

H]⁺.

Preparation 159: ((3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(5-dimethylaminomethyl- [l,2,4]oxadiazol-3-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-buty\ ester

To a combination of dimethylaminoacetic acid (17mg, 0.16mmol) and ((3R,4S)-4- (2,5-difluorophenyl)- 1 - {5 -[ 1 -(N-hydroxycarbamimidoyl)piperidin-4-ylmethoxy]pyrimidin- 2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 145, 50mg, 0.09mmol) in DMF (3mL) was added HOBt (28mg, 0.18mmol), followed by EDCI (35mg, 0.18mmol), and the reaction was allowed to stir at r.t. for 16 h, before being heated to 70°C for 90min. On cooling, the solvent was removed in vacuo. The resulting residue was purified by preparative HPLC (basic method) and fractions containing product were concentrated in vacuo to afford the title compound: RT = 2.93 min; mlz (ES ) = 615.2 [M+ H]⁺.

The following compounds were prepared by reacting ((3i?,45)-4-(2,5- difluorophenyl)- 1 - {5 -[ 1 -(N-hydroxycarbamimidoyl)piperidin-4-ylmethoxy]pyrimidin-2- yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 145) with the appropriate carboxylic acid building block, employing the procedure outlined in Preparation 159:

Preparation 167: N-Hydroxy-2-methox acetamidine

To a solution of methoxyacetonitrile (5.3mL, 70.42mmol) in EtOH (lOmL) was added a solution of hydroxylamine (50% in water, 4.6mL, 70.42mmol) and the reaction was heated to reflux for 16 h. The solvent was removed in vacuo, azeotroping with toluene, to afford the title compound: 1H NMR δ_Η (400MHz , CDC1₃): 5.29 (s, 1H), 4.87 (br. s., 2H), 3.92 (s, 2H), 3.33 (s, 3H).

Preparation 168: N-Hydroxytetrahydr furan-3-carboxamidine

To a solution of tetrahydrofuran-3-carbonitrile (lOOOmg, 10.3mmol) in IMS (7mL) was added hydroxylamine (50% in water, 750μί, 11.3mmol) and the reaction was heated to reflux for 16 h. On cooling, the solvent was removed in vacuo, azeotroping with toluene. The residue was purified by column chromatography (DCM:MeOH, 100:0, 95:5) to afford the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 7.90 (br. s, 1H), 4.60 (br. s, 2H), 4.10 - 3.85 (m, 2H), 3.80 - 3.60 (m, 2H), 3.03 - 2.82 (m, 1H), 2.30 - 1.90 (m, 2H).

Preparation 169: 2,2-Difluoro-N-hydrox acetamidine

To a solution of difluoroacetonitrile (2.21g, 28.7mmol) in EtOH (5mL) was added a solution of hydroxylamine (50% in water, 2.08mL, 31.6mmol) and the reaction was heated in a sealed tube for 16 h. On cooling, the solvent was removed in vacuo, azeotroping with toluene (x 3). The resulting residue was partitioned between DCM and water, and the organic phase separated. The aqueous phase was extracted with EtOAc (x 2), then organic fractions were combined, dried (Na₂S0₄), and the solvent removed in vacuo to afford the title compound: RT = 0.32 min; mlz (ES ) = 111.0 [M+ H] . Preparation 170: N-Hydroxy-l-methylcyclopropanecarboxamidine

To a solution of 1-methylcyclopropanecarboxylic acid amide (1.50g, 15.13mmol) in THF (225mL), cooled to 0°C, was added pyridine (2.5mL, 30.26mmol) and the reaction was stirred at this temperature for 1 h. TFAA (10.5mL, 75.66mmol) was then added to the mixture, in one portion, and the reaction continued to stir at 0°C for 15 min. Sat. NaHC0₃ solution was added, until pH 8 was reached, and then the mixture was diluted with DCM. The organic phase was separated, and the aqueous phase was extracted with DCM (x 2). Organic fractions were combined, dried (Na₂S0₄) and the solvent removed in vacuo to afford the intermediate product 1-methylcyclopropanecarbonitrile.

To a solution of the product in IMS (150mL) was added a solution of hydroxylamine (50% in water, 0.9mL, 13.7mmol) and the reaction was heated to 90°C for 16 h. On cooling, the solvent was removed in vacuo, and purification by column chromatography

(Heptane:EtOAc, 40:60, 20:80) afforded the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 6.68 (br. s, 1H), 4.57 (br. s, 2H), 1.29 (s, 3H), 0.96 - 0.90 (m, 2H), 0.59 - 0.51 (m, 2H).

Preparation 171: 2-Fluoro-N-hydroxy-2-methylpropionamidine

To a solution of 2-hydroxy-2-methylpropionitrile (2.00g, 23.5mmol) in DCM

(240mL), cooled to -78°C, was added DAST (4.65mL, 35.3mmol), drop-wise, over 3 min.

The reaction was allowed to warm to r.t. before stirring for a further 16 h. Water and sat.

NaHC0₃ solution were added, and the organic phase was separated and washed with sat.

NaHC0₃ solution . The aqueous fractions were combined and extracted further with DCM, then all the combined organic fractions were dried (Na₂S0₄) and the solvent removed in vacuo to afford the intermediate product 2-fluoro-2-methylpropionitrile: 1H NMR 5H

(300MHz, CDC1₃): 1.80 (s, 3H), 1.73 (s, 3H).

To a solution of the product in IMS (50mL) was added hydroxylamine (50% in water, 1.41mL, 23.30mmol) and the reaction was heated to 85°C for 16 h. On cooling, the solvent was removed in vacuo, azeotroping with toluene (x 2). Purification by column chromatography (heptane:EtOAc, 1 :1), followed by trituration with heptane, afforded the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 4.78 (br. s, 2H), 1.58 (d, J= 22.5Hz, 6H).

Preparation 172: 2-Ethoxyacetamide

To a solution of ethoxyacetic acid (2.07g, 19.85mmol) in DCM (20mL), cooled to 0°C, was added oxalyl chloride (2.02mL, 23.82mmol), followed by DMF (2 drops), and the reaction was stirred at this temperature for 1 h, before continuing to stir at r.t. for 2 h. The mixture was cooled down to 0°C and a solution of ammonia in MeOH (17%, 50mL) was cautiously added, after which the reaction was stirred at r.t for 16 h. The solvent was removed in vacuo and DCM was added. The mixture was filtered, washing with DCM, and the resulting filtrate was concentrated in vacuo to afford the title compound: 1H NMR 5H (300MHz, CDC1₃): 6.55 (br. s, 1H), 5.66 (br. s, 1H), 3.93 (s, 2H), 3.61 - 3.50 (m, 2H), 1.27 1.20 (m, 3H).

Preparation 173: 2-Ethoxy-N-hydroxyacetamidine

To a solution of 2-ethoxyacetamide (Preparation 172, 1.84g, 17.84mmol) in THF (290mL), cooled to 0°C, was added pyridine (3.0mL, 37.09mmol), followed by TFAA (12.90mL, 92.73mmol), and the reaction was stirred at 0°C for 15 min. Sat. NaHC0₃ solution was added, until pH 8 was reached, and then the mixture was extracted with DCM (x 2). The organic fractions were combined, washed with 1M HC1 solution, then dried (Na₂S0₄), and the solvent removed in vacuo to afford the intermediate product 1- methylcyclopropanecarbonitrile.

To a solution of the product in IMS (170mL) was added a solution of hydroxylamine (50% in water, 1.08mL, 17.98mmol) and the reaction was heated to 90°C for 16 h. On cooling, the solvent was removed in vacuo, and purification by column chromatography (Heptane:EtOAc, 20:80, 0: 100) afforded the title compound: 1H NMR δ_Η (300MHz, CDC1₃) 5.89 (s, 1H), 4.98 (br. s, 2H), 4.02 (s, 2H), 3.57 - 3.48 (m, 2H), 1.26 - 1.19 (m, 3H). Preparation 174: (R)-N-Hydroxytetrahydrofuran-2-carboxamidine

The title compound was prepared from (i?)-tetrahydrofuran-2-carbonitrile employing the procedure outlined in Preparation 168. Purification by column chromatography

(Heptane:EtOAc, 50:50, 0: 100) afforded the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 4.44 - 4.32 (m, 1H), 4.00 - 3.74 (m, 2H), 2.20 - 1.80 (m, 4H).

Preparation 175 : [(3R,4S)- l-(5-Br omo-3-cyanopyridin-2-yl)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]car amic acid tert-buty\ ester

To a solution of 5-bromo-2-hydroxynicotinonitrile (300mg, 2.00mmol) in MeCN (2mL) was added DBU (338μΙ., 2.26mmol), followed by BOP (lOOOmg, 2.26mmol), in one portion, and the reaction was stirred at r.t. for 18 h. The reaction mixture was partitioned between DCM and brine and the layers were separated. The aqueous phase was extracted with DCM (x 2) then the combined organic fractions were passed through a phase separator and concentrated in vacuo. Purification by column chromatography (IH:EtOAc, 100:0 - 90:10) afforded the title compound: RT = 4.49 min; m/z (ES⁺) = 479.1, 481.1 [M+ H]⁺.

Preparation 176 : [(3R,45)- 1- [3-Cyano-5-(4,4,5,5-tetramethyl- [ 1 ,3,2] dioxaborolan-2- yl)pyridin-2-yl]-4-(2,5-difluoro henyl)pyrrolidin-3-yl]carbamic acid tert-buty\ ester

To a combination of [ 1 , Γ- bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1 : 1) (15.2mg, 0.02mmol), [(3i?,45)-l-(5-bromo-3-cyanopyridin-2-yl)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 175, 299. Omg, 0.62mmol), bis(pinacolato)diboron (174.2mg, 0.69mmol), and KOAc (183.7mg, 1.87mmol), under argon, was added 1,4-dioxane (30mL) and the reaction was heated to 80°C for 16 h. The solvent was removed in vacuo and the resulting residue was partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic fractions were washed with brine, dried (MgS0₄), and the solvent removed in vacuo to afford the title compound: RT = 4.77 min; mlz (ES⁺) = 527.2 [M+ H] .

Preparation 177: 5-Bromo-2-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy] nicotinonitrile

To a solution of [(l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation 1, 272mg, 1.20mmol) in anhydrous THF (5mL), under argon, was added 5- bromo-2-hydroxynicotinonitrile (200mg, l .Olmmol), followed by triphenylphosphine (477mg, 1.82mmol). The resulting suspension was cooled to 0°C for 20 min and then TBAD (419mg, 1.82mmol) was added, portion- wise. After addition, the reaction was stirred for 20 min at 0°C and then allowed to warm to r.t. and stirred for a further 16 h. Removal of the solvent in vacuo and purification by column chromatography (IH:EtOAc, 90: 10) afforded the title compound: RT = 4.18 min; mlz (ES⁺) = 406.1, 408.0 [M+ H]⁺.

Preparation 178: (4-Hydroxymethyl-piperidin-l-yl)-(3-isopropyl

[l,2,4]oxadiazol-5-yl)-methanone

To a solution of 3-isopropyl-5-trichloromethyl-[l,2,4]oxadiazole (500mg, 2.0mmol) in IPA (lOmL) was added piperidin-4-yl-methanol (380mg, 3.3mmol) and the resulting reaction mixture was heated at 50°C for 16 h, followed by heating at 90°C for 5 h. Water (0.5mL) was added and heating at 90°C was continued for 16 h. The reaction mixture was purified by preparative HPLC to afford the title compound: RT = 2.65; mlz (ES⁺) = 254.11 [M+ H]⁺. Preparation 179: [(3R,4S)-l-{5-[l-(3-Isopropyl-[l,2,4]oxadiazole-5-carbonyl)-piperidin- 4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid terf-butyl ester

To a solution of (4-hydroxyrnethyl-piperidin-l-yl)-(3-isopropyl-[l,2,4]oxadiazol-5- yl)-methanone (Preparation 178, 36mg, 0.14mmol) in DCM (lmL) was added

triethylamine (40μί, 0.30mmol) and methanesulfonyl chloride (20uL, 0.20mmol) and the resulting reaction mixture was stirred at r.t. for 2 h before washing with 2M aqueous HCl and concentrating in vacuo to afford methanesulfonic acid l-(3-isopropyl-[l,2,4]oxadiazole-5- carbonyl)-piperidin-4-ylmethyl ester. A solution of [(3i?,4S)-4-(2,4,5-trifluorophenyl)-l-(5- hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid fert-butyl ester (Preparation 88, 50mg, 0.12mmol) in DMF (lmL) and potassium carbonate (50mg, 0.40mmol)_was added and the resulting reaction mixture stirred at 80°C for 16 h. The reaction mixture was cooled to r.t. and partitioned between DCM and water. The organics were separated, concentrated in vacuo and purified by preparative HPLC to afford the title compound: RT = 4.50 min; mlz

Preparation 180: [(3R,45)-l-{5-[l-(3-Methyl-butyryl)-piperidin-4-ylmethoxy]- pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

To a solution of l-(4-hydroxymethyl-piperidin-l-yl)-3-methyl-butan-l-one (28mg, 0.14mmol) in DCM (lmL) was added triethylamine (40uL, 0.3mmol) and methanesulfonyl chloride (20uL, 0.2mmol) and the resulting reaction mixture was shaken at r.t. for 2 h. The reaction mixture was washed with 1M aqueous HCl and the organics concentrated in vacuo to afford methanesulfonic acid l-(3-methyl-butyryl)-piperidin-4-ylmethyl ester. A solution of [(3i?,45)-4-(2,4,5-trifluorophenyl)-l-(5-hydroxypyrimidin-2-yl)pyrroli acid tert-butyl ester (Preparation 88, 50mg, 0.12mmol) in DMF (lmL) and potassium carbonate (50mg, 0.40mmol)_was added and the resulting reaction mixture stirred at 80°C for 16 h. The reaction mixture was cooled to r.t. and partitioned between DCM and water. The organics were separated, concentrated in vacuo and purified by preparative HPLC to afford the title compound: RT = 4.27 min; mlz (ES⁺) = 592.35 [M+ H]⁺.

Preparation 181: 4-((R)-l-Hydroxy-ethyl)-piperidine-l-carboxylic acid benzyl ester

To a solution of (i?)-l-piperidin-4-yl-ethanol acetate (35g, 185mmol) in DCM (300mL) was added sodium carbonate (58.8g, 555mmol) and water (280mL), followed by the dropwise addition of benzylchloro formate (25.1mL, 176mmol) and the resulting reaction mixture was stirred at r.t. for 16 h . The aqueous was separated and extracted with DCM (2 x) and the combined organics were dried (MgS0₄), filtered and concentrated in vacuo.

Purification by column chromatography (EtO Ac :Heptane, 3: 1 to 1 :0) afforded the title compound: RT = 0.70 min; mlz (ES⁺) = 264.1 [M+ H]⁺ (LCMS -method 2).

Preparation 182: 4-((R)-l-Methanesulfonyloxy-ethyl)-piperidine-l-carboxylic acid benzyl ester

To a solution of 4-((i?)-l-hydroxy-ethyl)-piperidine-l-carboxylic acid benzyl ester

(Preparation 181, 21.3g, 80.7mmol) in DCM (250mL) at 0°C was added triethylamine

(17.9mL, 129mmol) and the resulting reaction mixture stirred at 0°C for 0.5 h. Methane sulfonyl chloride (8.09mL, 105mmol) was added and the resulting reaction mixture was stirred at 0°C for 2 h then at r.t. for 2 h prior to the addition of water (300mL) and DCM

(lOOmL). The layers were separated and the aqueous extracted with DCM (2 x 350mL). The combined organics were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc:Heptane, 2: 1) afforded the title compound: RT = 2.68 min; mlz (ES⁺) = 342.1 [M+ H]⁺ (LCMS -method 4). Preparation 183: 4-[(S)-l-(2-Chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-l-carboxylic acid benzyl ester

To a solution of 4-((i?)-l-methanesulfonyloxy-ethyl)-piperidine-l-carboxylic acid benzyl ester (Preparation 182, 27.6g, 80.8mmol) in DMA (800mL) was added 2-chloro- pyrimidin-5-ol (10.9g, 130mmol) and cesium fluoride (12.7g, 83.4mmol) and the resulting reaction mixture stirred at 60°C for 96 h. Further cesium fluoride (7.50g, 49.7mmol) was added and stirring at 60°C continued for 72 h. Upon cooling, the reaction mixture was poured into water (1500mL) and diluted with EtOAc (lOOOmL) and brine (500mL). The layers were separated and the aqueous extracted with EtOAc (2 x 750mL). The combined organics were washed with watenbrine (1 : 1 , 4 x 500mL), dried (Na₂S0₄), filtered and concentrated in vacuo. Purification by column chromotograpy (DCM:MeOH, 99: 1 to 97.5:2.5) followed by further purification by column chromotograpy (Heptane:EtOAc, 3: 1 to 2:1) afforded the title compound: RT = 0.87 min; mlz (ES⁺) = 376.1 [M+ H]⁺ (LCMS - method 2).

Preparation 184: 4-(l-{(S)-2-[(3R,4S)-3-tei-i-Butoxycarbonylamino-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-l-carboxylic acid benzyl ester

To a solution of [(tra/75)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert- butyl ester (Preparation 38, 6.4 lg, 20.3mmol) in anhydrous DMSO (50mL) under argon was added 4-[(5)-l-(2-chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-l-carboxylic acid benzyl ester (Preparation 183, 6.00g, 16.0mmol) followed by DBU (2.5 lmL, 16.8mmol) and the resulting solution was stirred at 90°C for 49 h, followed by stirring at 100°C for 16 h.

Additional [(tra/75)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert- vXy\ ester (Preparation 38, 864g, 2.70mmol) was added and the resulting solution was heated at 120°C for 8 h. Further [(tra/75)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert- - I l l - butyl ester (Preparation 38, 2.0g, 6.32mmol) was added and the resulting solution was heated at 110°C for 16 h and at 140°C for 20h. The reaction mixture was poured into water (250mL) and extracted with EtOAc (2 x lOOmL). The combined organic extracts were washed with brine (2 x 50mL), dried (MgS0₄), filtered and concentrated in vacuo.

Purification by column chromatography (IH:EtOAc, 2: 1) afforded the title compound:

RT = 1.53 min; mlz (ES⁺) = 656.00 [M+ H]⁺ (LCMS -method 6).

Preparation 185: [(3R,4S)-l-[5-((S)-l-Piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5- trifluoro-phenyl)-pyrrolidin-3- l]-carbamic acid tert-butyl ester

To a solution of 4-(l-{(5)-2-[(3i?,45)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-l-carboxylic acid benzyl ester (Preparation 184, 7.44g, 11.3mmol) in EtOH (210mL) was added a slurry of 10% Pd/C (2.1 lg, 58.6mmol) in EtOH (20mL) and the resulting mixture stirred under an atmosphere of hydrogen at r.t. for 3h and at 50°C for 2 h. Upon cooling, the reaction mixture was filtered through Celite and the residue washed with methanol. The filtrate was concentrated in vacuo to afford the title compound: RT = 0.86 min; mlz (ES⁺) = 522.50 [M+ H]⁺ (LCMS -method

6).

Preparation 186: [(3R,45)-l-(5-{(S)-l-[l-(Butane-l-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl] -carbamic acid tert-butyl ester

To a solution of [(3i?,45)-l-[5-((5)-l-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5- trifluoro-phenyl)-pyrrolidin-3-yl] -carbamic acid tert-butyl ester (Preparation 185, 75mg, 0.14mmol) in DCM (5mL) was added triethylamine (30 μΐ_^, 0.22 mmol) and n- butanesulfonyl chloride (27mg, 0.17 mmol) and the resulting reaction mixture stirred at r.t. for 16 h overnight. The reaction mixture was partioned between DCM (lOmL) and water (lOmL) and the organic layer separated and concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 1.41 min; m/z (ES⁺) = 642.58 [M + H] (LCMS -method 6).

Preparation 187: [(3R,45)-l-(5-{(S)-l-[l-(2-Methyl-propane-l-sulfonyl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester

The title compound was prepared from [(3i?,45)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185) and 2-methylpropane-l-sulfonyl chloride employing the procedure outlined in Preparation 186: RT = 1.44 min; m/z (ES⁺) = 642.54 [M + H]⁺ (LCMS -method

6).

Preparation 188: [(3R,45)-l-(5-{(S)-l-[l-(Propane-2-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl] -carbamic acid tert-butyl ester

The title compound was prepared from [(3i?,45)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185) and propane -2-sulfonyl chloride employing the procedure outlined in Preparation 186: RT = 1.38 min; m/z (ES⁺) = 628.54 [M + H]⁺ (LCMS -method 6). Preparation 189: Trans-3-terf-butoxycarbonylamino-4-hydroxy-pyrrolidine-l- carboxylic acid tert-butyl ester

To a solution of trans-3-amino-4-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester (5.00g, 24.7mmol) in THF (50mL) was added triethylamine (8.00mL, 57.4mmol). The reaction mixture was cooled to 0°C and di-tert-butyldicarbonate (6.47g, 29.7mmol) was added portion wise. The resulting reaction mixture was stirred at 0°C for 15 min and at r.t. for 3 h, then diluted with DCM and washed with water and brine. The organic extract was dried (MgS0₄), filtered, concentrated in vacuo and triturated with IH. The resulting solid was collected by filtration to afford the title compound: 1H NMR δ_Η (400MHz, DMSO): 7.09 (s, 1H), 5.23 (s, 1H), 3.95 (m, 1H), 3.71 (m, 1H), 3.42 (m, 2H), 3.08 (m, 2H), 1.41 (s, 18H).

Preparation 190: 3,6-Diaza-bicyclo[3.1.0]hexane-3,6-dicarboxylic acid di-terf-butyl ester

To a solution of trans-3-tert-butoxycarbonylamino-4-hydroxy-pyrrolidine-l- carboxylic acid tert-butyl ester (Preparation 189, 4.00g, 13.2mmol) and triethylamine (3.00mL, 21.5mmol) in THF (40mL) under an atmosphere of argon at 0°C was added methanesulfonyl chloride (l . lOmL, 14.2mmol) dropwise over 5 min.

The reaction mixture was poured into water and extracted with DCM (3 x). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo to afford crude trans-3-tert-butoxycarbonylamino-4-methanesulfonyloxy-pyrrolidine-l- carboxylic acid tert-butyl ester. The crude product was dissolved in THF (40mL), purged with argon and cooled to 0°C. Sodium hydride (0.53g, 13.2mmol) was added portion wise over 5 minutes and the resulting reaction mixture was poured into water and extracted with DCM. The organic extract was washed with brine, dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 4.00 (m, 2H), 3.30 (m, 2H), 3.08 (s, 2H), 1.49 (s, 9H), 1.46 (s, 9H).

Preparation 191: l-((Trans)-4-amino-pyrrolidin-3-yl)-5-fluoro-lH-pyridin-2-one

To a solution of 3,6-diaza-bicyclo[3.1.0]hexane-3,6-dicarboxylic acid di-tert-butyl ester (Preparation 190, 330mg, 1.20mmol) and 5-fluoropyridin-2(lH)-one (656mg, 5.80mmol) in NMP (3mL) was added ^lBuOK (521mg, 4.64mmol) and the resulting reaction mixture was heated under microwave irradiation at 100°C for 30 minutes. The reaction mixture was diluted with DCM, washed with water, 1M aqueous NaOH and brine, then passed through a phase separator. The organics were concentrated in vacuo and the crude intermediate was purified by preparative HPLC. To a solution of the intermediate in DCM (2mL) was added TFA (400

5.00mmol) and the resulting reaction mixture was shaken at r.t. for 3 h before loading onto an SCX cartridge. The cartridge was eluted with MeOH then 3.5M NH₃ in MeOH, and the basic fraction collected and concentrated in vacuo to afford the title compound: 1H NMR δ_Η (400MHz, CDCI3): 7.56 - 7.65 (m, 1H), 7.21 - 7.28 (m, 1H), 6.46 - 6.56 (m, 1H), 4.82 - 4.90 (m, 1H), 3.45 - 3.55 (m, 2H), 3.37 - 3.44 (m, 1H), 3.12 (dd, J=11.72, 2.73 Hz, 1H), 2.70 (dd, J=10.35, 6.05 Hz, 1H).

Preparation 192: l-((Trans)-4-amino-pyrrolidin-3-yl)-lH-pyridin-2-one

The title compound was synthesized from 3,6-diaza-bicyclo[3.1.0]hexane-3,6- dicarboxylic acid di-tert-butyl ester (Preparation 190, 330mg, 1.20mmol) and

pyrid-2-one (552mg, 5.80mmol) employing a procedure similar to that outlined in

Preparation 191: 1H NMR δ_Η (400MHz, CDC1₃): 7.55 (dd, J=7.03, 1.95 Hz, 1 H), 7.28 -

7.37 (m, 1 H), 6.56 (d, J=8.98 Hz, 1 H), 6.10 - 6.27 (m, 1 H), 4.77 - 4.94 (m, 1 H), 3.48 - 3.58 (m, 2 H), 3.39 (dd, J=10.93, 6.64 Hz, 1 H), 3.16 (dd, J=12.11, 3.51 Hz, 1 H), 2.71 (dd, J=10.93, 6.25 Hz, 1 H). Preparation 193: l-((Trans)-4-amin -pyrrolidin-3-yl)-4-methyl-lH-pyridin-2-one

The title compound was synthesized from 3,6-diaza-bicyclo[3.1.0]hexane-3,6- dicarboxylic acid di-tert-butyl ester (Preparation 190, 330mg, 1.20mmol) and

4-methyl-2-pyridinol (633mg, 5.80mmol) employing a procedure similar to that outlined in Preparation 191: 1H NMR δ_Η (400 MHz, CD₃OD): 7.59 (d, J=7.07 Hz, 1 H), 6.41 (s, 1 H), 6.31 - 6.39 (m, 1 H), 4.72 - 4.84 (m, 1 H), 3.66 - 3.76 (m, 1 H), 3.41 - 3.53 (m, 2 H), 3.17 (dd, J=12.25, 5.18 Hz, 1 H), 2.78 (dd, J=l 1.78, 7.07 Hz, 1 H), 2.26 (s, 3 H) Preparation 194: l-((Trans)-4-amino-pyrrolidin-3-yl)-5-methyl-lH-pyridin-2-one

The title compound was synthesized from 3,6-diaza-bicyclo[3.1.0]hexane-3,6- dicarboxylic acid di-tert-butyl ester (Preparation 190), and

5-methyl-2-pyridinol employing a procedure similar to that outlined in Preparation 191 RT = 0.24 min; mlz (ES⁺) = 194.11 [M+ H]⁺.

Preparation 195: l-((Trans)-4-amino-pyrrolidin-3-yl)-5-fluoro-lH-pyridin-2-one

The title compound was synthesized from 3,6-diaza-bicyclo[3.1.0]hexane-3,6- dicarboxylic acid di-tert-butyl ester (Preparation 190), and

5-fluoro-2-pyridinol employing a procedure similar to that outlined in Preparation 191 = 0.20 min; mlz (ES⁺) = 198.09 [M+ H]⁺.

Preparation 196: (5)- 1- [1 -(3-Isopropyl- [1 ,2,4] oxadiazol-5-yl)piperidin-4-yl] ethanol

The title compound was synthesized from (S)-l-piperidin-4-yl ethanol (Preparation 11) employing a procedure similar to that outlined in Preparation 62: RT = 2.72 min; mlz

Preparation 197: 3-Chloro-6-{(S)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4- yl]-ethoxy}-pyridazine

To potaasium tertiary butoxide (395mg, 3.52mmol) was added a solution of (5)-l-[l- (3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (843mg, 3.52mmol) in THF (20mL) and the resulting reaction mixture was stirred at r.t. for 60 min. 3,6-Dichloro-l,2- diazine (500mg, 3.4mmol) in THF (lOmL) was added and the reaction mixture was stirred at r.t. for a further 60 min, then at 60°C for 16 h. Upon cooling, the solvent was removed in vacuo and the residue was partitioned between DCM (200mL) and brine (200mL). The organics were separated, washed with brine (200mL) and concentrated in vacuo. Purification by column chromatography (IH:EtOAc; 7:3) afforded the title compound: RT = 3.72 min; mlz (ES⁺) = 352.2 [M+ H]⁺.

Preparation 198: [(3R,4S)-l-(5-Bromo-4-methoxy-pyrimidin-2-yl)-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-but \ ester

To a solution of [(3 ?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert- butyl ester (Preparation 48, 1.49g, 5.00mmol) in DMSO (lOmL) was added DBU (748μΙ., 5.00mmol) and 5-bromo-2-chloro-4-methoxypyrimidine (1.12g, 5.00mmol) and the resulting reaction mixture was heated at 80°C for 19 h. Upon cooling, EtOAc (300mL) and brine (350mL) were added and the organic layer separated, dried (MgS0₄), filtered and concentrated in vacuo. Recrstallisation from MeOH (35mL) afforded the title compound: RT = 4.49 min; mlz (ES⁺) = 485.1, 487.1 [M+ H]⁺. Preparation 199: [(3R,4S)-4-(2,5-Difluoro-phenyl)-l-(5-hydroxy-4-methoxy-pyrimidin- 2-yl)-pyrrolidin-3-yl]-carbamic acid tert-but l ester

To a solution of [(3 ?,45)-l-(5-bromo-4-methoxy-pyrimidin-2-yl)-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 198, 650mg,

1.30mmol) in THF (21mL) was added boric acid trimethyl ester (460μί, 4.00mmol), then the reaction mixture was cooled to -78°C and n-BuLi in hexane (1.6M, 1.8mL, 2.90mmol) was added. The resulting reaction mixture was stirred at -78°C for 1 h, then quenched with water and allowed to warm to r.t. The rection mixture was partitioned between EtOAc (250mL) and brine (250mL) and the organic layer separated and concentrated in vacuo. The remainder was dissolved in THF, cooled to 0°C and aqueous NaOH (2M, 1.3mL, 3.30mmol) and hydrogen peroxide (30% aqueous solution, 0.34mL, 3.30mmol) were added. The resulting reaction mixture was stirred at 0°C for 30 min, poured into EtOAc (250mL) and brine (250mL) and the organic layer separated and concentrated in vacuo. Purification by column chromatography (IH:EtOAc; 8:2 to 7:3) afforded the title compound: RT = 2.75 min; m/z (ES⁺) = 423.2, 487.1 [M+ H]⁺.

Preparation 200: ((3R,45)-4-(2,5-Difluoro-phenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)-piperidin-4-ylmethoxy]-4-methoxy-pyrimidin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester

Methanesulfonic acid l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethyl ester (33.1mg, 109μιηο1), [(3i?,45)-4-(2,5-difluoro-phenyl)-l-(5-hydroxy-4-methoxy- pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 199, 46.1mg, 109μιηο1) and potassium carbonate (45.2mg, 327μιηο1) were dissolved in DMF (l .OmL) and heated at 80°C for 10 h. The DMF was removed in vacuo, azeotroping with toluene (3 x lOmL). The remainder was dissolved in DCM (lOOmL), washed with brine (150mL) and concentrated in vacuo. Purification by column chromatography (IH:EtOAc; 7:3 to 4:6) afforded the title compound: RT = 3.77 min; mlz (ES⁺) = 630.3 [M+ H]⁺.

Preparation 201: 4-[(S)-l-(2-Chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-l-carboxylic acid isopropyl ester and 4-[(S)-l-(2-Bromo-pyrimidin-5-yloxy)-ethyl]-piperidine-l- carboxylic acid isopropyl ester

4-((i?)-l-methanesulfonyloxy-ethyl)-piperidine-l-carboxylic acid isopropyl ester (2.93g, 9.99mmol), potassium carbonate (4.14g, 30.0mmol) and a mixture of 2-bromo-5- hydroxypyrimidine (682mg, 3.90mmol) and 2-chloro-5-hydroxypyrimidine (861mg, 6.25mmol) were heated in DMF (20mL) at 80°C for 16 h. EtOAc (350mL) and brine (250mL) were added to the reaction mixture and the organic layer separated, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotogrpahy (IH:EtOAc; 1 :1) afforded the title compounds as a 3:2 ratio of products: RT = 3.84 min; mlz (ES⁺) = 328.14, 372.09, 374.08 [M+ H]⁺.

Preparation 202: 4-((S)-l-{2-[(3S,4S)-3-tei"i-Butoxycarbonylamino-4-(2-oxo-piperidin-l- yl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-l-carboxylic acid isopropyl ester

To a solution of [(35',45)-4-(2-oxopiperidin-l-yl)pyrrolidin-3-yl]carbamic acid tert- butyl ester (Preparation 20, 70mg, 247μιηο1), 4-[(5)-l-(2-chloro-pyrimidin-5-yloxy)-ethyl]- piperidine-l-carboxylic acid isopropyl ester (Preparation 201, 49.8mg, 152μιηο1) and 4- [(5)-l-(2-bromo-pyrimidin-5-yloxy)-ethyl]-piperidine-l-carboxylic acid isopropyl ester (Preparation 201, 35mg, 95μιηο1) in DMSO (594μΕ) was added DBU (37.6mg, 247μmol) and the resulting reaction mixture was heated at 80°C for 48h. Upon cooling, the reaction mixture was poured into DCM (150mL) and brine (150mL) and the organics separated and concentrated in vacuo. Purification by Preparative HPLC afforded the title compound: RT = 3.88 min; mlz (ES⁺) = 575.4 [M+ H]⁺.

Preparation 203: 4-((S)-l-{2-[(3R,4S)-3-tei-i-Butoxycarbonylamino-4-(2,5-difluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-l-carboxylic acid

To a solution of 4-[(5)-l-(2-chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-l-carboxylic acid benzyl ester (Preparation 83, 3.00g, 7.98mmol) and [(3R,4S)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 3.57g,

12.0mmol) in DMSO (16mL) was added DBU (1.19mL, 7.98mmol) and the resulting reaction mixture was heated at 90°C for 40 h. Upon cooling, the reaction mixture was poured into DCM (350mL), washed with brine (300mL) and concentrated in vacuo. Purification by column chrommotography (DCM:MeOH; 99: 1) afforded the title compound: RT = 1.50 min; mlz (ES⁺) = 638.6 [M+ H]⁺ (LCMS - Method 6).

Preparation 204: {(3R,45)-4-(2,5-Difluoro-phenyl)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3- l}-carbamic acid tert-butyl ester

To a solution of 4-((5)-l-{2-[(3i?,45)-3-fert-butoxycarbonylamino-4-(2,5-difluoro- phenyl)-pyrrolidin- 1 -yl] -pyrimidin-5 -yloxy } -ethyl)-piperidine- 1 -carboxylic acid

(Preparation 203, 5.03g, 7.89mmol) in EtOH (71mL) was added Pd/C (10%, 1.5g, 42mmol) and the resulting reaction mixture was stirred under an atmosphere of hydrogen for 1.5 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate concentrated in vacuo to afford the title compound: RT = 0.83 min; mlz (ES⁺) = 504.5 [M + Hf (LCMS - Method 6).

Preparation 205: [(3R,45)-l-{5-[(S)-l-(l-Cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}- 4-(2,5-difluoro-phenyl)-pyrrolidin-3- l]-carbamic acid tert-buty\ ester

To a solution of {(3R,4S)-4-(2,5-difluoro-phenyl)-l-[5-((S)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204, 2.00g, 3.97mmol) in DCM (lOmL) was added NaHC0₃ (l .OOg, 11.9mmol) in H₂0 (lOmL). The reaction mixture was cooled to 0°C and cyanogen bromide (463mg, 4.37mmol) in DCM (20mL) was added over 15 min. The resulting reaction mixture was stirred at 0°C for 30 min before warming to r.t. and diluting with DCM (40mL). The organic phase was separated and concentrated in vacuo to afford the title compound: RT = 1.27 min; m/z (ES ) = 529.6 [M + H]⁺ (LCMS - Method 6). Preparation 206: [(3R,45)-l-{5-[(S)-l-(l-Cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}- 4-(2,4,5-trifluoro-phenyl)- rrolidin-3-yl]-carbamic acid tert-butyl ester

The title compound was synthesized from [(3 ?,45)-l-[5-((5)-l-piperidin-4-yl- ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 1.1 lg, 2.13mmol) employing a procedure similar to that outlined in Preparation 205: RT = 1.30 min; m/z (ES⁺) = 547.5 [M+ H]⁺ (LCMS - Method 6). Preparation 207: l-Fluoro-4-methoxy-2-((£)-2-nitro-vinyl)-benzene

To a solution of 2-fluoro-5-methoxybenzaldehyde (l .OOg, 6.49mmol) in MeOH

(2mL) was added nitromethane (420 μί, 7.8mmol) and the reaction mixture was cooled to - 10°C. A solution of NaOH (272mg, 6.81mmol) in H₂0 (lmL) was added dropwise and the resulting reaction mixture was stirred at -10°C to -5°C for 15 min. The reaction mixture was quenched with aqueous HCl (2M, 8mL) and extracted into DCM (14mL). The organics were separated, concentrated in vacuo and acetic anhydride (1.22mL, 13.0mmol) was added to the residue prior to cooling the mixture to 0°C. 4-Dimethylaminopyridine (55.5mg, 454μιηο1) was added and the mixture was stirred at r.t. for 16 h. Saturated aqueous NaHC0₃ solution was added to adjust the pH to pH7 and the resulting reaction mixture was stirred at r.t. The precipitate was collected by filtration, washed with H₂0 and dried in vacuo. Purification by column chromatography (IH:EtOAc; 1 :0 to 9: 1) afforded the title compound: 1H NMR 5H (400MHz, CDC1₃): 8.02 (d, J=13.67 Hz, 1H), 7.71 (d, J=13.67 Hz, 1H), 7.06 - 7.20 (m, 1H), 6.86 - 7.06 (m, 2H), 3.84 (s, 3H).

Preparation 208: (rrans)-l-Benzyl- -(2-fluoro-5-methoxy-phenyl)-4-nitro-pyrrolidine

To a solution of l-fluoro-4-methoxy-2-((E)-2-nitro-vinyl)-benzene (Preparation 207, 330mg, 1.70mmol) in DCM (8mL) at 0°C was added TFA (26μΙ., 0.33mmol), then N- benzyl-N-methoxymethyl-N-(trimethylsilyl)methylamine (0.5 lmL, 2.0mmol) was added dropwise over 5 min and the resulting reaction mixture was stirred at 0°C for 90 min.

Purification by column chromotogrpahy (DCM:MeOH; 0:1 to 9: 1) followed by further purification by column chromatography (IH:EtOAc; 1 :0 to 3 : 1) afforded the title compound: RT = 3.03 min; mlz (ES⁺) = 331.27 [M+ H]⁺. Preparation 209 : (Trans)-4-(2-Fluoro-5-methox -phenyl)-pyrrolidin-3-ylamine

A solution of (tra/75)-l-benzyl-3-(2-fluoro-5-methoxy-phenyl)-4-nitro-pyrrolidine (130mg, 0.39mmol) ) in MeOH (5mL) was passed through an H-Cube apparatus (10% Pd/C Catcart 70, lOOpsi, 50°C) at a flow rate of ImL per min. The solvent was removed in vacuo to afford the title compound: RT = 2.80 min; mlz (ES⁺) = 210.98 [M+ H]⁺.

Preparation 210: 4-Trimethylsilanyleth nyl-lH-pyrazole

To a solution of 4-iodopyrazole (2g, lOmmol) in THF (15mL) was added

(trimethylsilyl)acetylene (7.28mL, 51.6mmol), N-ethylethanamine (15mL, 140mmol), dichlorobis(triphenylphosphine)palladium (II) (l .Og, 1.5mmol) and copper(I) iodide (0.28g, 1.5mmol). The mixture was stirred under argon at r.t. for 16 h and the solvent removed in vacuo.

The residue was dissolved in Et₂0 and the insoluble impurities removed by filtration. The filtrate was concentrated in vacuo, dissolved in MeOH and the insoluble impurities removed by filtration. The filtrate was concentrated in vacuo and purified by column chromatography (IH:Et₂0; 4: 1 to 0: 1). Further purification by column chromatography (Et₂0:IH; 1 :0 to 1 : 1) afforded the title compound: RT = 3.40 min; mlz (ES⁺) = 165.09 [M+ H]⁺.

Preparation 211: 4-Ethynyl-lH-pyrazole

To a solution of 4-trimethylsilanylethynyl-lH-pyrazole (Preparation 210, 400mg, 2.4mmol) in THF (3mL) was added a solution of lithium hydroxide (58mg, 2.4mmol) in H₂0 (0.6mL) and the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was adjusted to pH 7 with acetic acid and concentrated in vacuo. The residue was partitioned between DCM and H₂0, then the organics separated and concentrated in vacuo to afford the title compound: RT = 1.88 min; mlz (ES⁺) = 93.01 [M+ H]⁺. Preparation 212: 4-Ethyl-lH-pyrazole

A solution of 4-ethynyl-lH-pyrazole (Preparation 210, 170mg, 1.8mmol) in EtOH (18mL) was passed through an H-Cube apparatus (10% Pd/C Catcart 70, 1 bar, r.t.) at a flow rate of lmL per min. The solvent was removed in vacuo to afford the title compound: RT = 1.88 min; mlz (ES⁺) = 97.05 [M+ H]⁺.

Preparation 213: (rrans)-3-terf-Butoxycarbonylamino-4-(4-ethyl-pyrazol-l-yl)- pyrrolidine-l-carboxylic acid terf-but l ester

A mixture of 3,6-diaza-bicyclo[3.1.0]hexane-3,6-dicarboxylic acid di-tert-butyl ester (Preparation 190, 0.207g, 0.728mmol) and 4-ethyl-lH-pyrazole (Preparation 212, 140mg, 1.4mmol) in toluene (2mL) was heated at 110°C for 16 h. The reaction mixture was diluted with DCM and washed with aqueous NaOH solution (2M) and brine. The organics were dried (MgS0₄), filtered and concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 3.95 min; mlz (ES⁺) = 381.18 [M+ H]⁺.

Preparation 214: (rrans)-4-(4-Ethyl- razol-l-yl)-pyrrolidin-3-ylamine

To a solution of (tra/?5)-3-tert-butoxycarbonylamino-4-(4-ethyl-pyrazol-l-yl)- pyrrolidine- 1-carboxylic acid tert-butyl ester (Preparation 213, 79mg, 0.21mmol) in DCM (2mL) was added TFA (250 μΐ_^, 3.2mmol) and the resulting reaction mixture was stirred at r.t. for 4 h. The reaction mixture was loaded onto an SCX cartridge and eluted with MeOH followed by NH₃ in MeOH. The basic fractions were concentrated in vacuo to afford the title compound: 1H NMR δ_Η (400 MHz, CDC1₃): 7.35 (s, 1H), 4.25 - 4.44 (m, 1H), 3.67 - 3.82 (m, 1H), 3.40 - 3.59 (m, 2H), 3.25 - 3.38 (m, 1H), 2.70 - 2.86 (m, 1H), 2.49 (q, J=7.55 Hz, 2H), 1.19 (t, J=7.62 Hz, 3H). Preparation 215: 5-Trichloromethyl- l,2,4]oxadiazole-3-carboxylic acid ethyl ester

To a suspension of ethyl-2-oximinooxamate (1.26g, 9.54mmol) in toluene (13mL, 120mmol) was added perchloroacetic anhydride (1.74mL, 9.54mmol) and the resulting reaction mixture was heated at 110°C for 17 h, prior to removal of the solvent in vacuo. The resisue was dissolved in EtOAc (80mL), washed with saturated aqueous NaHC0₃ solution (2 x 50mL) and concentrated in vacuo to afford the title compound: 1H NMR δπ (400 MHz, CDC1₃): 4.58 (q, J=7.29 Hz, 2 H), 1.50 (t, J=7.22 Hz, 3 H). Preparation 216: 5-[4-((S)-l-{2-[(3R,4S)-3-tei-i-Butoxycarbonylamino-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazole-3- carboxylic acid ethyl ester

A solution of [(3i?,45)-l-[5-((5)-l-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5- trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 250mg, 0.48mmol) and 5-trichloromethyl-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester

(Preparation 215, 186mg, 0.719mmol) in DMF (1.5mL) was heated at 50°C for 2 h. Upon cooling, the solvent was removed in vacuo and the residue partitioned between EtOAc (30mL) and H₂0 (20mL). The organic layer was separated, washed with brine (lOmL) and concentrated in vacuo. Purification by column chromotograpy (IH:EtOAc; 7:3 to 4:6) afforded the title compound: RT = 1.41 min; mlz (ES ) = 662.43 [M+ ] (LCMS - Method Preparation 217: [(3R,4S)-l-[5-((S)-l-{l-[3-(l-Hydroxy-l-methyl-ethyl)- [l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-3-yl]-carba

To a solution of 5-[4-((5)-l-{2-[(3i?,45)-3-tert-butoxycarbonylamino-4-(2,4,5- trifluoro-phenyl)-pyrrolidin- 1 -yl] -pyrimidin-5 -yloxy } -ethyl)-piperidin- 1 -yl] - [l,2,4]oxadiazole-3-carboxylic acid ethyl ester (Preparation 216, 171mg, 0.258mmol) in THF (4mL) at -20°C was added methylmagnesium bromide in Et₂0 (3M, 0.43mL,

1.29mmol) dropwise. The resulting reaction mixture was stirred at -20°C for 90 min, prior to the addition of further methylmagnesium bromide in Et₂0 (3M, 0.172mL, 0.516mmol). The resulting reaction mixture was stirred at -20°C for 90 min, then quenched with saturated aqueous NH₄C1 solution (5mL) and partitioined between H₂0 (15mL) and EtOAc (25mL). The aqueous layer was separated and further extracted with EtOAc (25mL). The combined organic layers were concentrated in vacuo and purified by Preparative HPLC to afford the title compound: RT = 1.29 min; m/z (ES⁺) = 648.47 [M+ H]⁺ (LCMS - Method 6).

Preparatino 218: [ l-(3-Isopropyl- [1 2,4] oxadiazol-5-ylmethyl)-azetidin-3-yl] -methanol

To a solution of azetidin-3-yl methanol hydrochloride (0.5g, 4mmol) in DMF (5mL) was added 5-(chloromethyl)-3-isopropyl-l,2,4-oxadiazole (0.78g, 4.8mmol) and

triethylamine (1.7mL, 12mmol) and the resulting reaction mixture was stirred at 40°C for 16 h. The reaction mixture was partitioned between EtOAc and H₂0 and the aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with brine and loaded onto an SCX cartridge, eluting with MeOH followed by NH3 in MeOH. The basic fractions were concentrated in vacuo and purified by preparative HPLC (basic method) to afford the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 3.80 (s, 2H), 3.72 (d, J=5.86 Hz, 2H), 3.42 - 3.55 (m, 2H), 3.16 - 3.27 (m, 2H), 2.94 - 3.13 (m, 1H), 2.64 - 2.74 (m, 1H), 1.30 (d, J=7.03 Hz, 6H). Preparation 219: [(3R,4S)-l-{5-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-ylmethyl)-azetidin-3- ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid terf-butyl ester

To a solution of [(3 ?,45)-4-(2,4,5-trifluorophenyl)-l-(5-hydroxypyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 88, 49mg, 0.12mmol) in THF (lmL) was added PS-PPI13 (1.52mmol/g, 119mg, 0.181mmol). The resulting reaction mixture was stirred at r.t. for 5 min prior to the addition of TBAD (31mg, 0.13mmol) in THF (0.5mL). After stirring at r.t. for a further 5 mins, a solution of [l-(3-isopropyl- [l,2,4]oxadiazol-5-ylmethyl)-azetidin-3-yl]-methanol (Preparation 218, 25mg, 0.12mmol) in THF (0.5mL) was added and the resulting reaction mixture was stirred at r.t. for 2 h. Further TBAD (31mg, 0.13mmol) and PS-PPh₃ (1.52mmol/g, 119mg, 0.181mmol) were added and the resulting reaction mixture was stirred at 40°C for 120 min. Upon cooling, the reaction mixture was filtered, the resin washed with DCM and MeOH and the filtrate concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 3.00 min; mlz (ES⁺) = 604.26 [M+ H]⁺.

Preparation 220: (rrans)-3-terf-Butoxycarbonylamino-4-(4-methyl-pyrazol-l-yl)- pyrrolidine-l-carboxylic acid terf-but l ester

The title compound was synthesized from 3,6-diaza-bicyclo[3.1.0]hexane-3,6- dicarboxylic acid di-tert-butyl ester (Preparation 190, 0.500 g, 1.76 mmol) and 4-methyl- lH-pyrazole (0.433 g, 5.28 mmol) employing a procedure similar to that outlined in

Preparation 213: RT = 3.72 min; mlz (ES⁺) = 367.24 [M+ H]⁺. Preparation 221 : (rrans)-4-(4-Meth l-pyrazol-l-yl)-pyrrolidin-3-ylamine

The title compound was synthesized from (trans)-3-tert-butoxycarbonylamino-4-(4- methyl-pyrazol-l-yl)-pyrrolidine-l-carboxylic acid tert-butyl ester (Preparation 220, lOOmg, 0.273mmol) employing a procedure similar to that outlined in Preparation 214: RT = 0.36 min; mlz (ES⁺) = 167.11 [M+ H]⁺.

Preparation 222: 2,2-Difluoro-N-hydrox -propionamidine

To a solution of 2,2-difluoro-propionitrile (1.00g, 11.Ommol) in IMS (30mL) was added hydroxylamine (50% aqueous solution, 792mg, 13.2mmol) and the resulting reaction mixture was heated at 90°C for 16 h. Upon cooling, the solvent was removed in vacuo and the remainder purified by column chromatography (Heptane :EtO Ac; 4:1) to afford the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 1.75 (t, J=19.1 Hz, 3H).

Preparation 223: 2,2,2-Trifluoro-N-hydr xy-acetamidine

To a solution of aqueous hydroxylamine (50%, 3.9mL, 63mmol) in EtOH (80mL) in a 600mL Paar apparatus was added trifluoroacetonitrile (5g, 50mmol) at 35°C and 15 PSi. The reaction mixture was stirred for 45 min and further trifluoroacetonitrile (5g, 5 Ommol) was added at 35°C and 15 PSi. The resulting reaction mixture was stirred at 35°C for 16 h. The solvent was removed in vacuo and the remainder triturated with Et₂0 (3 x 50mL). The resulting precipitate was dried in vacuo to afford the title compound: 1H NMR 5_H (400MHZ, d⁶-DMSO): 10.30 (s, 1H), 6.25-6.35 (bs, 1H).

Preparation 224: N-hydroxy(~2~H_5) ropionamidine

A solution of propionitrile-D5 (250mg, 4.2mmol) and aqueous hydroxylamine (50%, 0.3mL, 5.0mmol) in EtOH (5mL) was heated at 60°C for 4 h. Upon cooling, the solvent was removed in vacuo to afford the title compound: 1H NMR δ_Η (400MHz, d⁶-DMSO): 8.67 (s, 1H), 5.20-5.30 (bs, 1H).

Preparation 225: N-hydroxy(3,3,3— 2~H ropionamidine

A solution of (3,3,3-~2~H_3)propionitrile (240mg, 4.2mmol), and aqueous hydroxylamine (50%, 0.3mL, 5.0mmol) in EtOH (5mL) was heated at 60°C for 5 h. Further aqueous hydroxylamine (50%>, 0.13mL, 2.1mmol) was added and the resulting reaction mixture stirred at 60°C for 5 h. Upon cooling, the solvent was removed in vacuo to afford the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 8.10-8.60 (bs, 1H), 4.50-4.80 (bs, 1H), 2.17 (s, 2H). Preparation 226: [(3R,45)-4-(2,5-Difluoro-phenyl)-l-(5-{(5)-l-[l-(N- hydroxycarbamimidoyl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]- carbamic acid terf-butyl ester

A solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2-yl}- 4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid fert-butyl ester (Preparation 205, lOOmg, 0.2mmol) and aqueous hydroxylamine (50%>, 13μΕ, 0.22mmol) in EtOH (4mL) was heated at 60°C for 3 h. Removal of the solvent in vacuo, azeotroping with Et₂0, afforded the title compound: RT = 2.85 min; mlz (ES⁺) = 562.26 [M+ H]⁺. Preparation 227: [(3R,4S)-l-(5-{(S)-l-[l-(N-Hydroxycarbamimidoyl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester

The title compound was synthesised from [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4- yl)-ethoxy]-pyrimidin-2-yl} -4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 206, lOOmg, 0.2mmol) employing a procedure similar to that outlined in Preparation 226: RT = 2.93 min; mlz (ES⁺) = 580.19 [M+ H]⁺. Preparation 228: [(3R,45)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(4-methyl-thiazol-2- yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

A solution of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204, 30mg, 0.06mmol) and 2-chloro-4-methyl-l,3-thiazole (80mg, 0.6mmol) in DCM (2mL) were heated at 120°C for 30 min under microwave irradiation, followed by further heating at 140°C for 60 min under microwave irradiation. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH (2 x 4mL), followed by NH₃ in MeOH (3.5M, 2 x 4mL). The basic fractions were concentrated in vacuo and purified by MDP (acidic method) to afford the title compound: RT = 1.05 min; mlz (ES⁺) = 601.51 [M+ H]⁺. Preparation 229: [(3R,4S)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(lH-tetrazol-5-yl)- piperidin-4-yl]-ethoxy}-p rimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

To a solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2- yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 205, 200mg, 0.4mmol) in DMF (4mL) was added ammonium chloride (30mg, 0.57mmol) then sodium azide (37mg, 0.57mmol) and the resulting reaction mixture was stirred at r.t. for 20 min and at 100°C for 16 h. Upon cooling, the reaction mixture was partitioned between EtOAc (40mL) and water (40mL). The organics were separated, washed with bine (30mL), dried (MgS0₄), filtered and concentrated in vacuo. Trituration with Et₂0 and removal of the solvent in vacuo afforded the title compound: RT = 3.75 min; m/z (ES⁺) = 572.20 [M+ H] .

Preparation 230: [(3R,45)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(3-ethyl-lH-tetrazol-5- yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamicacid tert-butyl ester

To a solution of [(3i?,45)-4-(2,5-difluoro-phenyl)-l-(5-{(5)-l-[l-(lH-tetrazol-5-yl)- piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

(Preparation 229, 160mg, 0.28mmol) in DMF (0.5mL) and acetone (2.5mL) at r.t. was added potassium carbonate (120mg, 0.84mmol), followed by portionwise addition of iodoethane (45μί, 0.56mmol) and the resulting reaction mixture was heated at 50°C for 3.5 h. The solvent was removed in vacuo and the remainder partitioned between EtOAc (40mL) and aqueous NaOH solution (1M, 40mL). The organics were separated, washed with brine (40mL), dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by preparative HPLC and added to an SCX cartridge, eluting with MeOH (3 x 4mL), followed by NH₃ in MeOH (3.5M, 3 x 4mL). The basic fractions were concentrated in vacuo to afford the title compound: RT = 4.49 min; mlz (ES ) = 600.19 [M+ H] .

Preparation 231: [(3R,45)-l-(5-{(S)-l-[l-(2H-Tetrazol-5-yl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl] -carbamic acid tert-butyl ester

The title compound was synthesized from [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4- yl)-ethoxy]-pyrimidin-2-yl} -4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 206, 200mg, 0.4mmol) employing a procedure similar to that outlined in Preparation 229: RT = 3.82 min; mlz (ES⁺) = 590.19 [M+ H]⁺.

Preparation 232: [(3R,45)-l-(5-{(S)-l-[l-(2-Ethyl-2H-tetrazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl] -carbamic acid tert- butyl ester

The title compound was synthesised from [(3i?,45)-l-(5-{(5)-l-[l-(2H-tetrazol-5-yl)- piperidin-4-yl]-ethoxy} -pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 231, 200mg, 0.3mmol) employing a procedure similar to that outlined in Preparation 230: RT = 4.49 min; mlz (ES⁺) = 618.19 [M+ H]⁺.

Preparation 233: [l-(6-Ethyl-pyridazin-3-yl)-piperidin-4-yl]-methanol

3-Bromo-6-ethylpyridazine (300mg, 2mmol) and 4-(hydroxymethyl)piperidine (650mg, 5.6mmol) were heated together at 100°C for 20 min under microwave irradiation. The reaction mixture was diluted with DCM (lOmL), washed with water (lOmL) and the organic layer loaded onto an SCX cartridge, eluting with MeOH, followed by N¾ in MeOH (3.5M). The basic fractions were concentrated in vacuo and purified by column

chromotogrpahy (DCM:MeOH; 1 :0 to 95:5) to afford the title compound: RT = 1.63 min; mlz (ES⁺) = 222.08 [M+ H]⁺.

Preparation 234: [(3R,4S)-l-{5-[l-(6-Ethyl-pyridazin-3-yl)-piperidin-4-ylmethoxy]- pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

To a solution of [(3 ?,45)-4-(2,4,5-trifluorophenyl)- 1 -(5-hydroxypyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 88, 50mg, 0.122mmol) in THF (ImL) was added PS-PPh₃ (1.52 mmol/g, 120mg, 0.183mmol), followed by TBAD (31mg, 0.134mmol) in THF (0.5mL) and the resulting reaction mixture was stirred at r.t. for 5 min. A solution of [l-(6-ethyl-pyridazin-3-yl)-piperidin-4-yl] -methanol (Preparation 233, 27mg, 0.12mmol) in THF (0.5mL) was added and the resulting reaction mixture stirred at r.t. for 2 h. Further TBAD (31mg, 0.134mmol) and PS-PPh₃ (1.52 mmol/g, 120mg, 0.183mmol) were added and the reaction mixture stirred at 40°C for 2 h. The reaction mixture was filtered and the resin washed with MeOH. The filtrate was concentrated in vacuo and purified by preparative HPLC to afford the title compound: RT = 3.13 min; mlz (ES ) =

Preparation 235: [(3R,4S)-l-{5-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-3- ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester hydrochlori

To a solution of [l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-3-yl]methanol (Preparation 111, 32mg, 0.140mmol) in DCM (lmL) was added triethylamine (40μί, 0.3mmol) and methanesulfonyl chloride (20μί, 0.2mmol) and the resulting reaction mixture was shaken at r.t. for 2 h. The reaction mixture was washed with aqueous HC1 (1M) and concentrated in vacuo. A solution of [(3 ?,4S)-4-(2,4,5-trifluorophenyl)-l-(5- hydroxypyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid fert-butyl ester (Preparation 88, 50mg, 0.122mmol) in DMF (lmL) and potassium carbonate (50mg, 0.4mmol) were added and the resulting reaction mixture stirred at 80°C for 16 h. The reaction mixture was partitioned between DCM and water and the organics separated and concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 4.53 min; mlz (ES ) = 618.33 [ + H]⁺.

Preparation 236: (rrans)-l-Benzyl-3-nitro-4- henyl-pyrrolidine

To a solution of ((E)-2-nitro-vinyl)-benzene (lg, 7.0mmol) in DCM (lOmL) at 0°C was added TFA (0. lOmL, 1.3mmol), followed by dropwise addition of N-(methoxymethyl)- N-(trimethylsilylmethyl)benzylamine (2. OmL, 8.0mmol). The resulting reaction mixture was stirred at 0°C for 1.5 h and at r.t. for 1 h. Further N-(methoxymethyl)-N- (trimethylsilylmethyl)benzylamine (0.8mL, 3.2mmol) and TFA (O.lmL, 1.3mmol) were added and the reaction mixture stirred at 0°C for 30 min. The reaction mixture was diluted with DCM (40mL) and water (5 OmL) and the organic layer separated and concentrated in vacuo. Purification by column chromotogrpahy (IF EtOAc, 1 :0 to 3 : 1) afforded the title compound: RT = 2.57 min; mlz (ES⁺) = 283.13 [M+ H]⁺.

Preparation 237: (rrans)-4-Phenyl-pyrrolidin-3- l-ammonium

(7>a/?5)-l-Benzyl-3-nitro-4-phenyl-pyrrolidine (Preparation 236, 275mg, 0.974mmol) was passed through an H-Cube apparatus (10% Pd/C, 100 bar, 75°C) at a flow rate of lmL per min. The reaction mixture was loaded onto an SCX cartridge eluting with MeOH followed by NH₃ in MeOH (3.5M). The basic fractions were concentrated in vacuo to afford the title compound: RT = 2.98 min; mlz (ES⁺) = 163.01 [M+ H]⁺.

Preparation 238 : 5-Bromo-2-{(S)- 1- [ l-(3-isopropyl- [ 1 ,2,4] oxadiazol-5-yl)-piperidin-4- yl]-ethoxy}-pyrimidine

To a solution of (i?)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation 62, 0.50g, 2.1mmol), 5-bromo-pyrimidin-2-ol (0.36g, 2.1mmol) and PPh₃ (0.66g, 2.5mmol) in THF (20mL) was added DEAD (0.39mL, 2.5mmol) dropwise over 15 min and the resulting reaction mixture was stirred at r.t. for 16h. Further PPh₃ (0.33g,

1.25mmol), (R)- 1 -[ 1 -(3-isopropyl-[ 1 ,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation 62, 0.20g, 0.84mmol) and DEAD (0.20mL, 0.43mmol) were added and the resulting reaction mixture was stirred at r.t. for 72 h. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford the title compound: RT = 3.97 min; mlz (ES ) = 396.1, 398.1 [ + H]⁺.

Preparation 239: (£)-3-(4-Methyl-p ridin-2-yl)-acrylic acid ethyl ester

Triethylphosphonoacetate (5.38g, 24.0mmol) was added dropwise to a solution of sodium hydride (l .lg, 26.0mmol) in THF (120mL) at 0°C and the resulting reaction mixture was stirred at 0°C for 30 min. A solution of 4-methyl-pyridine-2-carbaldehyde (1.5g, 12mmol) in THF (30mL) was added dropwise and the resulting reaction mixture was allowed to warm to r.t. over 1.5 h. The reaction mixture was poured into water and extracted with EtOAc (3 x). The combined organic extracts were dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by column chromatography

(Heptane:EtOAc; 2: 1) to afford the title compound: RT = 2.49 min; mlz (ES⁺) =192.1 [M + H]⁺ (LCMS - Method 4). Preparation 240: (rrans)-l-Benzyl-4-(4-methyl-pyridin-2-yl)-pyrrolidine-3-carboxylic acid ethyl ester

To a solution of (E)-3-(4-methyl-pyridin-2-yl)-acrylic acid ethyl ester (Preparation 239, 1.97g, 10.3mmol) and N-(methoxyrnethyl)-N-(trimethylsilylmethyl)benzylamine (3.0mL, 12.4mmol) in DCM (8mL) at 0°C was added TFA (29mL, 1.03mmol) dropwise and the resulting reaction mixture was stirred at 0°C for 1 h and at r.t. for 16 h. The reaction mixture was poured into saturated aqueous NaHC0₃ solution and extracted with DCM (3 x). The combined organic extracts were dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc:Heptane; 3: 1 to 1 :0) afforded the title compound: RT = 0.86 min; mlz (ES⁺) =325.1 [M+ H]⁺ (LCMS - Method 2).

Preparation 241 : (rrans)-l-Benzyl-4-(4-methyl-pyridin-2-yl)-pyrrolidine-3-carboxylic acid

To a solution of (tra/?5)-l-benzyl-4-(4-methyl-pyridin-2-yl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 240, 3.26g, 10.06mmol) in MeOH (30mL) was added a solution of NaOH (680mg, 12.0mmol) in water (5mL) and the resulting reaction mixture was stirred at r.t. Aqueous HC1 (6M, 2.8mL) was added and the solvent removed in vacuo, azeotroping with toluene, to afford the title compound: RT = 2.26 min; mlz (ES ) =297.1 [M + H]⁺ (LCMS - Method 4).

Preparation 242: [(3R,4S)-l-Benzyl-4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl]- carbamic acid tert-buty\ ester

To a solution of (tra/75)-l-benzyl-4-(4-methyl-pyridin-2-yl)-pyrrolidine-3-carboxylic acid (Preparation 241, 2.96g, lOmmol) in 1,4-dioxane (40mL) was added triethylamine (2.1mL, 15mmol) and the resulting reaction mixture was cooled to 0°C. Diphenylphosphoryl azide (2.59mL, 12mmol) was added and the reaction mixture stirred at 0°C for 45 mins prior to the addition of tertiary butanol (5mL). After stirring at 0°C for 5 mins, the reaction mixture was warmed to r.t. and stirred at r.t. for 2 h and at 85 °C for 16 h. The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium hydrogen carbonate solution, dried (MgS0₄), filtered and concentrated in vacuo. The oil was triturated with heptane and the solid removed by filtration. The filtrate was purified by column

chromatography (EtOAc:Heptane; 5 : 1 to 1 :0) and the crude product triturated with heptane to afford [(trans)-l -benzyl -4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester. Purification by chiral HPLC (MTBE:MeOH:BA; 98:2:0.1 , 15ml/min, 265nm, RT = 5.1 min) afforded the title compound: RT = 3.03 min; mlz (ES⁺) =368.2 [M+ H]⁺ (LCMS - Method 4).

Preparation 243: [(3R, 4S)-4-(4-Methyl-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-buty\ ester

To a solution of [(3 ?,45)-l-benzyl-4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester (Preparation 242, 200mg, 0.544mmol) in EtOH (12mL) and AcOH (lmL) was added palladium hydroxide (7.6mg, 54μιηο1) and the resulting reaction mixture was stirred under an atmosphere of hydrogen for 16h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was partitioned between DCM (20mL) and saturated aqueous sodium bicarbonate solution (20mL). The organic phase was washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by preparative HPLC (basic method) afforded the title compound: RT = 1.90 min; mlz (ES ) =278.11 [Μ+ ηγ. Preparation 244 : 5-Bromo-2-{(S)- 1- [ l-(3-isopropyl- [ 1 ,2,4] oxadiazol-5-yl)-piperidin-4- yl]-ethoxy}-pyridine

To a solution of (i?)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethanol (Preparation 62, 400mg, 2mmol), 5-bromo-2-hydroxypyridine (290mg, 1.7mmol) and PPI13 (660mg, 2.5mmol) in THF at 0°C was added a solution of TBAD (580mg, 2.5mmol) in THF (0.5mL) in 3 portions over 20 min. The resulting reaction mixture was stirred at r.t. for 16 h and the solvent removed in vacuo. The residue was dissolved in EtOAc (200mL), washed with saturated aqueous NaHCC"3 solution (2 x 150mL) and brine (150mL), dried (MgSC^), filtered and concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 4.50 min; mlz (ES⁺) =395.1, 397.1 [M+ H]⁺.

Preparation 245 : 5-Bromo-2-{(5)- 1- [ l-(3-isopropyl- [ 1 ,2,4] oxadiazol-5-yl)-piperidin-4- yl]-ethoxy}-4-methyl-pyridine

The title compound was synthesized from ( ?)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]ethanol (Preparation 62, 400mg, 2mmol) and 5-bromo-2-hydroxy-4- methylpyridine (310mg, 1.7mmol) employing a procedure similar to that outlined in

Preparation 244: RT = 4.72 min; mlz (ES⁺) =409.1, 411.1 [M+ H]⁺.

Preparation 246: [(3R,4R)-4-(2,5-Difluoro-phenyl)-l-(5-{(5)-l-[l-(3-ethyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-piperidin-3-yl]-carbamic acid tert-buty\ ester

To a solution of [(3 ?,4i?)-4-(2,5-difluorophenyl)piperidin-3-yl]carbamic acid tert- butyl ester (Preparation 9, 60mg, 0.192mmol) and 2-chloro-5-{(5)-l-[l-(3-ethyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation 102, 54.1mg,

0.160mmol) in DMSO (0.32mL) was added DBU (24.4mg, 160μηιο1) and the resulting reaction mixture was stirred at 90°C for 144 h. Upon cooling, the reaction mixture was poured into DCM (175mL), washed with citric acid (1M, 2 x 150mL) and brine (200mL), dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: RT = 1.46 min; mlz (ES⁺) = 614.5 [M+ H]⁺.

Preparation 247: [(3R,45)-l-(5-{(S)-l-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4- yl] -ethoxy}-pyrimidin-2-yl)-4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl] -carbamic acid tert butyl ester

A solution of [(3 ?,45)-4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl] -carbamic acid tert- butyl ester (Preparation 243, 55.0mg, 0.198mmol), 2-chloro-5-{(5)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation 63, 78.6mg,

0.198mmol) and DBU (29.6μΙ., 0.198mmol) in DMSO (4mL) was heated at 80°C for 96 h. Upon cooling, the reaction mixture was diluted with chloroform (50mL) and the organic phase washed with brine (50mL) and concentrated in vacuo. Purification by preparative HPLC (basic method) afforded the title compound: RT = 3.23 min; mlz (ES⁺) = 593.61 [M +

H]⁺.

Preparation 248 : 6-Bromo-3- [ l-(3-isopropyl- [1 ,2,4] oxadiazol-5-yl)-piperidin-4- ylmethoxy]-2-methyl-pyridine

To a solution of 6-bromo-2-methyl-pyridin-3-ol (250mg, 1.33mmol), [(l-(3- isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation 1, 314mg, 1.40mmol) and PPh₃ (384mg, 1.46mmol) in THF was added TBAD (337mg, 1.46mmol) in three portions over 20 min and the resulting reaction mixture was stirred at r.t. for 96 days.

The solvent was removed in vacuo and the remainder dissolved in EtOAc (50mL). The solution was washed with aqueous HC1 solution (0.1M, 25mL), water (25mL) and brine (50mL), dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by preparative HPLC to afford the title compound: RT = 4.03 min; mlz (ES⁺) = 395.10, 397.09 [M+ H]⁺.

Preparation 249: ((3R,45)-4-(2,5-Difluoro-phenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)-piperidin-4-ylmethoxy]-6-methyl-pyridin-2-yl}-pyrrolidin-3-yl)-carbamic acid terf-butyl ester

[(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

(Preparation 48, 272mg, 0.911mmol), 6-bromo-3-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-ylmethoxy]-2-methyl-pyridine (Preparation 248, 300mg, 0.759mmol), biphenyl-2-yl(di-tert-butyl)phosphine (45.3mg, 0.152mmol) and potassium tertiary butoxide (106mg, 0.949mmol) in toluene (lOmL) were heated in a sealed tube at 150°C for 16 h. Upon cooling, the reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M). The fractions were concentrated in vacuo and purified by preparative HPLC (basic method) to afford the title compound: RT = 3.83 min; mlz (ES ) =

Preparation 250: l-Benzyl-4-hydrox methyl-piperidin

To sodium borohydride (50g, 1.31mmol) at 0°C was added a solution of l-benzyl-3- oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride (20g, 67.2mmol) in MeOH (350mL) with rapid overhead stirring. The resulting reaction mixture was stirred at r.t. for 16 h. Water (300mL) was added and stirring was continued for 4 h, prior to removal of the solvent in vacuo. The remainder was diluted with brine, extracted with EtOAc (4 x) and the combined organic extracts dried (MgS0₄), filtered through celite and concentrated in vacuo to afford the title compound: RT = 2.12, 2.27 min; mlz (ES⁺) = 222.1 [M+ H]⁺ (LCMS Method - 4). Preparation 251: Acetic acid (c/s)-4-acetoxymethyl-l-benzyl-piperidin-3-yl ester

To a solution of l-benzyl-4-hydroxymethyl-piperidin-3-ol (Preparation 250, in pyridine (140mL) was added acetic anhydride (70mL) and the resulting reaction mixture stirred at r.t. for 24 h. The solvent was removed in vacuo, azeotroping with toluene (3 x ), and the remainder purified by column chromatography (EtOAc: Heptane; 3:2 to 1 :0) to afford the title compound: RT = 2.72 min; mlz (ES⁺) = 306.1 [M+ H]⁺ (LCMS Method - 4).

Preparation 252: Acetic acid (frans)-4-acetoxymethyl-l-benzyl-piperidin-3-yl ester

The title compound was synthesised employing the method outlined in Preparation 251: RT = 2.82 min; mlz (ES⁺) = 306.1 [M+ H]⁺ (LCMS Method - 4).

Preparation 253: Acetic acid (ci^' -4-acetoxymethyl-piperidin-3-yl ester trifluoroacetate

A solution of acetic acid (czs)-4-acetoxymethyl-l-benzyl-piperidin-3-yl ester

(Preparation 251, 2.00g, 6.55mmol) in EtOH (300mL) and TFA (3mL) was passed through an H-Cube apparatus (10% pd/C Catcart 70, 50 atmospheres, 70°C) at a flow rate of ImL per min. The solvent was removed in vacuo, azeotroping from toluene (2 x), to afford the title compound: RT = 1.42 min; mlz (ES⁺) = 216.14 [M+ H]⁺. Preparation 254: Acetic acid (frans)-4-acetoxymethyl-piperidin-3-yl ester

trifluoroacetate

The title compound was synthesized from acetic acid (trans)-4-acetoxymethyl-l- benzyl-piperidin-3-yl ester (Preparation 252, 2.00g, 6.55mmol) employing a procedure similar to that outlined in Preparation 253: RT = 1.52 min; mlz (ES⁺) = 216.11 [M+ H]

Preparation 255: (cis)-l-(5-Chlor -pyrimidin-2-yl)-4-hydroxymethyl-piperidin-3-ol

Acetic acid (czs)-4-acetoxymethyl-piperidin-3-yl ester trifluoroacetate (Preparation 253, 0.690g, 2.10mmol), 2,5-dichloropyrimidine (0.375g, 2.51mmol), potassium carbonate (0.724g, 5.24mmol), NMP (8mL) and water (4mL, 200mmol) were combined in a microwave tube and stirred at r.t. for 5 min. The reaction mixture was heated at 100°C under microwave irradiation for 1 min, then the pressure released. The reaction mixture was further heated at 150°C for 10 min, under microwave irradiation, followed by a further 20 min, releasing the pressure inbetween. The reaction mixture was poured into water (300mL) and extracted with Et₂0 (4 x 200mL). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. The resulting oil was triturated with EtOAc and IH and the solid collected by filtration to afford the title compound: RT = 2.43 min; mlz (ES⁺) = 244.08 [M+ H]⁺.

Preparation 256: (irans)-l-(5-Chloro- rimidin-2-yl)-4-hydroxymethyl-piperidin-3-ol

The title compound was synthesised from acetic acid (tra/?s)-4-acetoxymethyl- piperidin-3-yl ester trifluoroacetate (Preparation 254, 0.130g, 0.395mmol), employing a procedure similar to that outlined in Preparation 255: RT = 2.57 min; mlz (ES ) = 244.11 [M+ H]⁺. Preparation 257: (cis)-l-(5-Chloro-pyrimidin-2-yl)-4-(2-chloro-pyrimidin-5- yloxymethyl)-piperidin-3-ol and (cis)-l-(5-bromo-pyrimidin-2-yl)-4-(2-chloro- pyrimidin-5- loxymethyl)-piperidin-3-ol

To a solution of (cz5)-l-(5-chloro-pyrimidin-2-yl)-4-hydroxyrnethyl-piperidin-3-ol (Preparation 255, 0.449g, 1.84mmol), 2-chloropyrimidin-5-ol (0.144g, l . lOmmol), 2- bromopyrimidin-5-ol (0.129g, 0.737mmol) and PPI13 (0.725g, 2.76mmol) in THF (35mL) was added TBAD (0.467g, 2.03mmol) and the resulting reaction mixture was stirred at 50°C for 3h. The solvent was removed in vacuo and the remainder partitioned between EtOAc (200mL) and water (200mL). The organics were separated, washed with brine, dried

(MgS0₄), filtered and concentrated in vacuo. The remainder was purified by column chromatography (EtOAcTH; 1 : 1) to afford the title compounds: RT = 3.42-3.48 min; mlz (ES⁺) = 356.03, 399.97, 401.97 [M+ H]⁺.

Preparation 258: (irans)-l-(5-Chloro-pyrimidin-2-yl)-4-(2-chloro-pyrimidin-5- yloxymethyl)-piperidin-3-ol and (frans)-l-(5-bromo-pyrimidin-2-yl)-4-(2-chloro- pyrimidin-5- loxymethyl)-piperidin-3-ol

The title compounds were synthesised from (trans)- 1 -(5 -chloro-pyrimidin-2-yl)-4- hydroxymethyl-piperidin-3-ol (Preparation 256, 0.306g, 1.26mmol), employing a procedure similar to that outlined in Preparation 257: RT = 3.38-3.44 min; mlz (ES⁺) = 356.03, 399.99, 401.98 [M+ H] Preparation 259: [(3R,4S)-l-{5-[(3R,4S)-l-(5-Chloro-pyrimidin-2-yl)-3-hydroxy- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-buty\ ester

To a solution of (cz5)-l-(5-chloro-pyrimidin-2-yl)-4-(2-chloro-pyrimidin-5- yloxymethyl)-piperidin-3-ol (Preparation 257, 0.204g, 0.573mmol), (czV)-l-(5-bromo- pyrimidin-2-yl)-4-(2-chloro-pyrimidin-5-yloxymethyl)-piperidin-3-ol (Preparation 257, 0.136g, 0.339mmol) and [(3 ?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert- butyl ester (Preparation 48, 0.427g, 1.43mmol) in DMSO (2.5mL) was added DBU

(0.143mL, 0.956mmol) and the resulting reaction mixture was heated at 80°C in a sealed tube for 48 h. The reaction mixture was poured into water (lOOmL), extracted with EtOAc (3 x lOOmL) and the combined orgainc extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by column chromotogrpahy (EtOAcTH; 65:35) to afford [(3^45)-l-{5-[(cz5)-l-(5-chloro-pyrimidin-2-yl)-3-hydroxy- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. Purification by chiral HPLC (MeCN:THF; 84: 16, 15ml/min, 250nm) afforded the title compound: RT = 4.27 min; mlz (ES⁺) = 618.29 [M+ H]⁺.

Preparation 260: [(3R,45)-l-{5-[(3S,4R)-l-(5-Chloro-pyrimidin-2-yl)-3-hydroxy- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-buty\ ester

The title compound was synthesised from (cz5)-l-(5-chloro-pyrimidin-2-yl)-4-(2- chloro-pyrimidin-5-yloxymethyl)-piperidin-3-ol and (cis)- 1 -(5-bromo-pyrimidin-2-yl)-4-(2- chloro-pyrimidin-5-yloxymethyl)-piperidin-3-ol (Preparation 257) employing the procedure outlined in Preparation 259: RT = 4.34 min; mlz (ES⁺) = 618.29 [M+ H]⁺. Preparation 261: [(3R,4S)-l-{5-[(3R,4R)-l-(5-Chloro-pyrimidin-2-yl)-3-hydroxy- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-buty\ ester

[(3i?,45)-l-{5-[(tran5)-l-(5-Chloro-pyrimidin-2-yl)-3-hydroxy-piperidin-4- ylmethoxy]-pyrimidin-2-yl} -4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester was synthesised from (tra/75)-l-(5-chloro-pyrimidin-2-yl)-4-(2-chloro-pyrimidin- 5-yloxymethyl)-piperidin-3-ol and {trans)- 1 -(5-bromo-pyrimidin-2-yl)-4-(2-chloro- pyrimidin-5-yloxymethyl)-piperidin-3-ol (Preparation 258) employing the procedure outlined in Preparation 259. Purification by chiral HPLC (DCM:EtOH; 94:6, 11 ml/min, 250nm) afforded the title compound: RT = 4.28 min; mlz (ES⁺) = 618.28 [M+ H]⁺.

Preparation 262: [(3R,45)-l-{5-[(3S,4S)-l-(5-Chloro-pyrimidin-2-yl)-3-hydroxy- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-buty\ ester

The title compound was synthesised from (tra/?5)-l-(5-chloro-pyrimidin-2-yl)-4-(2- chloro-pyrimidin-5-yloxymethyl)-piperidin-3-ol and (trans)-l-(5-bromo-pyrimidin-2-yl)-4- (2-chloro-pyrimidin-5-yloxymethyl)-piperidin-3-ol (Preparation 258) employing the procedure outlined in Preparation 261: RT = 4.32 min; mlz (ES⁺) = 618.28 [M+ H]⁺.

Preparation 263: (3S,45)-4-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5-yloxymethyl}-l-(5-chloro-pyrimidin-2-yl)-piperidin-3-ol

The title compound was synthesised from [(3i?,45)-l-{5-[(35',45)-l-(5-chloro- pyrimidin-2-yl)-3-hydroxy-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 262, 55mg, 0.089mmol) employing the procedure outlined in Example 205: RT = 2.70 min; mlz (ES ) = 518.20 [M +

H]⁺.

Preparation 264: (ci^'s)-4-Hydroxymeth l-piperidin

To a solution of acetic acid (czs)-4-acetoxymethyl-l-benzyl-piperidin-3-yl ester

(Preparation 251, 3.00g, 9.82mmol) in MeOH (60mL) was added potassium carbonate (13.6g, 98.24mmol) and the resulting reaction mixture was stirred at r.t. for 10 min. Water (50mL) was added and the reaction mixture extracted with EtOAc (3 x lOOmL). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo to afford the (3i?,45)-l-benzyl-4-(hydroxymethyl)piperidin-3-ol. The product was dissolved in EtOH (lOOmL) and passed twice through an H-Cube apparatus (10% Pd/C, 50 atmospheres, 70°C) at a flow rate of lmL per min. The solvent was removed in vacuo to afford the title compound: 1H NMR δ_Η (400 MHz, DMSO-d₆): 4.07 - 4.40 (m, 2 H), 3.62 (br. s, 1H), 3.14 - 3.52 (m, 3 H), 2.71 - 2.96 (m, 2 H), 2.29 - 2.46 (m, 1 H), 1.52 (m, 1 H), 1.12 - 1.43 (m, 2 H).

Preparation 265: (3R,4S)-3-Hydrox -4-hydroxymethyl-piperidine-l-carbonitrile

To a solution of (cz^'s)-4-hydroxymethyl-piperidin-3-ol (Preparation 264, 0.880g, 6.71mmol) in DCM (30mL) was added NaHC0₃ (1.69g, 20.1mmol) and water (5mL) and the resulting reaction mixture was cooled to 0°C. A solution of cyanogen bromide (0.853g, 8.05mmol) in DCM (lOmL) was added and the resulting reaction mixture was stirred at r.t. for 16 h. NaHC0₃ (lg, 11.9mmol) and MgS0₄ (lOg) were added and the reaction mixture stirred at r.t. for 10 min. The solids were removed by filtration, washing with DCM (250mL) and the filtrate concentrated in vacuo to afford the title compound: 1H NMR δπ (400 MHz, DMSO-de): 4.04 (br.s, 1H), 3.59 - 3.76 (m, 2H), 3.30 - 3.52 (m, 2H), 2.92 - 3.14 (m, 3H), 2.29 (br.s. 1H), 1.86 - 2.09 (m, 1H), 1.50 - 1.66 (m, 1H), 1.31 - 1.47 (m, 1H). Preparation 266: (cis)-4-Hydroxymethyl-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-3-ol

To a solution of (3i?,45)-3-hydroxy-4-hydroxyrnethyl-piperidine-l-carbonitrile

(Preparation 265, 0.637g, 4.67mmol) and N-hydroxyiosobutyramidine (0.57g, 5.6mmol) in EtOH (lOmL) was added a solution of zinc chloride (0.637g, 4.67mmol) in EtOH (lmL) dropwise over 5 min and the resulting reaction mixture was stirred at r.t. for 2 h. Aqueous HCl (12.5M, 5mL) was added and the reaction mixture heated at 80°C for 4 h. The solvent was removed in vacuo and the pH adjusted to pH 7 with saturated aqueous NaHC0₃ solution. The product was extracted into EtOAc (3 x 75mL) and the combined organic extracts washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc) afforded the title compound: RT = 2.17 min; mlz (ES ) =

Preparation 267: Methanesulfonic acid (3R, S)-3-hydroxy-l-(3-isopropyl- [1,2,4] oxadiazol-5-yl)-piperidin-4- lmethyl ester

To a solution of (cz5)-4-hydroxymethyl-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-3-ol (Preparatino 266, 0.170g, 0.704mmol) and triethylamine (0.118mL,

0.845mmol) in DCM (lOmL) at 0°C was added methanesulfonyl chloride (54.5μΕ,

0.704mmol) dropwise and the resulting reaction mixture was stirred at r.t. for 2 h. The reaction mixture was diluted with DCM (lOOmL), washed with saturated aqueous Na₂C0₃ solution and brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotograpy (DCM:MeOH; 96:4) afforded the title compound: RT = 2.72 min; mlz (ES⁺) = 320.07 [M+ H]⁺. Preparation 268: (cis)-4-(2-Chloro-pyrimidin-5-yloxymethyl)-l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-3-ol

To a solution of 2-chloro-5-hydroxypyrimidine (59mg, 0.45mmol) and potassium carbonate (75mg, 0.54mmol) in DMF (2mL) was added a solution of methanesulfonic acid (3i?,45)-3-hydroxy-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethyl ester

(Preparation 267, 0.145g, 0.454mmol) in DMF (3.8mL) and the resulting reaction mixture heated at 80°C for 16 h. Further potassium carbonate (31.3mg, 0.23mmol) was added and the reaction mixture heated at 80°C for 24h. The solvent was removed in vacuo, azeotroping with toluene (2 x), and the remainder diluted with EtOAc, washed with saturated aqueous Na₂C0₃ solution and brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc:IH; 3:2) afforded the title compound: RT = 0.92 min; mlz (ES⁺) = 354.32 [M+ H]⁺ (LCMS Method-6). Preparation 269: 2-Chloro-5-[(cis)-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-3-methoxy- piperidin-4-ylmethoxy]-pyrimidine

To a solution of (cz5)-4-(2-chloro-pyrimidin-5-yloxymethyl)-l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-3-ol (Preparation 268, 49mg, 0.14mmol) in THF (lOmL) was added sodium hydride (60% dispersion in mineral oil, 1 lmg, 0.28mmol) and the resulting reaction mixture stirred at r.t. for 10 min. Methyl iodide (43μί, 0.69mmol) was added and the reaction mixture stirred at r.t. for 3 h. Further sodium hydride (60% dispersion in mineral oil, 1 lmg, 0.28mmol) and methyl iodide (87μΕ, 1.4mmol) were added and the reaction mixture stirred at r.t. for 48 h. Water (50mL) was added and the reaction mixture extracted with EtOAc (3 x lOOmL). The combined organic extracts were washed with saturated aqueous NaHCOs solution and brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotogrpahy (EtOAcTH; 65:45) afforded the title compound: RT = 3.48 min; mlz (ES⁺) = 368.11 [M+ H]⁺. Preparation 270: [(3R,4S)-l-{5-[(3R,4S)-l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-3- methoxy-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- 3-yl]-carbamic acid tert- ty\ ester

To a solution of 2-chloro-5-[(cz^'5)-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-3-methoxy- piperidin-4-ylmethoxy]-pyrimidine (Preparation 269, 61mg, 0.16mmol) in DMSO (2.5mL) was added [(3i?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 0.105g, 0.332mmol) and DBU (24.8μΕ, 0.166mmol) and the resulting reaction mixture was heated at 75°C for 48 h, then at 85°C for 72 h. The reaction mixture was poured into water (lOOmL), extracted with EtOAc (3 x) and the combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo.

Purification by column chromatography (DCM:MeOH; 95:5) afforded [(3i?,45)-l-{5-[(cis)- (3-iopropyl-[l,2,4]oxadiazol-5-yl)-3-methoxy-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4- (2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. Purification by chiral HPLC (MeOH:THF; 93 :7, 12ml/min, 250nm) afforded the title compound: RT = 1.41 min; m/z (ES⁺) = 648.57 [M+ H]⁺ (LCMS Method-6).

Preparation 271: [(3R,45)-l-{5-[(3S,4R)-l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-3- methoxy-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- 3-yl]-carbamic acid tert- ty\ ester

The title compound was synthesized from 2-chloro-5-[(czV)-l-(3-isopropyl- [1 ,2,4]oxadiazol-5-yl)-3-methoxy-piperidin-4-ylmethoxy]-pyrimidine (Preparation 269) employing the procedure outlined in Preparation 270: RT = 1.41 min; m/z (ES ) = 648.57 [M + H]⁺ (LCMS Method-6). Preparation 272: 4-Fluoro-3-((£')-2-nitr -vinyl)-benzoic acid methyl ester

The title compound was synthesized from 4-fluoro-3-formyl-benzoic acid methyl ester (10. Og, 53.5mmol) employing a procedure similar to that outlined in Preparation 35, using IPA in place of MeOH: 1H NMR δ_Η (300MHz, CDC1₃): 8.25-8.22 (m, 1H), 8.20-8.10 (m, 1H), 8.07 (d, J=13.7 Hz, 1H), 7.27 (d, J=13.7 Hz, 1H), 7.29-7.23 (m, 1H), 3.92 (s, 3H).

Preparation 273: 3-((frans)-l-Benzyl-4-nitro-pyrrolidin-3-yl)-4-fluoro-benzoic acid methyl ester

The title compound was prepared from 4-fluoro-3-((E)-2-nitro-vinyl)-benzoic acid methyl ester (Preparation 272) employing a method similar to that outlined in Preparation 31, but the reaction was carried out at 0°C. Purification by column chromatography

(Heptane:EtOAc, 6: 1) afforded the title compound. RT = 3.15 min; mlz (ES⁺) = 359.2 [M + H]⁺ (LCMS Method - 4).

Preparation 274: (irans)-l-Benzyl-4-(2-fluoro-5-methoxycarbonyl-phenyl)-pyrrolidin-3- yl-ammonium

To a solution of 3-((tra/75)-l-benzyl-4-nitro-pyrrolidin-3-yl)-4-fluoro-benzoic acid methyl ester (Preparation 273, 14.7g, 41.0mmol) in AcOH (225mL) at 50°C was added zinc powder (3.88g, 243mmol) in four portions over 1.5 h. The resulting reaction mixture was heated at 50°C for 15 h. Upon cooling, the reaction mixture was filtered through celite, washing with AcOH (3 x lOOmL) and the filtrate concentrated in vacuo. The remainder was added cautiously to saturated aqueous NaHC0₃ solution (750mL) and extracted with DCM (3 x 300mL). The combined organic extracts were washed with water (750mL) and brine (500mL), dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotography (MeOH:DCM; 99: 1 to 98:2 to 97:3 to 96:4 to 95:5 to 94:6 to 92:8 to 90: 10) afforded the title compound: RT = 2.93 min; mlz (ES⁺) = 329.2 [M+ H]⁺ (LCMS Method - 4)·

Preparation 275: 3-((irans)-l-Benzyl-4-tert-butoxycarbonylamino-pyrrolidin-3-yl)-4- fluoro-benzoic acid methyl ester

To a solution of (tra/75)-l-benzyl-4-(2-fluoro-5-methoxycarbonyl-phenyl)-pyrrolidin- 3-yl-ammonium (Preparation 274, 2.37g, 7.22mmol) and triethylamine (3mL, 21.7mmol) in THF (30mL) at 0°C was added άι-tertiary - vXyl dicarbonate (2.36g, 10.83mmol) and the resulting reaction mixture stirred at 0°C for 1 h, then at r.t. for 16 h. The solvent was removed in vacuo and the remainder dissolved in EtOAc, washed with water and brine, dried (MgS0₄), filtered and concentrated in vacuo. The remainder was triturated with heptane and the solid collected by filtration to afford the title compound: RT = 0.97 min; mlz (ES ) = 429.3 [M+ H]⁺ (LCMS Method - 2).

Preparation 276: [(irans)-l-Benzyl-4-(2-fluoro-5-hydroxymethyl-phenyl)-pyrrolidin-3- yl]-carbamic acid terf-butyl ester

To a solution of 3-((tra/75)-l-benzyl-4-tert-butoxycarbonylamino-pyrrolidin-3-yl)-4- fluoro-benzoic acid methyl ester (Preparation 275, 1.95g, 4.55mmol) in THF (7mL) at - 10°C was added lithium aluminium hydride (1M, 2.3mL, 2.3mmol) over 3 min and the resulting reaction mixture was stirred at -10°C for 100 min. EtOAc (30mL) and saturated aqueous Rochelle's salt solution (lOmL) were added and the reaction mixture stirred at -

10°C for 16 h. The organic layer was separated, washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (DCM:EtOAc; 1 : 1) afforded the title compound: RT = 3.05 min; mlz (ES⁺) = 401.3 [M + H]⁺ (LCMS Method - 4)· Preparation 277: [(3R,4S)-l-Benzyl-4-(2-fluoro-5-fluoromethyl-phenyl)-pyrrolidin-3- yl]-carbamic acid tert-butyl ester

To a solution of [(trans)- l-benzyl-4-(2-fluoro-5-hydroxymethyl-phenyl)-pyrrolidin- 3-yl]-carbamic acid tert-butyl ester (Preparation 276, 1.34g, 3.35mmol) in DCM (20mL) at -78°C was added DAST (0.66mL, 5.02mmol) and the resulting reaction mixture stirred at - 78°C for 2 h. Water and saturated aqueous NaHC0₃ solution were added, then the reaction mixture was warmed to r.t. and extracted with DCM (4 x). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purifictaion by column chromotogrpahy (DCM:EtOAc; 6:1 to 5: 1) afforded [(trans)- 1 -benzyl-4-(2-fluoro-5- fluoromethyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. Purification by chiral HPLC (IH:IPA:diethylamine; 96:4:0.1, 15ml/min, 270nm, RT = 11.6 min), afforded the title compound: RT = 3.01 min; mlz (ES⁺) = 403.3 [M+ H]⁺ (LCMS Method - 3).

Preparation 278 : [(3R, S)-4-(2-Fluoro-5-fluor omethyl-phenyl)-pyr rolidin-3-yl] - carbamic acid tert-butyl ester

To a solution of [(3 ?,45)-l-benzyl-4-(2-fluoro-5-fluoromethyl-phenyl)-pyrrolidin-3- yl]-carbamic acid tert-butyl ester (Preparation 277, 0.092g, 0.23mmol) in DCE (1 lmL) and DIPEA (0.32mL, 1.8mmol) was added trichloroethyl chloroformate (47.2μΕ, 0.343mmol) dropwise and the resulting reaction mixture was heated under reflux conditions for 2 h. The solvent was removed in vacuo, the residue dissolved in AcOH (2mL) and zinc (50mg, 0.76mmol) was added portion wise. The resulting reaction mixture was stirred at r.t. for 2 h, MeOH (lOmL) was added and the reaction mixture filtered through celite. The filtrate was concentrated in vacuo and the residue purified by preparative HPLC to afford the title compound: RT = 0.72 min; mlz (ES⁺) = 313.34 [M+ H]⁺ (LCMS Method - 6).

Preparation 279: l-(2-Fluoro-5-methyl-phenyl)-2-nitro-ethanol

To a solution of 2-fluoro-5-methyl-benzaldehyde (5.0g, 36.2mmol) and nitromethane (2.35mL, 43.5mmol) in MeOH (90mL) at 0°C was added a solution of NaOH (1.52g, 38.0mmol) in H₂0 (15mL) dropwise over 10 min and the resulting reaction mixture was stirred at r.t. for 50 min. The reaction mixture was poured into saturated aqueous NH₄C1 solution and extracted with DCM (3 x). The combined organics were washed with brine, dried (MgSC^), filtered and concentrated in vacuo to afford the title compound: 1H NMR 5H (300MHz, CDCI3): 7.34-7.30 (m, 1H), 7.15-7.10 (m, 1H), 7.0-6.9 (m, 1H), 5.71-5.70 (m, 1H), 4.63-4.57 (m, 2H), 2.93 (br. s, 1H), 2.33 (s, 3H).

Preparation 280: l-Fluoro-4-methyl-2-((£)-2-nitro-vinyl)-benzene

To a solution of l-(2-fluoro-5-methyl-phenyl)-2-nitro-ethanol (Preparation 279, 7.18g, 36.1mmol) in acetic anhydride (6.8mL, 22.2mmol) was added DMAP (300mg, 2.5mmol) and the resulting reaction mixture was stirred at r.t. for 19 h. The reaction mixture was slowly poured into saturated aqueous NaHC0₃ solution and stirred vigorously for 1 h. The solid was collected by filtration, washing with saturated aqueous NaHC0₃ solution, then H₂0 to afford the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 8.04-7.99 (d, J=13.76 Hz, 1H), 7.74-7.69 (d, J=13.76 Hz, 1H), 7.30-7.26 (m, 2H), 7.1-7.0 (m, 1H), 2.36 (s, 3H).

Preparation 281: (rrans)-l-Benzyl-3-(2-fluoro-5-methyl-phenyl)-4-nitro-pyrrolidine

To a solution of l-fluoro-4-methyl-2-((E)-2-nitro-vinyl)-benzene (Preparation 280, 6.38g, 35.3mmol) in DCM (70mL) at 10°C was added TFA (0.27mL, 3.52mmol), followed by dropwise addition of N-(methoxyrnethyl)-N-(trimethylsilylmethyl)benzylamine (9.52mL, 38.8mmol) in DCM (30mL). The resulting reaction mixture was stirred at r.t. for 1.5 h, poured into saturated aqueous NaHC0₃ solution and extracted with DCM (3 x). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 7.35-7.26 (m, 5H), 7.1-7.0 (m, 2H), 7.0-6.9 (m, 1H), 5.04-5.02 (m, 1H), 4.17-4.15 (m, 1H), 3.77-3.65 (m, 2H), 3.5-3.46 (m, 1H), 3.3-3.26 (m, 1H), 3.1-3.0 (m, 1H), 2.65-2.60 (m, 1H), 2.30 (s, 3H).

Preparation 282: (rrans)-l-Benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl- ammonium

To a solution of (tra/75)-l-Benzyl-3-(2-fluoro-5-methyl-phenyl)-4-nitro-pyrrolidine (Preparation 281, 11.4g, 35.3mmol) in AcOH (90mL) at 30°C was added zinc (13.8g,

212mmol) portion wise over 30 min. The resulting reaction mixture was stirred at 30°C for 1 h, then filtered through celite washing with AcOH. The filtrate was concentrated in vacuo, the remainder dissolved in DCM (30mL) and poured slowly into saturated aqueous NaHC0₃ solution (900mL). The resulting mixture was stirred at r.t. for 16 h, the layers separated and the aqueous extracted with DCM (2 x). The combined organic extracts were dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotography (DCM:MeOH, 19:1 to 9: 1 to 17:3 to 4: 1 to 7:3 to 3:2) afforded the title compound: RT = 3.06 min; mlz (ES⁺) = 285.1 [M+ H]⁺ (LCMS Method - 4). Preparation 283: [(rrans)-l-Benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-buty\ ester

To a solution of (tra/75)-l-benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl- ammonium (Preparation 282, 5.6g, 19.7mmol) in THF (80mL) at 0°C was added triethylamine (5.65mL, 40mmol) and di-tert-butyldicarbonate (5.15g, 23.6mmol) in THF (30mL) and the resulting reaction mixture was stirred at r.t. for 21 h. The reaction mixture was poured into water, extracted with EtOAc (3 x) and the combined organic extracts washed with brine, dried (MgSC^), filtered and concentrated in vacuo. The resulting oil was dissolved in IH, allowed to stand at r.t. and the solid collected by filtration, washing with IH, to afford the title compound: RT = 3.36 min; mlz (ES ) = 385.1 [M+ H] (LCMS Method -

4)·

Preparation 284: [(3R,4S)-l-Benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester

The title compound was afforded via chiral HPLC separation of [(trans)- 1 -benzyl-4-(2- fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 283): IH:IPA:DEA 96:4:0.1, 15ml/min, 270nm, RT = 8.2 min.

Preparation 285: [(3R,4S)-4-(2-Fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

A solution of [(3 ?,45)-l-benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester (Preparation 284, 2.4g, 6.2mmol) in MeOH (124 mL) was passed through an H-Cube apparatus (10% Pd/C Catcart 70, lOObar, 50°C) at a flow rate of lmL per min. The solvent was removed in vacuo to afford the title compound: RT = 2.42 min; mlz (ES⁺) = 295.32 [M+ H]⁺. Preparation 286: l-(2,4-Difluoro-5-m thyl-phenyl)-2-nitro-ethanol

To a solution of 2,4-difluoro-5-methyl-benzaldehyde (15.0g, 96.1mmol) and nitromethane (7.33g, 120mmol) in IPA (150mL) at 0°C was added a solution of NaOH (5.22g, 131mmol) in H₂0 (20mL) dropwise over 10 min and the resulting reaction mixture was stirred at r.t. for 1 h. Water (90mL) and saturated aqueous NH₄C1 solution (105mL) were added and extracted with DCM (3 x 250mL). The combined organic extracts were washed with brine, dried (Na₂S0₄), filtered and concentrated in vacuo. Purification by column chromatography (IH:EtAOc, 9: 1 to 7:1 to 4: 1 to 3: 1) afforded the title compound: 1H NMR δ_Η (300MHz, CDCI3): 7.38-7.34 (m, 1H), 6.82-6.76 (m, 1H), 5.69-5.66 (m, 1H), 4.61-4.51 (m, 2H), 2.95 (s, 1H), 2.28 (s, 3H).

Preparation 287: l,5-Difluoro-2-methyl-4-((£)-2-nitro-vinyl)-benzene

The title compound was synthesized from l-(2,4-difluoro-5-methyl-phenyl)-2-nitro- ethanol (Preparation 286, 14.5g, 66.9mmol) employing a procedure similar to that outlined in Preparation 280: 1H NMR δ_Η (400MHz, CDC1₃): 7.99-7.96 (d, J=13.73 Hz, 1H), 7.68- 7.65 (d, J=13.73 Hz, 1H), 7.34-7.3 (m, 1H), 6.91-6.89 (m, 1H), 2.27 (s, 3H). Preparation 288: (rrans)-l-Benzyl- -(2,4-difluoro-5-methyl-phenyl)-4-nitro-pyrrolidine

The title compound was synthesized from l,5-difluoro-2-methyl-4-((E)-2-nitro- vinyl)-benzene (Preparation 287, 12. Og, 60.3mmol) employing a procedure similar to that outlined in Preparation 281: RT = 1.00 min; mlz (ES⁺) = 333.2 [M+ H]⁺ (LCMS Method- 2)· Preparation 289: (rrans)-l-Benzyl-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3- ylamine

The title compound was synthesized from (trans)- l-benzyl-3-(2,4-difluoro-5-methyl- phenyl)-4-nitro-pyrrolidine (Preparation 288, 21.0g, 63.3mmol) employing a procedure similar to that outlined in Preparation 282: RT = 0.93 min; mlz (ES⁺) = 303.2 [M+ H]⁺ (LCMS Method-2).

Preparation 290: [(rrans)-l-Benzyl-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-buty\ ester

The title compound was synthesised from ( rans)- l-benzyl-4-(2,4-difluoro-5-methyl- phenyl)-pyrrolidin-3-ylamine (Preparation 289, 9.5g, 31.5mmol) employing a procedure similar to that outlined in Preparation 283: RT = 3.25 min; mlz (ES⁺) = 403.3 [M+ H]⁺ (LCMS Method-3).

Preparation 291: [(3R,4S)-l-Benzyl-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-buty\ ester

The title compound was afforded via chiral HPLC separation of [(trans)- l-benzyl-4-

(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 290): IH:IPA:DEA 96:4:0.1, 15ml/min, 270nm, RT = 9.0 min. Preparation 292 : [(3R,4S)-4-(2,4-Difluoro-5-methyl-phenyl)-pyrrolidin-3-yl] -carbamic acid tert-buty\ ester

A solution of [(3 ?,45)-l-benzyl-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester (Preparation 291, 1.97g, 4.9mmol) in MeOH (100 mL) was passed through an H-Cube apparatus (10% Pd/C Catcart 70, 80bar, 50°C) at a flow rate of lmL per min. The solvent was removed in vacuo to afford the title compound: RT = 0.68 min; m/z (ES⁺) = 313.32 [M+ H]⁺ (LCMS Method-6).

Preparation 293: 3, N-Dimethoxy-N-methyl-isonicotinamide

A suspension of 3-methoxypyridine-4-carboxylic acid hydrochloride (5.48g,

28.9mmol) in thionyl chloride (40mL) was heated under reflux conditions for 6 h. Upon cooling, the solvent was removed in vacuo and the residue supended in DCM (150mL). Ν,Ο- Dimethylhydroxylamine hydrochloride (5.64g, 57.8mmol) was added and the suspension cooled to 0°C before the portionwise addition of triethylamine (16.1mL, 116mmol). The reaction was stirred at r.t.for a further 18 h before removal of the solvent in vacuo. The residue was partitioned between EtOAc (200mL) and water (120mL) and the aqueous layer separated and further extracted with chloroformTPA (4: 1, 3 x lOOmL). The combined organic extracts were concentrated in vacuo and the remainder purified by column chromatography (EtOAcTH; 3 : 1 to 1 :0) to afford the title compound: 1H NMR δ_Η (400 MHz, CDCls): 8.38 (s, 1 H), 7.14 - 7.21 (m, 1 H), 3.96 (s, 3 H), 3.49 (br. s., 3 H), 3.37 (br. s., 3 H).

Preparation 294: l-(3-Methoxy-pyridin-4-yl)-ethanone

To a solution of 3, N-dimethoxy-N-methyl-isonicotinamide (Preparation 293, 4.83g, 24.6mmol) in THF (40mL) at 0°C was added methylmagnesium bromide (3.0M in Et₂0, 12.3mL, 36.9mmol) and the resulting reaction mixture was stirred at 0-5°C for 90 min. The reaction was quenched with saturated aqueous NH₄C1 solution (50mL) and extracted with EtOAc (3 x 80mL). The combined organic extracts were concentrated in vacuo to afford the title compound: 1H NMR δ_Η (400 MHz, CDC1₃): 8.48 (s, 1 H), 8.36 (d, J=4.69 Hz, 1 H), 7.49 (d, J=5.08 Hz, 1 H), 4.04 (s, 3 H), 2.63 (s, 3 H).

Preparation 295: (R)-l-(3-Methoxy-pyridin-4-yl)-ethanol

To a solution of diphenyl[(25)-pyrrolidin-2-yl]methanol (623mg, 2.46mmol) in THF (25mL) was added boric acid, trimethyl ester (0.335mL, 2.95mmol) and the reaction mixture stirred at r.t. for 1 h. Borane-dimethylsulfide complex (4.67mL, 49.2mmol) was added and the resulting reaction mixture stirred at r.t. for 15 min prior to the slow addition of l-(3- methoxy-pyridin-4-yl)-ethanone (Preparation 294, 3.72g, 24.6mmol) in THF (5mL) over 1 h. The reaction mixture was stirred at r.t. for a further 1 h, then cautiously acidified by the dropwise addition of aqueous HC1 (12M) and the reaction mixture stirred at r.t. for 20 min. The pH was adjusted to pH 8 with saturated aqueous NaHC0₃ solution and the solution extracted with EtOAc (3 x 80mL). The combined organic extracts were concentrated in vacuo and the residue analysed by chiral HLPC (IH:MTBE:MeOH 75:20:5, lmL/min, 285nM) which indicated the ratio of enantiomers to be > 9: 1. The remainder was purified by column chromatography (DCM:MeOH; 1 :0 to 95:5) to afford the title compound: 1H NMR δ_Η (500 MHz, CDC1₃): 8.24 (d, J=4.42 Hz, 1 H), 8.20 (s, 1 H), 7.35 (d, J=4.98 Hz, 1 H), 5.12 (q, J=6.27 Hz, 1 H), 3.93 (s, 3 H), 1.47 (d, J=6.63 Hz, 3 H).

Preparation 296: (cis)-4-((R)-l-Hydroxy-ethyl)-3-methoxy-piperidine-l-carbonitrile

To a solution of (i?)-l-(3-methoxy-pyridin-4-yl)-ethanol (Preparation 295, 3.67g, 24.0 mmol) in MeOH (lOOmL) was added AcOH (1.50mL, 26.4mmol) followed by platinum dioxide (0.381g, 1.68mmol). The reaction mixture was placed under a hydrogen atmosphere (approximately 800 Psi) and stirred for 22 h. Furher AcOH (1.50mL, 26.4mmol) and platinum dioxide (0.381g, 1.68mmol) were added and the reaction mixture was stirred under a hydrogen atmosphere (approximately 800 Psi) at 40°C for 6 h, at r.t. for 15 h, at 40°C for 10 h and at r.t. for 83 h. The reaction mixture was filtered and the filtrate concentrated in vacuo to afford (i?)-l-((cz^'5)-3-methoxy-piperidin-4-yl)-ethanol acetate. The product was dissolved in DCM (lOOmL) and a slurry of NaHC0₃ (lO.lg, 0.12mol) in H₂0 (lOOmL) was added. The reaction mixture was cooled to 0°C, cyanogen bromide (2.80g, 26.4mmol) in DCM (30mL) was added and the resulting reaction mixture warmed to r.t. and stirred for 5 h. The organic layer was separated, concentrated in vacuo and the remainder purified by column chromatography (EtOAc:IH; 1 :1 to 1 :0) to afford the title compound: 1H NMR δπ (500 MHz, CDC1₃): 3.79 - 3.87 (m, 1 H), 3.75 (br. s., 1 H), 3.68 - 3.74 (m, 1 H), 3.47 - 3.52 (m, 1 H), 3.46 (s, 3 H), 3.05 (td, J=12.85, 3.04 Hz, 1 H), 2.89 (dd, J=13.82, 1.11 Hz, 1 H), 2.37 (d, J=7.19 Hz, 1 H), 2.07 - 2.13 (m, 1 H), 1.38 - 1.49 (m, 2 H), 1.25 (d, J=6.08 Hz, 3 H),

Preparation 297: (R)-l-[(cis)-l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-3-methoxy-piperidin- 4-yl]-ethanol

The title compound was synthesized from (czs)-4-((i?)-l-hydroxy-ethyl)-3-methoxy- piperidine-l-carbonitrile (Preparation 296) employing a procedure similar to that outlined in Preparation 266: 1H NMR δ_Η (500 MHz, CDC1₃): 4.46 - 4.54 (m, 1 H), 4.18 - 4.23 (m, 1

H), 3.76 - 3.86 (m, 2 H), 3.42 (s, 3 H), 3.08 (td, J=12.99, 2.76 Hz, 1 H), 2.95 (dd, J=14.37, 1.11 Hz, 1 H), 2.84 - 2.93 (m, 1 H), 2.48 (d, J=7.19 Hz, 1 H), 1.94 - 2.05 (m, 1 H), 1.46 - 1.57 (m, 2 H), 1.29 (d, J=6.63 Hz, 6 H), 1.26 (d, J=6.08 Hz, 3 H).

Preparation 298: 2-Chloro-5-{(5)-l-[(cw)-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-3- methoxy-piperidin-4-yl]-ethox -pyrimidine

To a solution of (i?)-l-[(cz5)-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-3-methoxy- piperidin-4-yl]-ethanol (Preparation 297, 0.2g, 0.7mmol) and 2-chloro-5- hydroxypyrimidine (0.121g, 0.928mmol) in THF (6mL) was added PPh₃ (0.390g, 1.48mmol) and TBAD (0.342g, 1.48mmol). The resulting reaction mixture was heated to 60°C and stirred for 2.5 h. Upon cooling, the reaction mixture was concentrated in vacuo and the remainder partitioned between EtOAc (30mL) and water (20mL). The organic layer was separated, washed with brine (20mL) and concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 1.15 min; mlz (ES⁺) = 382.4 [M+ H]⁺ (LCMS Method-6).

Preparation 299: 4-(2-Chloro-pyrimidin-5-yloxymethyl)-4-hydroxy-piperidine-l- carboxylic acid tert-butyl ester

To a solution of l-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (1.61g, 7.55mmol) in DMF (lOmL) was added 2-chloro-5-hydroxypyrimidine (1.08g, 8.30mmol) and potassium carbonate (1.56g, 11.3mmol) and the resulting reaction mixture was heated at 80°C for 20 h. The solvent was removed in vacuo and the residue partitioned between EtOAc (lOOmL) and water (50mL). The organic layer was separated, washed with brine (2 x 50mL) and concentrated in vacuo. Purification by column chromotogrpahy (EtOAcTH; 3:7 to 6:4) afforded the title compound: RT = 0.96 min; mlz (ES⁺) = 344.30 [M + H]⁺ (LCMS Method-6).

Preparation 300: 4-(2-Chloro-p rimidin-5-yloxymethyl)-piperidin-4-ol hydrochloride

To a solution of 4-(2-chloro-pyrimidin-5-yloxymethyl)-4-hydroxy-piperidine-l- carboxylic acid tert-butyl ester (Preparation 299, 0.566g, 1.65mmol) in 1,4-dioxane (5mL) was added HCl in 1,4-dioxane (4M, 5mL, 20mmol) and the resulting reaction mixture was stirred at r.t. for 4 h. The solvent was removed in vacuo to afford the title compound: RT = 0.37 min; mlz (ES⁺) = 244.22 [M+ H]⁺ (LCMS Method-6).

Preparation 301: 4-(2-Chloro-pyrimidin-5-yloxymethyl)-4-hydroxy-piperidine-l- carbonitrile

To a solution of 4-(2-chloro-pyrimidin-5-yloxyrnethyl)-piperidin-4-ol hydrochloride (Preparation 300, 0.432g, 1.54mmol) in DCM (15mL) was added NaHC0₃ (0.389g, 4.63mmol) in H₂0 (15mL). The resulting reaction mixture was cooled to 0°C and cyanogen bromide (0.196g, 1.85mmol) was added prior to warming the reaction mixture to r.t. and stirring for 5 h. The aqueous layer was separated, extracted with DCM (20mL) and the combined organic layers were concentrated in vacuo to afford the title compound: RT = 0.68 min; mlz (ES⁺) = 269.23 [M+ H]⁺ (LCMS Method-6).

Preparation 302: 4-(2-Chloro-pyrimidin-5-yloxymethyl)-l-(3-ethyl-[l,2,4]oxadiazol-5- yl)-piperidin-4-ol

To a solution of 4-(2-chloro-pyrimidin-5-yloxymethyl)-4-hydroxy-piperidine-l- carbonitrile (Preparation 301, 0.391g, 1.46mmol) and N-hydroxypropionamidine (0.154g, 1.75mmol) in EtOH (6mL) was added zinc dichloride (0.238g, 1.75mmol) in EtOH (2mL) dropwise. The resulting reaction mixture was stirred at r.t. for 2.5 h. Aquoues HC1 (12M, 0.36 ImL, 4.36mmol) was added and the reaction mixture heated under reflux conditions for 5 h. The solvent was removed in vacuo, the residue suspended in water (15mL) and the pH adjusted to ~ pH 8 with saturated aqueous NaHC0₃ solution. The mixture was extracted with EtOAc (3 x 25mL) and the combined organic extracts concentrated in vacuo to afford the title compound: RT = 0.81 min; mlz (ES⁺) = 340.30 [M+ H]⁺ (LCMS Method-6).

Preparation 303 : 2-Chloro-5- [ l-(3-ethyl- [ 1 ,2,4] oxadiazol-5-yl)-4-methoxy-piperidin-4- ylmethoxy]-pyrimidine

To a solution of 2-chloro-5-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)-4-methoxy-piperidin- 4-ylmethoxy]-pyrimidine (Preparation 302, lOOmg, 0.294mmol) in anhydrous DMF (3mL) at 0°C was added NaH (60% dispersion in mineral oil, 12.9mg, 0.324mmol) portion wise and the resulting reaction mixture was stirred at 0-5°C for 15 min. Methyl iodide (36.6μΕ, 0.589mmol) was added and the resulting reaction mixture was warmed to r.t. and stirred for 3 h. The reaction mixture was cooled to 0°C and further NaH (60% dispersion in mineral oil, 12.9mg, 0.324mmol)) and methyl iodide (36.6μί, 0.589mmol) were added. The reaction mixture was warmed to r.t. and stirred for a further 19 h. The solvent was removed in vacuo and the remainder partitioned between EtOAc (lOmL) and H₂0 (5mL). The organic layer was separated, washed with brine (5mL) and concentrated in vacuo to afford the title compound: RT = 0.95 min; mlz (ES⁺) = 354.32 [M+ H]⁺ (LCMS Method-6).

Preparation 304: 4-(2-Chloro-pyrimidin-5-yloxymethyl)-4-fluoro-piperidine-l- carboxylic acid tert-butyl ester

To a solution of 4-(2-chloro-pyrimidin-5-yloxymethyl)-4-hydroxy-piperidine-l- carboxylic acid tert-butyl ester (Preparation 299, 500mg, lmmol) in DCM (lOmL) at 0°C was added diethylaminosulfur trifluoride (0.23mL, 1.7mmol) dropwise. The resulting reaction mixture was stirred at 0-5°C for 1 h, then quenched with saturated aqueous NaHC0₃ solution (5mL) and the organic layer separated and concentrated in vacuo. Purification by column chromatography (EtOAcTH; 0: 1 to 1 :0) afforded the title compound: RT = 1.18 min; mlz (ES⁺) = 290.23 [M -56]⁺ (LCMS Method-6).

Preparation 305: 4-(2-Chloro-pyrimidin-5-yloxymethyl)-4-fluoro-piperidine-l- carbonitrile

The title compound was synthesized from 4-(2-chloro-pyrimidin-5-yloxymethyl)-4- fluoro-piperidine-l-carboxylic acid tert-butyl ester (Preparation 304, 410mg, 1.2mmol) employing the procedures outlined in Preparation 300 and Preparation 301: RT = 0.87 min; mlz (ES⁺) = 271.25 [M+ H]⁺ (LCMS Method-6).

Preparation 306 : 2-Chloro-5- [ l-(3-ethyl- [ 1 ,2,4] oxadiazol-5-yl)-4-fluoro-piperidin-4- ylmethoxy]-pyrimidine

Crude title compound was synthesized from 4-(2-chloro-pyrimidin-5-yloxymethyl)- 4-fluoro-piperidine-l-carbonitrile (Preparation 305, 0.23 lg, 0.853mmol) employing a procedure similar to that outlined in Preparation 302. Purification by column

chromatography (EtOAc:IH; 3:7 to 1 : 1) afforded the title compound: RT = 1.0 min; mlz (ES⁺) = 342.28 [M+ H]⁺ (LCMS Method-6).

Preparation 307: 5-Bromo-2-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4- ylmethoxy] -pyridine

The title compound was synthesised from [(l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]methanol (Preparation 1, 777mg, 3.45mmol) and 5-bromo-2- hydroxypyridine employing a procedure similar to that outlined in Preparation 244: RT = 4.28 min; mlz (ES⁺) = 381.06, 383.05 [M+ H]⁺.

Preparation 308: ((3R,45)-4-(2,5-Difluoro-phenyl)-l-{6-[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)-piperidin-4-ylmethoxy]-pyridin-3-yl}-pyrrolidin-3-yl)-carbamic acid terf-butyl ester

A mixture of [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 300mg, l .OOmmol), 5-bromo-2-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)-piperidin-4-ylmethoxy]-pyridine (Preparation 307, 0.320g, 0.838mmol), sodium tertiary butoxide (96.6mg, l .OOmmol) and biphenyl-2-yl(di-tert-butyl)phosphine (50mg, 0.168mmol) in a sealed tube in toluene (5mL) was degassed with argon for 20 min.

Tris(dibenzylideneacetone)dipalladium (38.4mg, 41.9μmol) was added and the resulting reaction mixture was heated at 90°C for 66 h. Upon cooling, the reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by 7.5% NH₄OH in MeOH (7.5%). The basic fraction was concentrated in vacuo and the remainder purified by preparative HPLC to afford the title compound: RT = 4.55 min; mlz (ES ) = 599.36 [M +

HT. Preparation 309: 2-Chloro-4-(l-ethox -vinyl)-5-methoxy-pyrimidine

To a solution of 2,4-dichloro-5-methoxypyrimidine (12.39g, 69.22mmol) in 1,4- dioxane (0.5L, 6000mmol) was added a solution of potassium carbonate (19.13g,

138.5mmol) in H₂0 (20mL). The solution was degassed with argon for 10 min and 1- ethoxyvinyltri-n-butyltin (25. Og, 69.2mmol) and Pd(PPh3)₂Cl₂ (2.43g, 3.46mmol) were added. The mixture was heated to 100°C for 30 min and the solvent removed in vacuo. The residue was partitioned between DCM (550mL) and H₂0 (600mL) and the organic layer separated and concentrated in vacuo. Purification by column chromatography (EtOAcTH; 2:3) afforded the title compound: RT = 3.04 min; mlz (ES⁺) = 215.0 [M+ H]⁺.

Preparation 310: 2-Chloro-5-methoxy- rimidine-4-carboxylic acid ethyl ester

To a solution of 2-chloro-4-(l-ethoxy-vinyl)-5-methoxy-pyrimidine (Preparation 309, 4.00g, 18.6mmol) in 1,4-dioxane (300mL) was added a solution of potassium meta- periodate (8.57g, 37.3mmol) in H₂0 (90mL). Potassium permanganate (294mg, 1.86mmol) was added and the resulting reaction mixture stirred at r.t. for 30 min. The reaction mixture was poured into DCM (400mL) and the organic layer separated. The aqueous was extracted with DCM (2 x 400mL) and the combined organic extracts dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: RT = 2.84 min; mlz (ES ) = 217.1 [M +

H]⁺.

Preparation 311: [(3R,4S)-l-(4-Carbamoyl-5-methoxy-pyrimidin-2-yl)-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-buty\ ester

To 2-chloro-5-methoxy-pyrimidine-4-carboxylic acid ethyl ester (Preparation 310, (1.3 lOg, 6.047mmol) at 0°C was added a solution of saturated aquoues ammonium hydroxide (20mL) and the resulting reaction mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo and the remainder purified by preparative HPLC. The crude product was dissolved in DMSO (5mL). [(3i?,45)-4-(2,5-Difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 462mg, 1.55mmol) and DBU (0.77 lmL, 5.16mmol) were added and the resulting reaction mixture stirred at r.t. for 1 h and at 95°C for 3 h. The solvent was removed in vacuo and the remainder triturated with EtOAc and MeOH. The solid was collected by filtration to afford the title compound: RT = 3.40 min; mlz (ES ) =

Preparation 312: 2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-5- hydroxy-pyrimidine-4-carboxylic acid amide

A mixture of [(3i?,45)-l-(4-carbamoyl-5-methoxy-pyrimidin-2-yl)-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 311, 1.7g, 3.8mmol) and lithium iodide (6.00g, 44.8mmol) in 2-methylpyridine (30mL) in a sealed tube was heated at 120°C under microwave irradiation. The solvent was removed in vacuo and the remainder partitioned between EtOAc (lOOmL) and water (200mL). The layers were separated and the aqueous extracted with EtOAc (3 x 50mL). The combined organic extracts were washed with brine (50mL), dried (MgS0₄), filtered and concentrated in vacuo.

Purification by preparative HPLC afforded the title compound: RT = 2.23 min; mlz (ES ) =

Preparation 313: [(3R,4S)-l-(4-Carbamoyl-5-hydroxy-pyrimidin-2-yl)-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-but \ ester

To a solution of 2-[(3i?,45)-3-amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-5- hydroxy-pyrimidine-4-carboxylic acid amide (Preparation 312, 135mg, 0.403mmol) in THF (lO.OmL) was added triethylamine (112μΕ, 0.805mmol) and di-tert-butyldicarbonate (132mg, 0.604mmol). The resulting reaction mixture was heated at 100°C for 2 h. Upon cooling, the reaction mixture was partitioned between aqueous potassium carbonate solution (10%, 20mL) and EtOAc (lOOmL). The layers were separated and the aqueous phase extracted with EtOAc (2 x 20mL). The combined organic extracts were washed with brine (20mL), dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAcTH; 1 :9 to 1 : 1) afforded the title compound: RT = 3.84 min; m/z

Preparation 314: [(3R,4S)-l-(4-Cyano-5-hydroxy-pyrimidin-2-yl)-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-but \ ester

To a solution of [(3i?,45)-l-(4-carbamoyl-5-hydroxy-pyrimidin-2-yl)-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 313, 85mg, 0.20mmol) in THF (5mL) at 0°C was added pyridine (63μΕ, 0.78mmol) and TFAA (1 ΙΟμΕ, 0.78mmol) and the resulting reaction mixture was stirred at 0°C for 10 min and at r.t. for 80 min. Further TFAA (55μί, 0.39mmol) was added and the reaction mixture stirred for 1 h. Aqueous potassium carbonate solution (10%, 20mL) and EtOAc (50mL) were added and the reaction mixture stirred vigorously for 10 min. The layers were separated and the aqueous layer was extracted with EtOAc (30mL). The combined organic extracts were washed with brine (30mL), dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (DCM:MeOH; 95:5) afforded the title compound: RT = 3.87 min; m/z (ES ) = 418.38 [Μ+ ηγ. Preparation 315: [(3R,4S)-4-(2-Fluoro-5-methyl-phenyl)-l-(5-{(S)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-buty\ ester

To a solution of 2-chloro-5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrimidine (Preparation 63, 60mg, 0.17mmol) and [(3i?,45)-4-(2-fluoro-5- methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 285, lOOmg, 0.3mmol) in DMSO (3.4mL) was added DBU (25.4μΕ, 0.17mmol) and the resulting reaction mixture was stirred at 90°C for 96 h. Upon cooling, the reaction mixture was partitioned between brine and EtOAc. The organic layer was separated, washed with brine (2 x) and concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 4.67 min; m/z (ES⁺) = 610.36 [M+ H]⁺.

Preparation 316: 2-Chloro-5-{l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-2- methoxy-ethoxy}-pyrimidine and 2-Bromo-5-{l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-2-methoxy-ethoxy}-pyrimidine

To a solution of l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]-2- methoxyethanol (Preparation 104, 3.477g, 12.91mmol), 2-chloro-pyrimidin-5-ol (1.45g, 1 l .lmmol), 2-bromo-pyrimidin-5-ol (0.88g, 16.1mmol) and PPh₃ (6.77g, 25.8mmol) in THF (150mL) was added TBAD (5.94g, 25.8mmol) and the resulting reaction mixture was stirred at 60°C for 75 min. Further TBAD (2.97g, 12.9mmol) and PPh₃ (3.39g, 12.9mmol) were added and the reaction mixture heated at 60°C for a further 30 min. The solvent was removed in vacuo, then the residue was dissolved in EtOAc and washed with water, aqueous NaOH solution (2M) and brine, dried (MgS0₄), filtered and concentrated in vacuo. The remainder was triturated with Et₂0, the precipitate collected by filtration and the filtrate was concentrated in vacuo. Purification by column chromotography (DCM then EtOAcTH; 1 : 1), followed by further purification by column chromotogrpahy (EtOAcTH; 2:3) afforded the title compound as an 11 :5 ratio of chloro:bromo isomers: RT = 3.67 min; mlz (ES ) = 382.10, 426.05, 428.05 [M+ H]⁺.

Preparation 317: [(3R,45)-l-(5-{l-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- 2-methoxy-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-buty\ ester

To a solution of 2-chloro-5-(2-methoxy-l-l-[3-(propan-2-yl)-l,2,4-oxadiazol-5- yl]piperidin-4-ylethoxy)pyrimidine (Preparation 316, 335mg, 0.877mmol), 2-bromo-5-(2- methoxy- 1-1 -[3-(propan-2-yl)- 1 ,2,4-oxadiazol-5-yl]piperidin-4-ylethoxy)pyrimidine

(Preparation 316, 170mg, 0.399mmol) and [(3i?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3- yljcarbamic acid tert-butyl ester (Preparation 39, 0.484g, 1.53mmol) in DMSO (5mL) was added DBU (0.191mL, 1.28mmol) and the resulting reaction mixture was stirred at 80°C for 16 h. Further [(3i?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 96mg, 0.30mmol) was added and the reaction mixture stirred at 80°C for 80 h. Upon cooling, the reaction mixture was poured into water and extracted with EtOAc (3 x). The combined organic extracts were dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotogrpahy (EtOAcTH; 1 : 1), followed by purification by preparative HPLC afforded the title compound: RT = 4.50 min; mlz (ES ) = 662.22 [M + H]⁺.

Preparation 318: 4-Oxiranyl-piperidine-l-carboxylic acid benzyl ester

The title compound was synthesized from 4-formyl-piperidine-l-carboxylic acid benzyl ester (15. Og, 60.6mmol) employing a procedure similar to that outlined in

Preparation 103: RT = 3.47 min; mlz (ES⁺) = 262.2 [M+ H]⁺. Preparation 319: 4-(l-Hydroxy-2-methoxy-ethyl)-piperidine-l-carboxylic acid benzyl ester

The title compound was synthesised from 4-oxiranyl-piperidine-l-carboxylic acid benzyl ester (Preparation 318, 7.0g, 27mmol) employing a procedure similar to that outlined in Preparation 104: RT = 0.92 min; mlz (ES⁺) = 294.3 [M+ H]⁺ (LCMS Method- 6).

Preparation 320: 4-[l-(2-Chloro-pyrimidin-5-yloxy)-2-methoxy-ethyl]-piperidine-l- carboxylic acid benzyl ester

The title compound was synthesized from 4-(l-hydroxy-2-methoxy-ethyl)-piperidine- 1-carboxylic acid benzyl ester (Preparation 319, l .Og, 3.4mmol) and 2-chloro-5- hydroxypyrimidine (0.556g, 4.26mmol) employing a procedure similar to that outlined in Preparation 316: RT = 1.23 min; mlz (ES⁺) = 406.4 [M+ H]⁺ (LCMS Method-6).

Preparation 321: 4-(l-{2-[(3R,4S)-3-ter^Butoxycarbonylamino-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-2-methoxy-ethyl)-piperidine-l-carboxylic acid benzyl ester

The title compound was synthesized from 4-[l-(2-chloro-pyrimidin-5-yloxy)-2- methoxy-ethyl]-piperidine-l-carboxylic acid benzyl ester (Preparation 320, l.OOg,

1.48mmol) and [(3i?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 0.70 lg, 2.22mmol) employing a procedure similar to that outlined in Preparation 317: RT = 1.48 min; mlz (ES ) = 686.6 [M+ ] (LCMS Method-6).

Preparation 322: 4-((R)-l-{2-[(3R,4S)-3-tei-i-Butoxycarbonylamino-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-2-methoxy-ethyl)-piperidine-l-carboxylic acid benzyl ester

The title compound was isolated from 4-(l-{2-[(3i?,45)-3-fert-butoxycarbonylamino- 4-(2,4,5-trifluoro-phenyl)-pyrrolidin- 1 -yl]-pyrimidin-5-yloxy} -2-methoxy-ethyl)-piperidine- 1-carboxylic acid benzyl ester (Preparation 321) via chiral HPLC: (MeOH:THF; 80:20, 14ml/min, 250nm, RT = 7.5 min): RT = 1.48 min; mlz (ES⁺) = 686.6 [M+ H]⁺ (LCMS Method-6). The stereochemistry of * centre has been arbitrarily assigned.

Preparation 323: ((lS,25)-2-(5,5-Difluoro-2-oxo-piperidin-l-yl)-4-{5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-4-methyl-pyrimidin-2-yl}-cyclopentyl)- carbamic acid tert-buty\ ester

To a solution of 2-chloro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]-4-methylpyrimidine (Preparation 57, 150mg, 0.43mmol) and [(3S,4S)-4-(5,5- difluoro-2-oxopiperidin-l-yl)pyrrolidin-3-yl] carbamic acid tert-butyl ester (Preparation 93, 270mg, 0.85mmol) in DMSO (2.5mL) in a sealed tube was added DBU (64μΕ, 0.43mmol) and the resulting reaction mixture was stirred at 80°C for 120 h. Upon cooling, the reaction mixture was diluted with EtOAc, washed with aqueous citric acid solution (0.1M), saturated aqueous NaHC0₃ solution and brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotogrpahy (DCM:MeOH) afforded the title compound: RT = 3.93 min; mlz (ES⁺) = 635.24 [M+ Hf). Preparation 324: [(3R,4S)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-4-methyl-pyrimidin-2-yl)-pyrrolidin-3- yl]-carbamic acid tert-but l ester

To a solution of methanesulfonic acid (i?)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]ethyl ester (Preparation 129, 250mg, 1.7mmol) and 2-chloro-4- methylpyrimidin-5-ol (250mg, 1.7mmol) in DMA (15mL) in a sealed tube was added cesium fluoride (260mg, 1.7mmol) and the resulting reaction mixture was stirred at 65°C for 72 h. Further cesium fluoride (260mg, 1.7mmol) was added and the reaction mixture heated at 70°C for 24 h. Further cesium fluoride (260mg, 1.7mmol) was added and the reaction mixture heated at 80°C for 24 h. Upon cooling, the reaction mixture was diluted with EtOAc, washed with H₂0 (5 x 20mL) and brine (20mL), dried (MgS0₄), filtered and concentrated in vacuo. The remainder was dissolved in DMSO (2.5mL), [(3i?,45)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 143mg, 0.478mmol) and DBU (40.9μΕ, 0.273mmol) were added and the resulting reaction mixture stirred at 80°C for 16 h. Upon cooling, the reaction mixture was diluted with EtOAc, washed with aquoues citric acid solution (0.1M), saturated NaHC03 solution and brine, dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: RT = 4.70 min; m/z (ES⁺) = 628.16 [M+ H]⁺.

Preparation 325 : (3R,4S)-3-tert-Butoxycarbonylamino-4-(5-chloro-2-fluoro-phenyl)- pyrrolidine-l-carboxylic acid tert-but l ester

The title compound was synthesised in a multi-step synthesis from 5-chloro-2- fluorobenzaldehyde employing procedures similar to those outlined in the synthesis of

Preparation 44: RT = 4.40 min; m/z (ES⁺) = 415.12 [M+ H]⁺. Preparation 326: (3R,4S)-4-(5-Chloro-2-fluoro- henyl)-pyrrolidin-3-ylamine

The title compound was synthesised from (3i?,4S)-3-tert-butoxycarbonylamino-4-(5- chloro-2-fluoro-phenyl)-pyrrolidine-l-carboxylic acid tert-butyl ester (Preparation 325, 1.21g, 2.92mmol) employing a procedure similar to that outlined in Example 205: RT = 1.42 min; m/z (ES⁺) = 215.00 [M+ H]⁺.

Preparation 327: [(3R,45)-l-(5-{(S)-l-[l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid terf-butyl ester

The title compound was synthesized from 2-chloro-5-{(5)-l-[l-(3-ethyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation 102) and [(3R,4S)-4- (2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 285) employing a proceudure similar to that outlined in Prepartion 315: RT = 4.47 min; m/z

Preparation 328: [(3R,4S)-l-(5-Bromo-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid tert-but \ ester

To a solution of 5-bromo-2-chloropyrimidine (l .Og, 5.17mmol) in DMSO (lOmL) was added [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 2.3 lg, 7.75mmol) and DBU (0.773mL, 5.17mmol) and the resulting reaction mixture was stirred at 80°C for 6 h. Upon cooling, the reaction mixture was poured into water (lOOmL) and extracted with EtOAc (75mL). The organic extract was washed with brine (25mL), dried (MgS0₄), filtered and concentrated in vacuo. Recrystallisation (EtOAc) afforded the title compound: RT = 4.32 min; mlz (ES⁺) = 455.0 [M+ H]⁺. Preparation 329: 4-Vinyl-piperidin -l-carboxylic acid benzyl ester

To a suspension of methyltriphenylphosphonium bromide (2.23g, 6.25mmol) in THF (75mL) at -20°C was added dropwise n-BuLi in hexane (1.6M, 3.90mL, 6.25mmol) and the resulting reaction mixture was stirred at -20°C for 30 min. A solution of 4-formyl-piperidine- 1-carboxylic acid benzyl ester (1.03g, 4.16mmol) in THF (9mL) was added and the reaction mixture warmed to r.t. and stirred for 1 h. The reaction mixture was poured into water (lOOmL) and extracted into Et₂0 (2 x 50mL). The combined organic extracts were dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by column chromotogrpahy (IH:EtOAc; 4: 1) to afford the title compound: RT = 4.07 min; mlz (ES ) =

Preparation 330: 4-((_JE)-2-{2-[(3R,4S)-3-tei'i-Butoxycarbonylamino-4-(2,5-difluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yl}-vinyl)-piperidine-l-carboxylic acid benzyl ester

4-Vinyl-piperidine- 1-carboxylic acid benzyl ester (Preparation 329, 109.0mg, 0.444mmol), [(3i?,45)-l-(5-bromo-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester (Preparation 328, lOlmg, 0.222mmol), Pd(PPh₃)₄ (25mg, 0.022mmol) and triethylamine (62μΕ, 0.444mmol) in DMF (0.5mL) in a sealed tube were heated at 115°C for 3 h..Upon cooling, the reaction mixture was partioned between water and Et₂0 and the organic layer dried (MgS0₄), filtered and concentrated in vacuo. The remainder was loaded onto a reverse phase silica column and eluted with MeOH:H₂0 (4: 1 to 9:1) to afford the title compound: RT = 4.75 min; mlz (ES ) = 620.51 [M+ H] .

Preparation 331 : {(3R,45)-4-(2,5-Difluoro-phenyl)-l- [5-(2-piperidin-4-yl-ethyl)- pyrimidin-2-yl]-pyrrolidin-3- l}-carbamic acid tert-buty\ ester

To a solution of 4-((E)-2-{2-[(3i?,45)-3-tert-butoxycarbonylamino-4-(2,5-difluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yl}-vinyl)-piperidine-l-carboxylic acid benzyl ester (Preparation 330, 82.0mg, 0.132mmol) in EtOH (lmL) was added a suspension of Pd/C (10%) in EtOH (lmL) and the resulting reaction mixture stirred under an atmosphere of hydrogen for 1.5 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate concentrated in vacuo to afford the title compound: RT = 2.68 min; mlz (ES )

Preparation 332: [(3R,4S)-l-(5-{2-[l-(5-Chloro-pyrimidin-2-yl)-piperidin-4-yl]-ethyl}- pyrimidin-2-yl)-4-(2,5-difluoro- henyl)-pyrrolidin-3-yl]-carbamic acid tert-buty\ ester

To a solution of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-(2-piperidin-4-yl-ethyl)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 331, 64.0mg, 0.131mmol) in t-BuOH (2.5mL) in a sealed tube was added 2,5-dichloropyrimidine (19.6mg, 0.131mmol) and triethylamine (Ί9μΙ_^, 0.567mmol). The resulting reaction mixture was heated under microwave irradiation at 110°C for 30 min. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M) and the basic fractions were concentrated in vacuo to afford the title compound: RT = 4.92 min; mlz (ES ) = 600.22 [Μ+ ηγ. Preparataion 333: [(3R,4S)-l-{5-[2-(l-Cyano-piperidin-4-yl)-ethyl]-pyrimidin-2-yl}-4- (2,5-difluoro-phenyl)-pyrrolidin-3- l]-carbamic acid tert-buty\ ester

To a solution of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-(2-piperidin-4-yl-ethyl)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 331, 102mg, 0.209mmol) in DCM (2mL) was added a solution of NaHC0₃ (52.7mg, 0.628mmol) in H₂0 (lmL) and the reaction mixture was cooled to 0°C. A solution of cyanogen bromide (24.4mg, 0.230mmol) in DCM (lmL) was added dropwise and the resulting reaction mixture was stirred at r.t. for 30 min. The reaction mixture was partitioned between DCM and water and the organic layer was dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotogrpahy (DCM:MeOH; 97.5:2.5) afforded the title compound: RT = 1.23 min; m/z (ES⁺) = 513.5 [M+ H]⁺ (LCMS Method - 6).

Preparation 334: [(c/s)-3-Fluoro-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- methanol

To a solution of (l-benzyl-5-fluoro-l,2,3,6-tetrahydro-pyridin-4-yl)-methanol (0.172g, 0.777mmol) in MeOH (3mL) was added Pd/C (10%) as a slurry in MeOH (2mL) and the resulting reaction mixture was stirred under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo prior to purification by column chromatography (DCM:NH₃ in MeOH (7M); 9: 1). The residue was dissolved in DCM (2mL), a solution of potassium carbonate (0.137g, 0.991mmol) in H₂0 (2mL) was added and the reaction mixture was cooled to 0°C. A solution of cyanogen bromide (38.5g, 0.363mmol) in DCM (0.5mL) was added dropwise and the reaction mixture stirred at 0°C for 30 min and at r.t for 1 h. The organic layer was separated, dried (MgS0₄), filtered and concentrated in vacuo. The remainder was dissolved in EtOH (8mL) and N- hydroxyisobutyramidine (32.5mg, 0.319mmol) was added, followed by zinc dichloride in Et₂0 (1M, 0.319mL, 0.319mmol). The reaction mixture was stirred at r.t. for 16 h. HC1 in 1,4-dioxane (4M, 0.332mL, 1.33mmol) was added and the reaction mixture stirred at 70°C for 5 h. The solvent was removed in vacuo and the remainder partitioned between DCM and water. The organic layer was dried (MgSC^), filtered and concentrated in vacuo. Purification by column chromatography (DCM:MeOH; 98:2) afforded the title compound: RT = 0.75 min; mlz (ES⁺) = 244.28 [M+ H]⁺ (LCMS Method - 6).

Preparation 335: 2-Chloro-5-[(cis)-3-fluoro-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-ylmethoxy]-pyrimidine

To a solution of [(cz5)-3-fluoro-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- methanol (Preparation 334, 65mg, 0.27mmol), 2-chloro-5-hydroxypyrimidine (35mg, 0.267mmol) and PPh₃ (105mg, 0.401mmol) in THF (3mL) was added TBAD (92.3mg, 0.401mmol) and the resulting reaction mixture was stirred at 50°C for 4 h. Further PPh₃ (25mg, 0.095mmol) and TBAD (25mg, 0.109mmol) were added and the resulting reaction mixture was stirred at 60°C for 2 h. Further PPh₃ (25mg, 0.095mmol) and TBAD (25mg, 0.109mmol) were added and the resulting reaction mixture was stirred at 60°C for 1 h. The solvent was removed in vacuo and the remainder purified by column chromatography (DCM:MeOH; 98:2) to afford the title compound: RT = 1.07 min; mlz (ES⁺) = 356.31 [M + H]⁺ (LCMS Method - 6).

Preparation 336: [(3R,45)-l-{5-[(3R,4S)-3-Fluoro-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid ieri-buty\ ester

A solution of 2-chloro-5-[(cz5)-3-fluoro-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-ylmethoxy]-pyrimidine (Preparation 335, 99mg, 0.28mmol), [(3R,4S)-4-(2,4,5- trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 0.176g, 0.556mmol) and DBU (41.6μΙ., 0.278mmol) in DMSO (l .OOmL) was stirred at 90°C for 16 h, then at 110°C for 8 h. Upon cooling, the reaction mixture was poured into water, extracted into EtOAc, washed with brine (2 x), dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc:IH) afforded [(cz5)-l-{5-[(3i?,45)-3- fluoro-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4- (2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. Purification by chiral HPLC (MeOH:MTBE; 60:40, 15ml/min, 250nm) afforded the title compound: RT = 1.38 min; mlz (ES⁺) = 636.5 [M+ H]⁺ (LCMS Method - 6).

Preparation 337: [(3R,45)-l-{5-[(3S,4R)-3-Fluoro-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-ylmethoxy] -pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl] - carbamic acid tert-buty\ ester

The title compound was isolated from [(cz5)-l-{5-[(3i?,45)-3-fluoro-l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid tert-butyl ester (see Preparation 336) via chiral HPLC (MeOH:MTBE; 60:40, 15ml/min, 250nm): RT = 1.38 min; mlz (ES⁺) = 636.5 [M+ H]⁺ (LCMS Method - 6).

Preparation 338: [(c/s-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-3-methyl-piperidin-4-yl]- methanol

To a solution of cz^'s- l-N-Boc-3-methyl-piperidine-4-carboxylic acid (0.463g, 1.90mmol) in DMF (8mL) was added potassium carbonate (0.263g, 1.90mmol) followed by methyl iodide (0.142mL, 2.28mmol) and the reaction mixture was stirred at r.t. for lh. The mixture was poured into aqueous potassium carbonate (10%) and extracted with EtOAc (2 x 20mL). The combined organic extracts were washed with brine (2 x 25mL), dried (MgS0₄), filtered and concentrated in vacuo to afford (cz^'s)-3-methyl-piperidine-l,4-dicarboxylic acid 1 -tert-butyl ester 4-methyl ester. The intermediate was dissolved in THF (3mL), cooled to 0°C and LiAlH₄ (73mg, 1.92mmol) in THF (3mL) was added. The resulting reaction mixture was warmed to r.t., Et₂0 (5mL) was added and the reaction mixture was cooled to 0°C prior to the addition of aqueous NaOH solution (15%, 73μί) and water (293μί). The reaction mixture was stirred at r.t. for 1 h prior to the addition of MgS0₄, then filtered and concentrated in vacuo to afford (cis)-4-hydroxymethyl-3-methyl-piperidine-l-carboxylic acid tert- vXy\ ester. This intermediate was dissolved in HCl in 1,4-dioxane (4M, 3.0mL, 12.0mmol) and the reaction mixture stirred at r.t. for 1 h. The solvent was removed in vacuo to afford ((cis)-3-methyl-piperidin-4-yl)-methanol hydrochloride. To a solution of this intermediate in DCM (5mL) at 0°C was added NaHC0₃ (0.608g, 7.24mmol) in H₂0 (5mL), followed by dropwise addition of a solution of cyanogen bromide (0.21 lg, 1.99mmol) in DCM (3mL). The resulting reaction mixture was stirred at 0°C for 1 h and at r.t. for 2 h. The organic phase was separated, dried (MgS0₄), filtered and concentrated in vacuo. The remainder was dissolved in EtOH (25mL) and N-hydroxyisobutyramidine (0.183g,

1.79mmol) was added, followed by zinc dichloride in Et₂0 (1M, 1.79mL, 1.79mmol). The reaction mixture was stirred at r.t. for 2 h, then HCl in 1,4-dioxane (4M, 1.86mL, 7.46mmol) was added and the reaction mixture was stirred at 70°C for 6 h. Upon cooling, the solvent was removed in vacuo and the residue partitioned between DCM and water. The organic layer was separated, dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by column chromatography (DCM:MeOH; 97:3) to afford the title compound: RT = 0.80 min; mlz (ES⁺) = 240.4 [M+ H]⁺ (LCMS Method - 6).

Preparation 339: 2-Chloro-5-[(c/s)-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-3-methyl- piperidin-4-ylmethoxy]-pyrimidine

To a solution of [(cz^'5-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-3-methyl-piperidin-4-yl]- methanol (Preparation 338, 0.106g, 0.443mmol), 2-chloro-5 -hydro xypyrimidine (57.8mg, 0.443mmol) and PPh₃ (0.174g, 0.664mmol) in THF (5mL) was added TBAD (0. 153g, 0.664mmol) and the resulting reaction mixture was stirred at 50°C for 3 h. Upon cooling, the reaction mixture was partitioned between EtOAc (25mL) and water (25mL). The organic layer was separated, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (IH:EtOAc; 3:2) afforded the title compound: RT = 1.17 min; mlz (ES⁺) = 352.3 [M+ H]⁺ (LCMS Method - 6). Preparation 340 : [(3R,4S)- 1-{5- [(cis)- l-(3-Isopropyl- [ 1 ,2,4] oxadiazol-5-yl)-3-methyl- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-buty\ ester

To a solution of 2-chloro-5-[(cz^'5)-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-3-methyl- piperidin-4-ylmethoxy]-pyrimidine (Preparation 339, 89mg, 0.25mmol) and [(3R,4S)-4- (2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 0.16g, 0.50mmol) in DMSO (lmL) was added DBU (37.8μΙ., 0.253mmol) and the resulting reaction mixture was stirred at 70°C for 48 h. Further [(3R,4S)-4-(2,4,5- trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 0.1 Og,

0.31mmol) in DMSO (0.5mL) was added and the reaction mixture was stirred at 100°C for 16 h. Upon cooling, the reaction mixture was poured into water (25mL) and the suspension extracted with EtOAc. The organic extract was washed with brine (2 x lOmL), dried

(MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (IH:EtOAc; 2: 1), followed by further purification by preparative HPLC afforded the title compound: RT = 1.47 min; m/z (ES⁺) = 632.53 [M+ H]⁺ (LCMS Method - 6).

Preparation 341: [(3R,45)-l-[5-((S)-l-{l-[(R)-3-(Tetrahydro-furan-3-yl)- [l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-3-yl]-carba

To a solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2- yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 206, 660mg, 1.21mmol) and N-hydroxytetrahydrofuran-3-carboxamidine (Preparation 168, 0.188g, 1.45mmol) in EtOH (0.72mL, 1.45mmol) was added zinc dichloride in EtOH (2M, 0.724mL, 1.45mmol) and the resulting reaction mixture was stirred at r.t. for 16 h. HC1 in 1 ,4-dioxane (4M, 1.51mL, 6.04mmol) was added and the reaction mixture was heated to 80°C for 6 h. Upon cooling, the reaction mixture was poured into DCM (200mL) and saturated aqueous NaHC0₃ solution (200mL). The organic layer was separated, dried (MgSC^), filtered and concentrated in vacuo to afford (3i?,45)-l -[5-((5)-l- { l-[3-(tetrahydro- mran-3-yl)-[l ,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-tri phenyl)-pyrrolidin-3-ylamine. The intermediate was dissolved in THF (15mL) and H₂0 (15mL) and triethylamine (0.252mL, 1.81mmol) and di-fert-butyldicarbonate (0.395g, 1.81mmol) were added. The resulting reaction mixture was stirred at r.t. for 16 h, then the THF was removed in vacuo. The aqueous residue was diluted with saturated aqueous citric acid solution (75mL) and extracted with DCM (2 x 150mL). The combined organic extracts were concentrated in vacuo and purified by column chromatography (EtOAcTH; 3 : 1) to afford [(3R.4S)- 1 -[5-((S)- 1 - { 1 -[3-(tetrahydro-furan-3-yl)-[l ,2,4]oxadiazol-5-yl]-piperidin-4- yl} -ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester. Purification by chiral HPLC (MTBE:THF; 75 :25, 12ml/min, 250nm, RT = 13.9 min) afforded the title compound: RT = 1.35 min; mlz (ES⁺) = 660.5 [M + H]⁺ (LCMS Method - 6).

Preparation 342: [(3R,45)-l-[5-((S)-l-{l-[(S)-3-(Tetrahydro-furan-3-yl)- [l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-3-yl]-carba

The title compound was isolated from [(3i?,45)-l-[5-((5)-l- {l -[3-(tetrahydro-furan-3- yl)-[l ,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (see Preparation 341) via chiral HPLC (MTBE:THF; 75 :25, 12ml/min, 250nm, RT = 12.2 min): RT = 1.35 min; mlz (ES⁺) = 660.5 [M + H]⁺ (LCMS Method - 6).

Preparation 343: 2-[4-((S)-l-{2-[(3R,4S)-3-tei-i-Butoxycarbonylamino-4-(2,5-difluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-oxazole-4-carboxylic acid ethyl ester

To a solution of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204, 250mg, 0.50mmol) and ethyl-2-chlorooxazole-4-carboxylate (109mg, 0.620mmol) in DMSO

(1.5mL, 21mmol) was added DIPEA (108μΕ, 0.620mmol) and the resulting reaction mixture was heated under microwave irradiation at 120°C for 30 min. The reaction mixture was partitioned between EtOAc (50mL) and water (30mL) and the organic layer separated, washed with brine (30mL), passed through a hydrophobic frit and concentrated in vacuo. Purification by column chromatography (IH:EtOAc; 1 :4 to 3:7) afforded the title compound: RT = 1.39 min; mlz (ES⁺) = 643.47 [M+ H]⁺ (LCMS Method - 6).

Preparation 344: 5-[4-((S)-l-{2-[(3R,4S)-3-tei-i-Butoxycarbonylamino-4-(2,5-difluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazole-3- carboxylic acid ethyl ester

The title compound was synthesized from {(3 ?,45)-4-(2,5-difluoro-phenyl)-l-[5-((5)- l-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204) and 5-trichloromethyl-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester (Preparation 215) employing a procedure similar to that outlined in Preparation 216: RT = 1.37 min; mlz (ES⁺) = 644.42 [M + H]⁺ (LCMS Method - 6). Preparation 345: [(3R,4S)-l-(5-{(S)-l-[l-(3-Acetyl-[l,2,4]oxadiazol-5-yl)-piperidin-4- ethoxy}-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester

To a solution of solution of 5-[4-((5)-l-{2-[(3i?,45)-3-fert-butoxycarbonylamino-4-

(2,5-difluoro-phenyl)-pyrrolidin-l -yl]-pyrimidin-5-yloxy} -ethyl)-piperidin- 1 -yl]- [l,2,4]oxadiazole-3-carboxylic acid ethyl ester (Preparation 344, 1.24g, 1.93mmol) in anhydrous THF (12mL) at -78°C was added methyl magnesium bromide (1.44mL,

4.33mmol) and the resulting reaction mixture was stirred between -75°C and -65°C for 4 h. The reaction was quenched with saturated aquoues NH₄C1 solution (5mL) and warmed to r.t. The mixture was partitioned between EtOAc (25mL) and saturated aquoues NH₄CI solution (25mL). The aqueous layer was separated and extracted with EtOAc (2 x 25mL). The combined organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. Purification by column chromotogrpahy (EtOAcTH; 35:65 to 3: 1) afforded the title compound: RT = 1.35 min; mlz (ES⁺) = 614.46 [M+ H]⁺ (LCMS Method - 6).

Preparation 346: {(3R,45)-4-(2,5-Difluoro-phenyl)-l-[5-((5)-l-{l-[3-(l-hydroxy-l- methyl-propyl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin-4-yl}-ethoxy)-pyrimidin-2-yl] - pyrrolidin-3-yl}-carbamic acid tert-but \ ester

To a solution of [(3i?,45)-l-(5-{(5)-l-[l-(3-acetyl-[l,2,4]oxadiazol-5-yl)-piperidin-4- yl]-ethoxy} -pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 345, 200mg, 0.326mmol) in THF (3mL) at -70°C was added ethyl magnesium chloride (1M in THF, 0.733mL, 0.733mmol) dropwise and the resulting reaction mixture was stirred at -78°C for 3 h. The reaction was quenched with saturated aqueous NH₄CI solution (2mL) and the mixture allowed to warm to r.t. and then partitioned between saturated aqueous NH₄C1 solution and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were passed through a hydrophobic frit and concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 1.32 min; mlz (ES⁺) = 644.49 [M+ H]⁺ (LCMS Method - 6).

Preparation 347: [(3R,45)-l-[5-((S)-l-{l-[3-(l-Cyclopropyl-l-hydroxy-ethyl)- [l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid tert-but \ ester

The title compound was synthesised from [(3i?,45)-l-(5-{(5)-l-[l-(3-acetyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 345) and

cyclopropylmagnesium bromide employing the procedure outlined in Preparation 346 = 1.35 min; mlz (ES⁺) = 656.49 [M+ H]⁺ (LCMS Method - 6).

Preparation 348: (R)-N-Hydroxy-2-methoxy-propionamidine

A solution of (2i?)-2-methoxypropanenitrile (lOOmg, l .Ommol) and hydro xylamine (50% aqueous solution, 86μΕ, 1.4mmol) in EtOH (5mL, 80mmol) were heated at 60°C for 4 h. The solvent was removed in vacuo to afford the title compound: RT = 0.65 min; mlz (ES⁺) = 119.01 [M+ H]⁺ (LCMS Method - 8).

Preparation 349: 3,N-Dihydroxy-2,2- imethyl-propionamidine

A solution of 3-hydroxy-2,2-dimethylpropanenitrile (0.500g, 5.04mmol) and hydroxylamine (50%> aqueous solution, 0.37 lmL, 6.05mmol) in EtOH (5.89mL) was heated at 60°C for 4 h. Further hydroxylamine (50% aqueous solution, 0.155mL, 2.52mmol) was added and the reaction mixture heated at 60°C for 3 h. The solvent was removed in vacuo to afford the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 8.90 (s, 1H), 5.25 (br. s, 2H), 4.61 - 5.58 (m, 1H), 3.39 - 3.37 (dd, 2H), 1.04 (s, 6H). Preparation 350: {(3R,45)-4-(2,5-Difluoro-phenyl)-l-[5-((S)-l-{l-[3-(l-hydroxy-l- methyl-ethyl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin-4-yl}-ethoxy)-pyrimidin-2-yl] -pyrrolidin- 3-yl}-carbamic acid terf-but l ester

The title compound was synthesized from 5-[4-((S)-l- {2-[(3R,4S)-3-tert- butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)- piperidin-l-yl]-[l ,2,4]oxadiazole-3-carboxylic acid ethyl ester (Preparation 344) employing a procedure similar to that outlined in Preparation 217: RT = 1.32 min; m/z (ES ) = 630.52 [M + H]⁺ (LCMS Method - 6). Preparation 351: 4-((5)-l-{2-[(3R,4S)-3-te^Butoxycarbonylamino-4-(2,4-difluoro-5- methyl-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-l-carboxylic acid benzyl ester

A solution of 4-[(5)-l-(2-chloro-pyrimidin-5-yloxy)-ethyl]-piperidine-l-carboxylic acid benzyl ester (Preparation 183, 0.400g, 1.06mmol), [(3i?,45)-4-(2,4-difluoro-5-methyl- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 292, 0.399g,

1.28mmol) and DBU (0.159mL, 1.06mmol) in DMSO (2mL) in a sealed tube was heated at 80°C for 120 h. Upon cooling the reaction mixture was poured into H₂0 (50mL) and extracted with EtOAc (3 x 50mL). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAcTH; 1 : 1) afforded the title compound: RT = 1.58 min; m/z (ES⁺) = 652.50 [M + H]⁺ (LCMS Method - 6).

Preparation 352: {(3R,45)-4-(2,4-Difluoro-5-methyl-phenyl)-l-[5-((S)-l-piperidin ethoxy)-pyrimidin-2-yl]-p rrolidin-3-yl}-carbamic acid tert-butyl ester

The title compound was synthesized from 4-((S)-l-{2-[(3R,4S)-3-tert- butoxycarbonylamino-4-(2,4-difluoro-5 -methyl-phenyl)-pyrrolidin- 1 -yl] -pyrimidin-5 - yloxy}-ethyl)-piperidine-l-carboxylic acid benzyl ester (Preparation 351, (0.600g,

0.921mmol) employing a method similar to that outlined in Preparation 185: RT = 0.90 min; m/z (ES⁺) = 518.45 [M+ H]⁺ (LCMS Method - 6).

Preparation 353: 5-[4-((5)-l-{2-[(3R,4S)-3-tei-i-Butoxycarbonylamino-4-(2,4-difluoro-5- methyl-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-

[1,2,4] oxadiazole-3-car xylic acid ethyl ester

The title compound was synthesized from {(3i?,45)-4-(2,4-difluoro-5-methyl- phenyl)- 1 -[5-((5)-l -piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl} -carbamic acid tert-butyl ester (Preparation 352) and 5-trichloromethyl-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester (Preparation 215) employing a procedure similar to that outlined in Preparation 216: RT = 1.44 min; m/z (ES⁺) = 658.48 [M+ H]⁺ (LCMS Method - 6).

Preparation 354: {(3R,45)-4-(2,4-Difluoro-5-methyl-phenyl)-l-[5-((S)-l-{l-[3-(l- hydroxy-l-methyl-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]- pyrrolidin-3-yl}-carb

The title compound was synthesized from 5-[4-((S)-l-{2-[(3R,4S)-3-tert- butoxycarbonylamino-4-(2,4-difluoro-5 -methyl-phenyl)-pyrrolidin- 1 -yl] -pyrimidin-5 - yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester (Preparation 353) employing a procedure similar to that outlined in Preparation 217: RT = 1.32 min; mlz (ES⁺) = 644.52 [M + H]⁺ (LCMS Method - 6).

Preparation 355: 4-Fluoro-benzoic acid 1-carboxy-cyclopropyl ester

To a solution of 1 -hydroxy- 1-cyclopropanecarboxylic acid (0.500g, 4.90mmol) in pyridine (1.25mL) and chloroform (lmL) at 0°C was added 4-fluoro-benzoyl chloride (0.608mL, 5.14mmol) and the resulting reaction mixture was heated at 70°C for 40 min. Upon cooling, the reaction mixture was poured into water (20mL) and extracted with chloroform (3 x 15mL). The combined organic extracts were washed with 2M HCl (20mL) and then extracted into saturated aqueous NaHC0₃ solution (2 x 20mL). The combined NaHC0₃ extracts were aj dusted to pH 1 with 12M HCl and then extracted into chloroform (3 x 20mL). The combined organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. Purification by column chromatography (EtOAcTH; 1 :9 to 3: 10) afforded the title compound: RT = 0.94 min; mlz (ES^~) = 223.18 [M - H]⁺ (LCMS Method - 6).

Preparation 356: 4-Fluoro-benzoic acid 1-carbamoyl-cyclopropyl ester

To a solution of 4-fluoro-benzoic acid 1-carboxy-cyclopropyl ester (Preparation 355, 0.423g, 1.89mmol) in THF (13mL) was added EDCI (0.434g, 2.26mmol) and HOBt and the resulting reaction mixture was stirred at r.t. for 10 min. NH₃ in 1,4-dioxane (0.5M,

37.74mL, 18.87mmol) was added and the reaction mixture stirred at r.t. for 72 h. The solvent was removed in vacuo and the remainder partitioned between water (lOOmL) and EtOAc (200mL). The organic layer was separated and washed with saturated aqueous NaHC0₃ solution and brine, dried (MgS0₄), filtered and concentrated in vacuo: RT = 0.82 min; mlz (ES⁺) = 224.19 [M+ Hf (LCMS Method - 6).

Preparation 357: 4-Fluoro-benzoic acid l-(5-trichloromethyl-[l,2,4]oxadiazol-3-yl)- cyclopropyl ester

To a solution of 4-fluoro-benzoic acid 1-carbamoyl-cyclopropyl ester (Preparation 356, 0.290g, 1.30mmol) in THF (lOmL) at 0°C was added triethylamine (0.54mL, 3.9mmol) followed by TFAA (0.28mL, 1.9mmol) and the resulting reaction mixture was stirred for 1 h. The reaction was quenched with water (50mL), extracted into DCM (2 x 70mL) and the combined organic extracts were passed through a hydrophobic frit and concentrated in vacuo. The remainder was dissolved in EtOH (lOmL) and hydroxylamine (50% aqueous solution, 87.6μί, 1.43mmol) was added. The resulting reaction mixture was heated at 60°C for 1.5 h, then the solvent removed in vacuo. The remainder was dissolved in toluene (20mL), perchloroacetic anhydride (0.237mL, 1.30mmol) was added and the reaction mixture heated at 90°C for 3 h. The solvent was removed in vacuo and the remainder purified by column chromatography (EtOAcTH; 5:95) to afford the title compound: RT = 1.42 min; m/z (ES⁺) = 365.07 [M+U]⁺ (LCMS Method - 6).

Preparation 358: 4-Fluoro-benzoic acid l-{5-[4-((5)-l-{2-[(3R,4S)-3-tert- butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}- ethyl)-piperidin- 1- l] - [ 1 ,2,4] oxadiazol-3-yl}-cyclopropyl ester

A solution of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204, 0.276g, 0.547mmol) and 4-fluoro-benzoic acid l-(5-trichloromethyl-[l,2,4]oxadiazol-3-yl)- cyclopropyl ester (Preparation 357, O. lOOg, 0.274mmol) in DMSO (lmL) was stirred at r.t. for 16 h. The reaction mixture was poured into water (50mL) and extracted with EtOAc (3 x 50mL). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotogrpahy (EtOAc) afforded the title compound: RT = 1.55 min; mlz (ES⁺) = 750.50 [M+U]⁺ (LCMS Method - 6).

Preparation 359: Benzoic acid 1-cyan -cyclobutyl ester

To a solution of a-oxobenzeneacetonitrile (4.00g, 30.5mmol) and cyclobutanone

(4.02mL, 61. Ommol) in toluene (30mL) was added DBU (0.182mL) and the resulting reaction mixture was stirred at r.t. for 20 h. The solvent was removed in vacuo and the residue purified by column chromotogrpahy (EtOAc:IH; 5:95) to afford the title compound: 1H NMR δ_Η (400 MHz, CDC1₃): 8.04 - 8.10 (m, 2 H), 7.62 - 7.68 (m, 1 H), 7.48 - 7.55 (m, 2 H), 2.90 - 3.02 (m, 2 H), 2.57 - 2.71 (m, 2 H), 2.17 - 2.29 (m, 1 H), 2.09 - 2.17 (m, 1 H).

Preparation 360: Benzoic acid l-(5-trichloromethyl-[l,2,4]oxadiazol-3-yl)-cyclobutyl ester

To a suspension of benzoic acid 1-cyano-cyclobutyl ester (Preparation 359, 3.84g,

19.1mmol) in EtOH (50mL) was added hydroxyl amine (50% aqueous solution, 1.29mL, 21.Ommol) and the resulting reaction mixture was heated at 70°C for 2.5 h. The solvent was removed in vacuo and the remainder suspended in toluene (50mL). Perchloroacetic anhydride (3.49mL, 19.1mmol) was added and the reaction mixture heated under reflux conditions for 3h. The solvent was removed in vacuo and the remainder purified by column chromatography (EtOAcTH; 0: 1 to 5:95) to afford the title compound: RT = 1.47 min; mlz (ES⁺) = 361.11 [Μ+ηγ (LCMS Method - 6).

Preparation 361: Benzoic acid l-{5-[4-((S)-l-{2-[(3R,4S)-3-ter )utoxycarbonylamino-4- (2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]- [1,2,4] oxadiazol-3-yl}-cyclobutyl ester

A solution of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204, 0.20g, 0.397mmol) and benzoic acid l-(5-trichloromethyl-[l,2,4]oxadiazol-3-yl)-cyclobutyl ester (Preparation 360, 0.215g, 0.596mmol) in DMF (0.8mL) was heated at 50°C for 5 h. The solvent was removed in vacuo and the resisdue purified by preparative HPLC to afford the title compound: RT = 1.60 min; m/z (ES⁺) = 746.52 [M+H]⁺ (LCMS Method - 6).

Preparation 362: {(3R,45)-4-(2,5-Difluoro-phenyl)-l-[5-((S)-l-{l-[3-(l-hydroxy- cyclobutyl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin-4-yl}-ethoxy)-pyrimidin-2-yl] -pyrrolidin-3- yl}-carbamic acid tert-but l ester

To a solution of benzoic acid l-{5-[4-((5)-l-{2-[(3i?,45)-3-tert- butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)- piperidin-l-yl]-[l,2,4]oxadiazol-3-yl} -cyclobutyl ester (Preparation 361, 80mg, O. l lmmol) in THF (2mL), MeOH (lmL) and H₂0 (lmL) was added lithium hydroxide monohydrate (5.4mg, 0.13mmol) and the resulting reaction mixture was stirred at r.t. for 2 h. Further lithium hydroxide monohydrate (5.4mg, 0.13mmol) was added and the reaction mixture heated at 50°C for 1.5 h. The solvent was removed in vacuo and the remainder partitioned between DCM (20mL) and water (lOmL). The organic layer was passed through a hydrophobic frit and the solvent removed in vacuo to afford the title compound: RT = 1.29 min; m/z (ES⁺) = 642.52 [M+H]⁺ (LCMS Method - 6).

Preparation 363: Benzoic acid l-{5-[4-((S)-l-{2-[(3R,4S)-3-tert-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]- [1,2,4] oxadiazol-3- l}-cyclobutyl ester

The title compound was synthesized from [(3 ?,45)-l-[5-((5)-l-piperidin-4-yl- ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 0.88g, 1.7mmol) and benzoic acid l-(5-trichloromethyl- [l,2,4]oxadiazol-3-yl)-cyclobutyl ester (Preparation 360, 0.303g, 0.839mmol) employing a procedure similar to that outlined in Preparation 358: RT = 1.61 min; mlz (ES ) = 764.54 [M+H]⁺ (LCMS Method - 6).

Preparation 364: 3,N-Dihydroxy-3-meth l-butyramidine

A solution of hydroxylamine (50% aqueous solution, 1.24mL, 40.4mmol) and 3- hydroxy-3-methyl-butyronitrile (lg, lO. lmmol) in EtOH (lOmL) was stirred at r.t. for 1.5 h. The solvent was removed in vacuo, azeotroping with toluene, to afford the title compound: 1H NMR δ_Η (400MHz, CDC1₃): 2.53 (s, 2H), 1.42 (s, 6H).

Preparation 365: [(3R,45)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(2H-tetrazol-5-yl)- piperidin-4-yl]-ethoxy}- rimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

To a solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2- yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 205, 300mg, 0.6mmol) in DMF (5mL) was added ammonium chloride (47mg, 0.87mmol) and sodium azide (57mg, 0.87mmol) and the resulting reaction mixture was stirred at r.t. for 15 min and at 100°C for 7 h. Uon cooling, the reaction mixture was diluted with water (lOmL) and brine (lOmL) and extracted with EtOAc (2 x 20mL). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by preparative HPLC to afford the title compound: RT = 1.14 min; mlz (ES ) = 572.45 [M+H]⁺ (LCMS Method - 6). Preparation 366 : 2- {5- [4-((S> 1- {2- [(3R,4S)-3-tei-i-Butoxycarbonylamino-4-(2,5-difluoro- phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-tetrazol-2-yl}-2- methyl-propionic acid eth l ester

[(3i?,45)-4-(2,5-Difluoro-phenyl)- 1 -(5- {(S)- 1 -[ 1 -(2H-tetrazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 365, 0.126g, 0.220mmol), 2-bromo-2-methyl-propionic acid ethyl ester (98.5μί, 0.661mmol), potassium iodide (3.7mg, 22μmol) and triethylamine (0.50mL) in DMF (0.50mL) were heated at 70°C for 16 h. Upon cooling, the reaction mixture was partitioned between EtOAc and water and the organic layer separated, washed with brine (2 x), passed through a hydrophobic frit and concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 1.51 min; m/z (ES⁺) = 686.52 [M+H]⁺ (LCMS Method - 6).

Preparation 367: {(3R,45)-4-(2,5-Difluoro-phenyl)-l-[5-((5)-l-{l-[2-(2-hydroxy-l,l- dimethyl-ethyl)-2H-tetrazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3- yl}-carbamic acid tert-but l ester

To a solution of 2-{5-[4-((5)-l-{2-[(3i?,45)-3-tert-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin- 1 -yl] -pyrimidin-5 -yloxy} -ethyl)-piperidin- 1 -yl] -tetrazol-2-yl}-2- methyl-propionic acid ethyl ester (Preparation 366, 65mg, 95μιηο1) in THF (2mL) at -20°C was added L1AIH₄ in THF (1M, 95μΙ_^, 95μιηο1) and the resulting reaction mixture stirred at - 20°C for 1 h. The reaction mixture was quenched with saturated aqueous NH₄CI solution and extracted into EtOAc. The organic layer was separated, passed through a hydrophobic frit and concentrated in vacuo. Purification by column chromotogrpahy (IH:EtOAc; 2: 1 to 1 :1) afforded the title compound: RT = 1.32 min; m/z (ES⁺) = 644.48 [M +H]⁺ (LCMS Method - 6). Preparation 368: (R)-l-(3-Fluoro-pyridin-4-yl)-ethanol =^/ OH

To a solution of diphenyl[(2S)-pyrrolidin-2-yl]methanol (0.50g, 2.0mmol) in THF (22.1mL) was added boric acid, trimethyl ester (0.27mL, 2.4mmol) and the resulting reaction mixture stirred at r.t. for 1 h. Borane dimethyl sulfide ((3.76mL, 39.7mmol) was added dropwise and the reaction mixture stirred for 15 min prior to the dropwise addition of l-(3- fluoropyridin-4-yl)ethanone (2.76g, 19.8mmol) in THF (22mL) over 1 h. The reaction mixture was stirred at r.t. for 90 min and then quenched with aqueous HCl (12M) and stirred for 30 min. The mixture was adjusted to pH 8 with saturated aquoues NaHC0₃ solution, extracted with EtOAc (2 x 50mL) and the combined organic extracts passed through a hydrophobic frit and concentrated in vacuo. Purification by column chromatography (DCM:MeOH) afforded the title compound: RT = 0.43 min; mlz (ES⁺) = 142.09 [M+H]⁺ (LCMS Method - 6).

Preparation 369: l-Benzyl-3-fluoro-4-((R)-l-h droxy-ethyl)-pyridinium bromide

To a solution of (i?)-l-(3-fluoro-pyridin-4-yl)-ethanol (Preparation 368, 2.20g, 15.6mmol) in acetone (35mL) was added benzyl bromide (2.04mL, 17.1mmol) and the resulting reaction mixture heated under reflux conditions for 10 h. The solvent was removed in vacuo to afford the title compound: RT = 0.48 min; mlz (ES⁺) = 232.18 [M ]⁺ (LCMS Method - 6).

Preparation 370: (R)-l-(l-Benzyl-5-fluoro-l,2,3,6-tetrahydro-pyridin-4-yl)-ethanol

To a solution of 1 -benzyl-3-fluoro-4-((i?)- 1 -hydroxy-ethyl)-pyridinium bromide

(Preparation 369, 4.86g, 15.6mmol) in MeOH (80mL) at 0°C was added sodium

borohydride (1.92g, 50.6mmol) portionwise and the resulting reaction mixture was stirred at r.t. for 16 h. The solvent was removed in vacuo, the remainder partitioned between EtOAc (50mL) and water (50mL) and the organic layer separated, dried (MgS0₄) and concentrated in vacuo. Purification by column chromotogrpahy (IH:EtOAc; 2:1) afforded the title compound: RT = 0.50 min; mlz (ES⁺) = 236.22 [M+U]⁺ (LCMS Method - 6). Preparation 371: (R)-l-[(cw)-l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)-3-fluoro-piperidin-4-yl]- ethanol

The title compound was synthesized from (i?)-l-(l-benzyl-5-fluoro-l,2,3,6- tetrahydro-pyridin-4-yl)-ethanol (Preparation 370) and N-hydroxypropionamidine employing a procedure similar to that outlined in Prepartion 334: RT = 0.72 min; mlz (ES ) = 244.24 [Μ+ηγ (LCMS Method - 6).

Preparation 372: Methanesulfonic acid (R)-l-[(ci^'s)-l-(3-ethyl-[l,2,4]oxadiazol-5-yl)-3- fluoro-piperidin-4-yl] -ethyl ester

To a solution of (i?)-l-[(c 5)-l-(3-ethyl-[l,2,4]oxadiazol-5-yl)-3-fluoro-piperidin-4- yl]-ethanol (Preparation 371, 0.184g, 0.756mmol) and triethylamine (0.21 lmL, 1.51mmol) in DCM (lOmL) at 0°C was added dropwise methanesulfonyl chloride (70.2μΕ, 0.908mmol) and the resulting reaction mixture was stirred at 0°C for 15 min and at r.t. for 30 min. The reaction mixture was washed with saturated aquoues NaHC0₃ solution (2 x lOmL), passed through a hydrophobic frit and concentrated in vacuo. Purification by column

chromatography (DCM:MeOH; 99: 1) afforded the title compound: RT = 0.89 min; mlz (ES⁺) = 322.25 [M+H]⁺ (LCMS Method - 6). Preparation 373: 2-Chloro-5-{(5)-l-[(cw)-l-(3-ethyl-[l,2,4]oxadiazol-5-yl)-3-fluoro- piperidin-4-yl]-ethoxy}-pyrimidine

A solution of methanesulfonic acid (i?)-l-[(cz^'5)-l-(3-ethyl-[l,2,4]oxadiazol-5-yl)-3- fluoro-piperidin-4-yl] -ethyl ester (Preparation 372, 0.230g, 0.716mmol), 2-chloro-5- hydroxypyrimidine (96.2mg, 0.737mmol) and cesium fluoride (0.112g, 0.737mmol) in DMA (7mL) was heated at 60°C for 16 h. Further cesium fluoride (0.112g, 0.737mmol) was added and the reaction mixture was heated at 60°C for 16 h. Further cesium fluoride (0.112g, 0.737mmol) was added and the reaction mixture was heated at 60°C for 16 h. The reaction mixture was partitioned between EtOAc (20mL) and water (20mL) and the organic layer was separated, washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. The remainder was dissolved in DMA (5mL) and cesium fluoride (0.112g, 0.737mmol) was added and the reaction mixture heated at 60°C for 16 h. Further cesium fluoride (0.112g, 0.737mmol) was added and the reaction mixture was heated at 60°C for 16 h. Further cesium fluoride (0.112g, 0.737mmol) was added and the reaction mixture was heated at 60°C for 16 h. The reaction mixture was partitioned between water (20mL) and EtOAc (20mL) and the organic layer was separated, washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by column chromatography (DCM:MeOH; 99: 1) and further purified by preparative HPLC to afford the title compound: RT = 1.04 min; mlz (ES ) = 356.23 [Μ+Ή]⁺ (LCMS Method - 6).

Preparation 374: [(3R,45)-l-(5-{(S)-l-[(3S,4R)-l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)-3- fluoro-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3- yl]-carbamic acid tert-buty\ ester

A solution of 2-chloro-5-{(5)-l-[(cz5)-l-(3-ethyl-[l,2,4]oxadiazol-5-yl)-3-fluoro- piperidin-4-yl]-ethoxy}-pyrimidine (Preparation 373, 21mg, 59μιηο1), [(3i?,45)-4-(2,4,5- trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 98mg, 0.31mmol) and DBU (17.6μΕ, 0.118mmol) in DMSO (lmL) was heated at 80°C for 16 h then at 90°C for 8 h. Upon cooling, water (lOmL) and EtOAc (lOmL) were added and the organic phase separated, washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by column chromotogrpahy (DCM:MeOH; 99: 1) and further purified by chiral HPLC (MTBE:MeOH:THF; 75:20:5, 14ml/min, 250nm) to afford the title compound: RT = 1.36 min; mlz (ES⁺) = 636.43 [M+H]⁺ (LCMS Method - 6). Preparation 375: [(3R,4S)-l-(5-{(S)-l-[(3R,4S)-l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)-3- fluoro-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3- yl]-carbamic acid tert- ty\ ester

The title compound was synthesised employing the procedure outlined in Example 374: RT = 1.36 min; m/z (ES⁺) = 636.43 [M+U]⁺ (LCMS Method - 6).

Preparation 376: [(3R,45)-l-{5-[(S)-l-(l-Benzooxazol-2-yl-piperidin-4-yl)-ethoxy]- pyrimidin-2-yl}-4-(2,5-difluoro- henyl)-pyrrolidin-3-yl]-carbamic acid terf-butyl ester

A mixture of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204, 50mg, O.lmmol), 2-chlorobenzoxazole (20mg, O.lmmol), sodium tertiary butoxide (14mg,

0.15mmol) and (l,l'bis-(diphenylphosphino)-ferrocene) palladium dichloride (14mg, 20μmol) in toluene (2.5mL) was heated under microwave irradiation at 130°C for 60 min. The solvent was removed in vacuo and the remainder purified by preparative HPLC to afford the title compound: RT = 1.46 min; m/z (ES⁺) = 621.46 [M+H]⁺ (LCMS Method - 6).

Preparation 377: [(3R,45)-l-(5-{(S)-l-[l-(3-Acetyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester

The title compound was synthesized from 5-[4-((S)-l-{2-[(3R,4S)-3-tert- butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy} -ethyl)- piperidin-l-yl]-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester (Preparation 26) employing a procedure similar to that outlined in Preparation 344: RT = 1.37 min; mlz (ES ) = 632.5 [M+H]⁺ (LCMS Method - 6). Preparation 378: [(3R,45)-l-[5-((S)-l-{l-[3-(l-Cyclopropyl-l-hydroxy-ethyl)-

[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-3-yl]-carba

The title compound was synthesised from [(3R,4S)-l-(5-{(S)-l-[l-(3-acetyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 377) and

cyclopropylmagnesium bromide employing the procedure outlined in Preparation 346: RT = 1.37 min; mlz (ES⁺) = 674.5 [M+ H]⁺ (LCMS Method - 6). Preparation 379: 7-Benzyl-3-oxa-7-aza-bic clo[3.3.1]nonan-9-one

To a solution of tetrahydropyron-4-one (24g, 240mmol) and paraformaldehyde (18g, 600mmol) in IPA (600mL) at 65 °C was added a solution of benzylamine (28.8mL,

264mmol) and acetic acid (15.2mL, 264mmol) in IPA (600mL) dropwise over 1.5 h and the resulting reaction mixture was stirred at 65 °C for 1 h. Upon cooling, the solvent was removed in vacuo, the remainder diluted with water (1 L) and aqueous HCl (IM, 90mL), and extracted with Et₂0 (2 x lOOmL). The aqueous was basified to pH 13 with aqueous NaOH solution (IM, 2L) and extracted with EtOAc (3 x). The combined EtOAc extracts were dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: RT = 0.74 min; mlz (ES⁺) = 232.1 [M+ H]⁺ (LCMS Method - 2). Preparation 380: 7-Benzyl-3-oxa-7-aza- icyclo[3.3.1]nonane-9-carbonitrile

To a solution of 7-benzyl-3-oxa-7-aza-bicyclo[3.3.1]nonan-9-one (Preparation 379, lOg, 43.3mmol) and toluene sulfonyl methyl isocyanide (1 lg, 103.9mmol) in DME (146mL) and EtOH (4mL) at 0°C was added potassium tertiary butoxide (11.65g, 103.9mmol) portionwise over 20 min and the resulting reaction mixture was stirred at 0°C for 1.5 h, then at 40°C for 1 h. Upon cooling, the reaction mixture was filtered and the filtrate concentrated in vacuo. The remainder was dissolved in EtOAc, washed with water and brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotogrpahy (DCM:MeOH; 97:3 to 5:95 to 1 :9) afforded the title compound: RT = 2.51 min; mlz (ES⁺) = 243.2 [M+ H]⁺ (LCMS Method - 4).

Preparation 381: 7-Benzyl-3-oxa-7-aza-bicyclo[3.3.1]nonane-9-carboxylic acid ethyl ester

A solution of 7-benzyl-3-oxa-7-aza-bicyclo[3.3.1]nonane-9-carbonitrile

(Preparation 380, 10. Og, 41.3mmol) in aqueous HC1 (12M, 80mL) was heated under reflux conditions for 6 h. The solvent was removed in vacuo and the remainder dissolved in EtOH (lOOmL) and concentrated aqueous sulphuric acid (few drops) and heated under reflux conditions for 20 h. The reaction mixture was concentrated to one quarter of the original volume, poured into saturated aqueous NaHC0₃ solution and extracted with EtOAc. The organic extract was washed with brine, dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: RT = 2.99 min; mlz (ES⁺) = 290.2 [M+ H]⁺ (LCMS Method - 4). Preparation 382: (7-Benzyl-3-oxa-7-aza-bic clo[3.3.1]non-9-yl)-methanol

To a suspension of lithium aluminium hydride (10.26g, 0.27mmol) in THF (140mL) at 0°C was added a solution of 7-benzyl-3-oxa-7-aza-bicyclo[3.3.1]nonane-9-carboxylic acid ethyl ester (Preparation 381, 19.5g, 67.47mmol) in THF (160mL) over 40 min. The resulting reaction mixture was heated at 60°C for 4.5 h. The reaction mixture was cooled to 0°C and Na2S04.H₂0 was added portionwise until all effervescence ceased. EtOAc was added and the mixture filtered through celite, washing with EtOAc, and the filtrate concentrated in vacuo to afford the title compound: RT = 2.25 min; mlz (ES⁺) = 248.2 [M + H]⁺ (LCMS Method - 4).

Preparation 383: (3-Oxa-7-aza-bicyclo[3.3.1]non-9-yl)-methanol

To a solution of (7-benzyl-3-oxa-7-aza-bicyclo[3.3.1]non-9-yl)-methanol

(Preparation 382, 2.2g, 9.1mmol) in IMS was added Pd/C (5%) and the resulting reaction mixture was stirred under an atmosphere of hydrogen at r.t. for 16 h. The reaction mixture was filtered through celite, washing with IMS, and the filtrate concentrated in vacuo to afford the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 4.2-3.8 (m, 6H), 3.4-3.15 (m, 2H), 3.15-2.95 (m, 2H), 2.5-2.2 (m, 4H), 1.6-1.5 (m, 1H).

Preparation 384: 9-Hydroxymethyl-3-oxa-7-aza-bic clo[3.3.1]nonane-7-carbonitrile

To a solution of (3-oxa-7-aza-bicyclo[3.3.1]non-9-yl)-methanol (Preparation 383, 4.05g, 17.7mmol) in DCM (35mL) at 0°C was added NaHC0₃ (4.46g, 53.1mmol) and H₂0 (35mL). A solution of cyanogen bromide (2.25g, 21.3mmol) in DCM (15mL) was slowly added and the resulting reaction mixture stirred at 0°C for 45 min, then at r.t. for 16 h. The reaction mixture was extracted with DCM (3 x) and the combined organic extracts dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotogrpahy (EtOAc) afforded the title compound: 1H NMR δ_Η (300MHz, CDC1₃): 4.2-4.1 (m, 1H), 4.0- 3.7 (m, 4H), 3.65-3.4 (m, 3H), 3.4-3.3 (m, 1H), 2.2-1.85 (m, 1H), 1.85-1.7 (m, 2H), 1.6-1.5 (m, 1H).

Preparation 385: [7-(3-Ethyl-[l,2,4]oxadiazol-5-yl)-3-oxa-7-aza-bicyclo[3.3.1]non-9-yl]- methanol The title compound was synthesised from 9-hydroxymethyl-3-oxa-7-aza- bicyclo[3.3.1]nonane-7-carbonitrile (Preparation 384) and N-hydroxypropionamidine employing a procedure similar to that outlined in Preparation 51: RT = 1.77 min; mlz (ES ) = 254.1 [M+ H]⁺ (LCMS Method - 4).

Preparation 386: (lS,5R)-9-(2-Chloro-pyrimidin-5-yloxymethyl)-7-(3-ethyl- [l,2,4]oxadiazol-5-yl)-3-oxa-7-aza-bic clo[3.3.1]nonane

To a solution of 2-chloro-5-hydroxypyrimidine (130mg, 0.99mmol), [7-(3-ethyl- [l,2,4]oxadiazol-5-yl)-3-oxa-7-aza-bicyclo[3.3.1]non-9-yl]-methanol (Preparation 385, 250mg, 0.99mmol) and PPh₃ (777mg, 2.96mmol) in THF (20mL) was added 1,1^*- (azodicarbonyl)dipiperidine (0.747g, 2.96mmol) and the resulting reaction mixture was heated at 60°C for 2 h. Further PPh₃ (259mg, 0.99mmol) and 1,1'-

(azodicarbonyl)dipiperidine (249mg, 0.99mmol) were added and the reaction mixture stirred at 60°C for 4 h. Further PPh₃ (259mg, 0.99mmol) and 1 , l'-(azodicarbonyl)dipiperidine

(249mg, 0.99mmol) were added and the reaction mixture stirred at r.t. for 16 h. Purification by column chromotogrpahy (EtOAc:IH; 2:3) afforded the title compound: RT = 0.89 min; mlz (ES⁺) = 366.3 [M+ H]⁺ (LCMS Method - 6). Preparation 387: ((3R,45)-4-(2,5-Difluoro-phenyl)-l-{5-[(lR,55)-7-(3-ethyl-

[l,2,4]oxadiazol-5-yl)-3-oxa-7-aza-bicyclo[3.3.1]non-9-ylmethoxy]-pyrimidin-2-yl}- pyrrolidin-3-yl)-carbamic acid tert-but \ ester

To a solution of (15',5i?)-9-(2-chloro-pyrimidin-5-yloxymethyl)-7-(3-ethyl- [l,2,4]oxadiazol-5-yl)-3-oxa-7-aza-bicyclo[3.3.1]nonane (Preparation 386, 70.63mg,

0.1931mmol) and [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 60mg, 0.2mmol) in DMSO (0.8mL) was added DBU (58μΕ, 0.386mmol) and the resulting reaction mixture was heated at 85°C for 120 h. Upon cooling, the reaction mixture was diluted with DCM (lOOmL), washed with aqueous citric acid solution (1M, lOOmL) and brine (lOOmL), dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromotogrpahy (DCM:MeOH; 98:2), followed by further purification by preparative HPLC afforded the title compound: RT = 1.23 min; mlz (ES ) = 628.5 [M+ H]⁺ (LCMS Method - 6).

Preparation 388: l-Fluoro-2-((ii)-2-nitro-vinyl)-benzene

The title compound was syntheised from 2-f uorobenzaldehyde employing a procedure similar to that outlined in Preparation 30: 1H NMR δ_Η (300MHz, CDC1₃): 8.05 (d, J=13.8 Hz, 1H), 7.73 (d, J=13.8Hz, 1H), 7.4-7.6 (m, 2H), 7.1-7.3 (m, 2H).

Preparation 389: (rrans)-l-Benzyl-3- 2-fluoro-phenyl)-4-nitro-pyrrolidine

The title compound was synthesised from l-f uoro-2-((E)-2-nitro-vinyl)-benzene (Preparation 388) employing a procedure similar to that outlined in Preparation 31: RT = 0.93 min; mlz (ES⁺) = 301.2 [M+ H]⁺ (LCMS Method - 2).

Preparation 390: [(rrans)-l-Benzyl-4-(2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid terf-butyl ester

The title compound was synthesised from (trans)- l-benzyl-3-(2-fluoro-phenyl)-4- nitro-pyrrolidine (Preparation 389) employing a procedure similar to that outlined in

Preparation 32: RT = 2.99 min; mlz (ES⁺) = 371.3 [M+ H]⁺ (LCMS Method - 3). Preparation 391: [(3R,4S)-l-Benzyl-4-(2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid terf-butyl ester

The title compound was afforded via chiral HPLC separation of [(trans)- 1 -benzyl-4- (2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 390):

IH:IPA:BA 96:4:0.1, 15ml/min, 270nm, RT = 10.6 min.

Preparation 392: [(3R,4S)-4-(2-Fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

A solution of [(3 ?,45)-l-benzyl-4-(2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 391, 880mg, 2.38mmol) in MeOH (47.5mL) was passed through an H-Cube apparatus (10% Pd/C Catcart 30, 30bar, 90°C) at a flow rate of ImL per min. The solvent was removed in vacuo to afford the title compound: RT = 0.63 min; m/z (ES⁺) = 281.3 [M+ H]⁺ (LCMS Method - 6).

Preparation 393: (R)-l-{l-[3-((5)-l-Methoxy-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4- yl}-ethanol

The title compound was syntheseised from 4-((i?)-l-hydroxyethyl)piperidine-l- carbonitrile (Preparation 98) and (5)-N-hydroxy-2-methoxypropionamidine (Preparation 148) employing a procedure similar to that outlined in Preparation 100: RT = 0.58 min; m/z (ES⁺) = 256.2 [M+ H]⁺ (LCMS Method - 2). Preparation 394: Methanesulfonic acid (R)-l-{l-[3-((S)-l-methoxy-ethyl)- [l,2,4]oxadiazol-5-yl]-piperidin- -yl}-ethyl ester

The title compound was synthesized from (i?)-l-{l-[3-((5)-l-methoxy-ethyl)- [l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethanol (Preparation 393) employing a procedure similar to that outlined in Preparation 101: RT = 0.65 min; mlz (ES⁺) = 334.2 [M+ H]⁺ (LCMS Method - 2).

Preparation 395: 2-Chloro-5-((5)-l-{l-[3-((S)-l-methoxy-ethyl)-[l,2,4]oxadiazol-5-yl]- piperidin-4-yl}-ethoxy)-pyrimi ine

The title compound was synthesised from methanesulfonic acid (i?)-l-{l-[3-((5)-l- methoxy-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl} -ethyl ester (Preparation 394) employing a procedure similar to that outlined in Preparation 373. Purification by column chromotogrpahy (DCM:MeOH; 99:1 to 96:4): RT = 2.09 min; mlz (ES⁺) = 368.2 [M+ H]⁺ (LCMS Method - 3).

Preparation 396: {(3R,45)-4-(2-Fluoro-phenyl)-l-[5-((S)-l-{l-[3-((S)-l-methoxy-ethyl)- [l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-buty\ ester

To a solution of 2-chloro-5-((S)-l-{l-[3-((S)-l-methoxy-ethyl)-[l,2,4]oxadiazol-5- yl]-piperidin-4-yl}-ethoxy)-pyrimidine (Preparation 395, 131mg, 0.357mmol) in DMSO (0.72mL) was added [(3i?,45)-4-(2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 392, 150mg, 0.535mmol) and the resulting reaction mixture heated at 80°C for 88 h. Upon cooling, the reaction mixture was partitioned between DCM (150mL) and saturated aqueous citiric acid solution (150mL). The organics were separated, washed with brine (lOOmL) and concentrated in vacuo. The remainder was purified by preparative HPLC to afford the title compound: RT = 1.34 min; mlz (ES⁺) = 612.5 [M+ H]⁺ (LCMS Method - 6).

Preparation 397: 4-Fluoro-benzoic acid l-{5-[4-((5)-l-{2-[(3R,45)-3-tert- butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}- ethyl)-piperidin- 1- l] - [ 1 ,2,4] oxadiazol-3-yl}-cyclopropyl ester

The title compound was synthesized from [(3 ?,45)-l-[5-((5)-l-piperidin-4-yl- ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185) and 4-fluoro-benzoic acid l-(5-trichloromethyl-[l,2,4]oxadiazol-3- yl)-cyclopropyl ester (Preparation 357) employing a procedure similar to that outlined in Preparation 358: RT = 1.58 min; mlz (ES⁺) = 768.51 [M+ H]⁺ (LCMS Method - 6).

Preparation 398: 4-((5)-l-{2-[(3R,4S)-3-tei-i-Butoxycarbonylamino-4-(2-fluoro-5- methyl-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidine-l-carboxylic acid benzyl ester

The title compound was synthesized from 4-[(5)-l-(2-chloro-pyrimidin-5-yloxy)- ethyl]-piperidine-l-carboxylic acid benzyl ester (Preparation 183) and [(3i?,45)-4-(2-fluoro- 5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 285)

employing a procedure similar to that outlined in Preparation 351: RT = 1.55 min; mlz (ES⁺) = 634.49 [M+ H]⁺ (LCMS Method - 6). Preparation 399: {(3R,4S)-4-(2-Fluoro-5-methyl-phenyl)-l-[5-((S)-l-piperidin ethoxy)-pyrimidin-2-yl]-p rrolidin-3-yl}-carbamic acid tert-butyl ester

The title compound was synthesized from 4-((S)-l-{2-[(3R,4S)-3-tert- butoxycarbonylamino-4-(2-fluoro-5 -methyl-phenyl)-pyrrolidin- 1 -yl] -pyrimidin-5 -yloxy } - ethyl)-piperidine-l-carboxylic acid benzyl ester (Preparation 398) employing a procedure similar to that outlined in Preparation 185: RT = 0.87 min; m/z (ES⁺) = 500.46 [M+ H]⁺ (LCMS Method - 6).

Preparation 400: 4-Fluoro-benzoic acid l-{5-[4-((S)-l-{2-[(3R,4S)-3-teri- butoxycarbonylamino-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-l-yl]-pyrimidin-5- yloxy}-ethyl)-piperidin-l- l]-[l,2,4]oxadiazol-3-yl}-cyclopropyl ester

The title compound was synthesised from {(3i?,45)-4-(2-fluoro-5-methyl-phenyl)-l- [5-((5)-l-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 399) and 4-fluoro-benzoic acid l-(5-trichloromethyl-[l,2,4]oxadiazol-3- yl)-cyclopropyl ester (Preparation 357) employing a procedure similar to that outlined in Preparation 358: RT = 1.61 min; m/z (ES⁺) = 746.58 [M+ H]⁺ (LCMS Method - 6).

Preparation 401: 4-((S)-l-{2-[(3R,4S)-3-tei"i-Butoxycarbonylamino-4-(2-fluoro-phenyl)- pyrrolidin-l-yl]-pyrimidin-5- loxy}-ethyl)-piperidine-l-carboxylic acid benzyl ester

The title compound was synthesized from 4-[(5)-l-(2-chloro-pyrimidin-5-yloxy)- ethyl]-piperidine-l-carboxylic acid benzyl ester (Preparation 183) and [(3i?,45)-4-(2-fluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 392) employing a procedure similar to that outlined in Preparation 351 : RT = 1.50 min; mlz (ES ) = 620

[M + H]⁺ (LCMS Method - 6).

Preparation 402: {(3R,45)-4-(2-Fluoro-phenyl)-l-[5-((S)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3- l}-carbamic acid tert-butyl ester

The title compound was synthesized from 4-((S)-l- {2-[(3R,4S)-3-tert- butoxycarbonylamino-4-(2-fluoro-phenyl)-pyrrolidin- 1 -yl]-pyrimidin-5-yloxy} -ethyl)- piperidine-l-carboxylic acid benzyl ester (Preparation 401) employing a procedure similar to that outlined in Preparation 185: RT = 0.80 min; mlz (ES⁺) = 486.44 [M + H]⁺ (LCMS Method - 6).

Preparation 403: Benzoic acid l-{5-[4-((S)-l-{2-[(3R,4S)-3-tei"i-butoxycarbonylamino-4- (2-fluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]- [1,2,4] oxadiazol-3- l}-cyclobutyl ester

The title compound was synthesised from {(3i?,45)-4-(2-fluoro-phenyl)-l-[5-((5)-l- piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester

(Preparation 402) and benzoic acid l-(5-trichloromethyl-[l ,2,4]oxadiazol-3-yl)-cyclobutyl ester (Preparation 360) employing a procedure similar to that outlined in Preparation 358: RT = 1.59 min; mlz (ES⁺) = 728.57 [M + H]⁺ (LCMS Method - 6).

Preparation 404: Benzoic acid l-{5-[4-((S)-l-{2-[(3R,4S)-3-tert-butoxycarbonylamino-4- (2-fluoro-5-methyl-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]- [1,2,4] oxadiazol-3-yl}-cyclobutyl ester

The title compound was synthesised from {(3i?,45)-4-(2-fluoro-5-methyl-phenyl)-l- [5-((5)-l-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 399) and benzoic acid l-(5-trichloromethyl-[l,2,4]oxadiazol-3-yl)- cyclobutyl ester (Preparation 360) employing a procedure similar to that outlined in

Preparation 358: RT = 1.62 min; m/z (ES⁺) = 742.56 [M+ H]⁺ (LCMS Method - 6).

Preparation 405: N-Hydroxy-l-hydroxymethyl-cyclopropanecarboxamidine

A solution of hydroxylamine (50% aqueous solution, 0.4 lmL, 6.69mmol) and 1- (hydroxymethyl)cyclopropanecarbonitrile (0.50g, 5.15mmol) in EtOH (20mL) was heated at 60°C for 4 h. Further hydroxylamine (50% aqueous solution, 0.789mL, 12.9mmol) was added and the reaction mixture stirred at 60°C for 4 h. The solvent was removed in vacuo to afford the title compound: 1H NMR δ_Η (400MHz, DMSO-d6): 8.83 (s, 1H), 5.25 (br. s., 2H), 4.64 (t, 1H), 3.44 (d, J=5.5 Hz, 2H), 0.77-0.75 (m, 2H), 0.56-0.54 (m, 2H).

Preparation 406: 5-[4-((S)-l-{2-[(3R,4S)-3-tei-i-Butoxycarbonylamino-4-(2-fluoro-5- methyl-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]- [1,2,4] oxadiazole-3-carbox lic acid methyl or ethyl ester

A solution of {(3i?,4_lS)-4-(2-fiuoro-5-methyl-phenyl)-l-[5-((5)-l-piperidin-4-yl- ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 399, 120mg, 0.240mmol) and 5-trichloromethyl-[l,2,4]oxadiazole-3-carboxylic acid ethyl ester (Preparation 215, 31.2mg, 0.120mmol) in DMSO (lmL) was stirred at r.t. for 96 h. The reaction mixture was loaded onto an SCX cartridge that had been pre-eluted with MeOH followed by aqueous HCl (1M) followed by MeOH. The reaction mixture was eluted with MeOH, followed by NEt₃ in MeOH (2M) and the desired fractions concentrated in vacuo. Purification by column chromotogrpahy afforded a 4: 1 mixture of the title compounds: RT = 1.37, 1.42 min; m/z (ES⁺) = 626.5, 640.5 [M+ H]⁺ (LCMS Method - 6). Preparation 407: {(3R,4S)-4-(2-Fluoro-5-methyl-phenyl)-l-[5-((S)-l-{l-[3-(l-hydroxy-l- methyl-ethyl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin-4-yl}-ethoxy)-pyrimidin-2-yl] -pyrrolidin- 3-yl}-carbamic acid tert-but \ ester

The title compound was synthesized from 5-[4-((S)-l-{2-[(3R,4S)-3-tert- butoxycarbonylamino-4-(2-fluoro-5 -methyl-phenyl)-pyrrolidin- 1 -yl] -pyrimidin-5 -yloxy } - ethyl)-piperidin-l-yl]-[l,2,4]oxadiazole-3-carboxylic acid methyl or ethyl ester

(Preparation 406) employing a procedure similar to that outlined in Preparation 217: RT = 1.30 min; m/z (ES⁺) = 626.5 [M+ H]⁺ (LCMS Method - 6).

Preparation 408: (R)-l-[l-(5-Ethyl- rimidin-2-yl)-piperidin-4-yl]-ethanol

A solution of ( ?)-l-piperidin-4-yl ethanol (Preparation 61, 0.50g, 3.87mmol) and 2- bromo-5-ethylpyrimidine (0.693g, 3.70mmol) in DBU (0.6mL) was heated at 100°C under microwave irradiation for 30 min. Upon cooling, the reaction mixture was poured into water and extracted with EtOAc (3 x). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification (chromatography) afforded the title compound: RT = 0.72 min; m/z (ES⁺) = 236.28 [M+ H]⁺ (LCMS Method - 6).

The following compounds were prepared by reaction of ( ?)-l-piperidin-4-yl ethanol (Preparation 61) with 2-chloro-5-ethylpyrazine or 2,5-dichloropyrimidine employing a procedure similar to that outlined in Preparation 408:

Preparation 411: Methanesulfonic acid (R)-l-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4- yl] -ethyl ester

To a solution of (i?)-l-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-ethanol

(Preparation 408, 0.484g, 2.06mmol) and triethylamine (0.40mL, 2.87mmol) in DCM (30mL) at 0°C was added methanesulfonyl chloride (0.20mL, 2.58mmol) and the resulting reaction mixture was stirred for 30 min. The reaction mixture was washed with water and saturated aqueous NaHC0₃ solution and concentrated in vacuo to afford the title compound: RT = 0.96 min; m/z (ES⁺) = 314.29 [M+ H]⁺ (LCMS Method - 6).

The following compounds were prepared by reaction of the appropriate alcohol building block (Preparation 409 or 410) with methanesulfonyl chloride employing a procedure similar to that outlined in Preparation 411:

Preparation 414: 2-Chloro-5-(lS)-l-[l-(5-ethylpyrimidin-2-yl)piperidin-4- yl] ethoxypyrimidine

A solution of methanesulfonic acid (i?)-l-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]- ethyl ester (Preparation 411, 1.36g, 4.34mmol), 2-chloro-5 -hydro xypyrimidine (1.13g, 8.68mmol) and potassium carbonate (1.50g, 10.8mmol) in DMF (8mL) was heated in a sealed tube at 80°C for 16 h. Upon cooling, the reaction mixture was partitioned between EtOAc and water and the organic extract separated, dried (MgS0₄) and concentrated in vacuo. Purification (chromatography) afforded the title compound: RT = 1.20 min; m/z (ES ) = 348.29 [M+ H]⁺ (LCMS Method - 6). The following compounds were prepared by reaction of the appropriate mesylate building block (Preparation 412 or 413) with 2-chloro-5-hydroxypyrimidine employing a procedure similar to that outlined in Preparation 414:

Preparation 417: (R)-l-{l-[3-(l,l-Difluoro-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}- ethanol

The title compound was synthesised from 4-((i?)-l-hydroxyethyl)piperidine-l- carbonitrile (Preparation 98) and 2,2-difluoro-N-hydroxy-propionamidine (Preparation 222) employing a procedure similar to that outlined in Preparation 100: 1H NMR 5H

(300MHz, CDC1₃): 4.3-4.2 (m, 2H), 3.7-3.6 (m, 1H), 3.1-3.0 (m, 2H), 2.1-1.9 (m, 4H), 1.8- 1.7 (m, 1H), 1.6-1.3 (m, 3H), 1.2 (d, J=6.43 Hz, 3H).

Preparation 418: 2-Chloro-5-((5)-l-{l-[3-(l,l-difluoro-ethyl)-[l,2,4]oxadiazol-5-yl]- piperidin-4-yl}-ethoxy)-pyrimidine

To a solution of 2-chloro-5-hydroxypyrimidine (82.4mg, 0.632mmol), (i?)-l-{l-[3- (l,l-difluoro-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethanol (Preparation 417,

150mg, 0.57mmol) and PPh₃ (226mg, 0.861mmol) in THF (6mL) was added TBAD (198mg, 0.861mmol) and the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was partitioned between DCM and water and the organic extract dried (MgS0₄), filtered and concentrated in vacuo. Purification (chromatography) afforded the title compound: RT = 1.21 min; mlz (ES⁺) = 374.23 [M+ H]⁺ (LCMS Method - 6).

The following compounds were prepared by reaction of 4-((i?)-l- hydroxyethyl)piperidine-l-carbonitrile (Preparation 98) with the appropriate amidoxime building block employing a procedure similar to that outlined in Preparation 100:

The following compounds were prepared by reaction of the appropriate alcohol building block (Preparation 419 or 420) with methanesulfonyl chloride employing a procedure similar to that outlined in Preparation 411:

Preparation 421: 2-Chloro-5-{(5)-l-[l-(3-trifluoromethyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-ethoxy}-pyrimidine

To a solution of methanesulfonic acid (i?)-l-[l-(3-trifluoromethyl-[l,2,4]oxadiazol-5- yl)-piperidin-4-yl] -ethyl ester (Preparation 419, 1.34g, 3.90mmol) and 2-chloro-5- hydroxypyrimidine (1.13g, 8.68mmol) in DMA (27mL) was added cesium fluoride (1.19g, 7.81mmol) and the resulting reaction mixture was stirred at 70°C for 72 h. Upon cooling, the reaction mixture was diluted with water and saturated aqueous NaHC0₃ solution and extracted with EtOAc (2 x). The combined organic extracts were washed with brine (8 x), dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc: Heptane; 1 : 1) followed by further purification by column chromatography

(DCM:MeOH:NH ) afforded the title compound: RT = 2.68 min; m/z (ES⁺) = 378.4 [M + H]⁺ (LCMS Method - 3). Preparation 422 : 5-{(S)-l-[l-(3-terf-Butyl- [ 1 ,2,4] oxadiazol-5-yl)-piperidin-4-yl] -ethoxy}- 2-chloro-pyrimidine

The title compound was synthesised from methanesulfonic acid (R)-l-[l-(3-tert- butyl-[l ,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethyl ester (Preparation 420) and 2-chloro-5- hydroxypyrimidine employing a procedure similar to that outlined in Preparation 421: RT = 2.65 min; mlz (ES⁺) = 366.4 [M+ H]⁺ (LCMS Method - 3).

Preparation 423: [(3R,45)-l-[5-((S)-l-{l-[(S)-2-(Tetrahydro-furan-3-yl)-2H-tetrazol-5- yl] -piperidin-4-yl}-ethoxy)-pyrimidin-2-yl] -4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl] - carbamic acid tert-buty\ est r

A solution of [(3i?,45)-l-(5-{(5)-l-[l-(2H-tetrazol-5-yl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 231, 0.250g, 0.424mmol), 3-iodotetrahydrofuran (0.252g, 1.27mmol) and triethylamine (lmL, 7mmol) in DMF (lmL) was heated at 80°C for 28 h. Upon cooling, EtOAc (50mL) was added, the solution washed with water (30mL) and brine (2 x 30mL), passed through a hydrophobic frit and concentrated in vacuo. The remainder was purified by preparative HPLC to afford [(3i?,45)-l-[5-((5)-l-{l-[2-(tetrahydro-furan-3-yl)-2H-tetrazol-5- yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester. Purification by chiral HPLC ((MeOH:MeCN:THF 45:40: 15, 15ml/min, 250nm) afforded the title compound: RT = 1.39 min; mlz (ES⁺) = 660.50 [M + H]⁺ (LCMS Method - 6). Preparation 424: [(3R,4S)-l-[5-((S)-l-{l-[(R)-2-(Tetrahydro-furan-3-yl)-2H-tetrazol-5- yl] -piperidin-4-yl}-ethoxy)-pyrimidin-2-yl] -4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl] - carbamic acid tert-butyl ter

The title compound was synthesized from [(3i?,45)-l-(5-{(5)-l-[l-(2H-tetrazol-5-yl)- piperidin-4-yl]-ethoxy} -pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 231) employing the procedure outlined in Preparation 423: RT = 1.39 min; m/z (ES⁺) = 660.50 [M+ H]⁺ (LCMS Method - 6). Example 1: (3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy] rimidin-2-yl}pyrrolidin-3-ylamine hydrochloride

To a solution of 2-choro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidine (Preparation 2, 67mg, 0.20mmol) and [(3i?,45)-4-(2,5- difluorophenyl)pyrrolidin-3-yl] carbamic acid tert-butyl ester (Preparation 48, 60mg, 0.20mmol) in DMSO (0.4mL), under argon, was added DBU (30μΙ., 0.20mmol) and the mixture was heated to 100°C for 16 h. A further portion of 2-choro-5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2, 20mg, 0.06mmol) was added and heating continued for 8 h. The mixture was cooled to r.t. and partitioned between DCM and brine. The organic phase was separated, dried (Na₂S0₄) and the solvent removed in vacuo. To a solution of the residue in DCM (8mL) was added TFA (2mL) and the mixture was stirred at r.t. for 1 h. The crude reaction mixture was purified by SCX cartridge, eluting with MeOH followed by NH₄OH in MeOH, and the basic fraction collected. Further purification by column chromatography (DCM:MeOH, 98:2) afforded the title compound as the free base, which was dissolved in a solution of 4M HC1 in dioxane.

The solvent was removed in vacuo to afford the title compound: RT = 2.82 min; m/z (ES ) = 500.2 [M+ H]⁺. Example 2: (3R,4R)-4-(2,5-Difluorophenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy] rimidin-2-yl}piperidin-3-ylamine hydrochloride

The title compound was prepared from 2-choro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2) and [(3i?,4i?)-4-(2,5- difluorophenyl)piperidin-3-yl]carbamic acid tert-butyl ester (Preparation 9) employing the procedure outlined in Example 1: RT = 2.88 min; m/z (ES⁺) = 514.3 [M+ H]⁺.

Example 3: (3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy] ridin-2-yl}pyrrolidin-3-ylamine hydrochloride

A combination of 2-bromo-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyridine (Preparation 3, 38mg, O.lOmmol), [(3R,4S)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 36mg, 0.12mmol), sodium tert-butoxide (34mg, 0.35mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-l- phosphabicyclo[3.3.3]undecane (3mg, O.Olmmol) in toluene (3mL) was degassed with argon for 10 min. tra(dibenzylideneacetone)dipalladium (9mg, O.Olmmol) was added and the mixture was degassed with argon for a further 10 min before heating in a microwave reactor at 120°C for 30 min. The reaction mixture was partitioned between DCM (lOOmL) and brine (lOOmL), then the organic phase was separated, dried (MgS0₄) and the solvent removed in vacuo to afford the tert-butyl carbamate protected intermediate product.

The crude product was dissolved in DCM (5mL), and TFA (5mL) was added before stirring the mixture at r.t. for 20 min. Removal of the reaction solvent in vacuo and purification by column chromatography (DCM:MeOH, 96:4) afforded the title compound as the free amine. The product was dissolved in a solution of HC1 in dioxane (4M), then removal of the solvent in vacuo afforded the title compound: RT = 2.52 min; m/z (ES ) = 499.3 [Μ+ ηγ. Example 4: (3R,4R)-4-(2,5-Difluorophenyl)-5'-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy] -3,4,5,6-tetr ahydro-2H- [ 1 ,2 ' ] bipyridinyl-3-ylamine hydrochloride

The title compound was prepared from 2-bromo-5-[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)piperidin-4-ylmethoxy]pyridine (Preparation 3) and [(3i?,4i?)-4-(2,5- difluorophenyl)piperidin-3-yl]carbamic acid tert-butyl ester (Preparation 9) employing a similar method to that outlined in Example 3, but the tert-butyl protected amine intermediate was purified by column chromatography (IH:EtOAc, 60:40). To a solution of the product in DCM (5mL) was added TFA (5mL) and the reaction was stirred at r.t. for 20 min. The crude reaction mixture was passed directly down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. The residue was dissolved in a solution of HC1 in dioxane (4M), then removal of the solvent in vacuo afforded the title compound: RT = 2.63 min; m/z (ES⁺) = 513.3 [M+ H]⁺.

Example s: (3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy] razin-2-yl}pyrrolidin-3-ylamine hydrochloride

A combination of 2-bromo-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrazine (Preparation 4, 115mg, 0.30mmol), [(3R,4S)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 107mg, 0.36mmol), sodium tert-butoxide (lOlmg, 1.05mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza- l-phosphabicyclo[3.3.3]undecane (lOmg, 0.03mmol) in dioxane (4mL) was degassed with argon for 10 min. tra(dibenzylideneacetone)dipalladium (9mg, O.Olmmol) was added and the mixture was degassed with argon for a further 5 min before being heated in a microwave reactor at 120°C for 30 min. The reaction mixture was passed directly down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected.

Further purification by preparative HPLC afforded the title compound as the free amine. The product was dissolved in a solution of HC1 in dioxane (4M), then removal of the solvent in vacuo afforded the title compound: RT = 2.80 min; mlz (ES⁺) = 500.2 [M+ H] .

Example 6: (3R,4S)-l-{5-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrazin-2-yl}-4- -trifluorophenyl)pyrrolidin-3-ylamine hydrochloride

2-Bromo-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrazine (Preparation 4) was reacted with [(3i?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39) employing a procedure similar to that outlined in

Example 5, but the reaction mixture was heated for a further 30 min at 120°C. After SCX purification the residue was dissolved in DCM (5mL), and TFA (5mL) was added. After stirring at r.t. for 15 min the reaction mixture was passed directly down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. Further purification by column chromatography (DCM:MeOH, 97.5:2.5) afforded the title compound as the free amine. The product was dissolved in a solution of HC1 in dioxane (4M), then removal of the solvent in vacuo afforded the title compound: RT = 2.83 min; mlz (ES ) = 518.4 [M+ H]⁺.

Example 7: 4-{6-[(3S,4S)-3-Amino-4-(2-oxopiperidin-l-yl)pyrrolidin-l-yl]pyridin-3- yloxymethyl}piperidine-l-carbox lic acid isopropyl ester hydrochloride

A combination of 4-(6-bromopyridin-3-yloxymethyl)piperidine-l-carboxylic acid isopropyl ester (Preparation 15, 107mg, 0.30mmol), [(35',45)-4-(2-oxopiperidin-l- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 20, 109mg, 0.35mmol), 9,9- dimethyl-4,5-bis(diphenylphosphino)xanthene (lOmg, 0.02mmol) and sodium tert-butoxide (lOlmg, 1.05mmol), in toluene (4mL), was bubbled with argon for 15 min. tris- (dibenzylideneacetone)dipalladium (6mg, O.Olmmol) was added and the resulting mixture was heated to 100°C for 24 h. The crude mixture was filtered and diluted with EtOAc. The organic mixture was washed with sat. NaHCCb solution, dried (MgS0₄) and the solvent removed in vacuo. Purification by column chromatography (DCM:MeOH, 90: 10) afforded the title compound as the free amine. The product was re-dissolved in a solution of HCl in dioxane (4M), then the solvent was removed in vacuo to afford the title compound: RT = 2.23 min; mlz (ES⁺) = 460.2 [M+ H]⁺.

Example 8 : 4- {6- [(3R, S)-3- Amino-4-(2,5-difluorophenyl)pyrrolidin- 1-yl] pyridin-3- yloxymethyl}piperidine-l-carbox lic acid isopropyl ester hydrochloride

4-(6-Bromopyridin-3-yloxymethyl)piperidine-l-carboxylic acid isopropyl ester

(Preparation 15) was reacted with [(3 ?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48) employing a procedure similar to that outlined in

Example 7. The crude reaction mixture was partitioned between DCM and brine, then the organic phase was separated, dried (MgS0₄) and the solvent removed in vacuo. Purification by column chromatography (DCM:MeOH, 98:2, 96:4, 92:8,90: 10) afforded the title compound as the free amine. The product was re-dissolved in a solution of HCl in dioxane

(4M) and the solvent was removed in vacuo to afford the title compound: RT = 2.57 min; mlz

Example 9: 4-[(3R,4R)-3-Amino-4-(2,5-difluorophenyl)-3,4,5,6-tetrahydro-2H- [l,2']bipyridinyl-5'-yloxymethyl]piperidine-l-carboxylic acid isopropyl ester hydrochloride

4-(6-Bromopyridin-3-yloxymethyl)piperidine-l-carboxylic acid isopropyl ester

(Preparation 15) was reacted with [(3i?,4i?)-4-(2,5-difluorophenyl)piperidin-3-yl]carbamic acid tert-butyl ester (Preparation 9) employing a procedure similar to that outlined in

Example 7, but the reaction was heated to 90°C. The crude mixture was concentrated in vacuo, re-dissolved in MeOH, and filtered. The filtrate was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. The material was further purified by preparative HPLC, and the resulting product was passed down a second SCX cartridge, eluting with MeOH then NH₄OH in MeOH. The basic fraction was collected and concentrated in vacuo. The product was dissolved in a solution of HC1 in dioxane (4M) and the solvent was removed in vacuo to afford the title compound: RT = 2.75 min; mlz (ES⁺) = 489.2 [M+ H]⁺.

Example 10: 4- {4- [(3R,4R)-3-Amino-4-(2,5-difluorophenyl)piperidin- 1- yl]phenoxymethyl}piperidine-l-carbox lic acid isopropyl ester hydrochloride

A combination of 4-(4-bromophenoxymethyl)piperidine-l-carboxylic acid isopropyl ester (Preparation 22, 96mg, 0.3mmol), [(3i?,4i?)-4-(2,5-difluorophenyl)piperidin-3- yljcarbamic acid tert-butyl ester (Preparation 9, 31mg, O.lmmol), triethylamine (41 μΙ_^, 0.3mmol), copper acetate monohydrate (20mg, O.lmmol) and 4A molecular sieves in DCM (6mL) was stirred at r.t. for 80 h. The reaction mixture was filtered, and filtrate concentrated in vacuo. The residue was re-dissolved in MeOH and passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. To the product in DCM (lOmL) was added TFA (2mL) and the reaction was stirred at r.t. for 1 h. The material was passed down a second SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. Further purification by preparative HPLC afforded the title compound as the free amine. The product was dissolved in a solution of HC1 in dioxane (4M), then the solvent was removed in vacuo to afford the title compound: RT = 3.10 min; mlz (ES⁺) = 488.3 [M+ H]⁺.

Example 11: 4-{2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l-yl]pyrimidin-5- yloxymethyl}piperidine-l-carbox lic acid isopropyl ester hydrochloride

To a solution of 4-(2-chloropyrimidin-5-yloxymethyl)piperidine-l-carboxylic acid isopropyl ester (Preparation 25, 47mg, 0.15mmol) and [(3R,4S)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 45mg, 0.15mmol) in DMSO (0.3mL) under argon was added DBU (23 uL, 0.15mmol) and the mixture was heated to 100°C for 16 h. After cooling to r.t. the mixture was partitioned between DCM (lOOmL) and brine (lOOmL), then the organic phase was separated and concentrated in vacuo. The residue was re-dissolved in DCM (lOmL), and TFA (3mL) was added before stirring at r.t. for 1 h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. Further purification by column chromatography (DCM:MeOH, 98:2) afforded the title compound as the free amine. The product was dissolved in a solution of HC1 in dioxane (4M) and the solvent was removed in vacuo to afford the title compound: RT = 2.88 min; mlz (ES⁺) = 476.3 [M+ H]⁺.

Example 12: 4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyrimidin-5-yloxy}ethyl) iperidine-l-carboxylic acid isopropyl ester hydrochloride

To a solution of 4-[l-(2-chloropyrimidin-5-yloxy)ethyl]piperidine-l-carboxylic acid isopropyl ester (Preparation 27, 113mg, 0.31mmol) and [(3R,4S)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 112mg, 0.38mmol) in DMSO (0.63mL), under argon, was added DBU (47μΙ., 0.20mmol) and the reaction was heated to 100°C for 72 h. The mixture was cooled to r.t. and partitioned between EtOAc and brine. The organic phase was separated, dried (MgS0₄) and

concentrated in vacuo. Purification by column chromatography (IH:EtOAc, 60:40) followed by chiral HPLC (MTBE:THF 90: 10, 13ml/min, 235nm, RT = 19.4 min) afforded the intermediate product 4-(l - {2-[(3i?,45)-3-fert-butoxycarbonylamino-4-(2,5- difluorophenyl)pyrrolidin- 1 -yl]pyrimidin-5 -yloxy } ethyl)piperidine- 1 -carboxylic acid isopropyl ester: RT = 4.55 min; mlz (ES⁺) = 590.3 [M+ H]⁺.

To a solution of the product in DCM (5mL) was added TFA (lmL) and the reaction was stirred at r.t. until complete. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. Removal of the solvent in vacuo afforded the title compound as the free amine, which was re-dissolved in Et₂0 (3mL). A solution of HC1 in dioxane (4M) was added and the solvent was removed in vacuo to afford the title compound: RT = 2.75 min; mlz (ES⁺) = 490.2 [M + H]⁺. Example 13: (3R,4S)-4-(2,4-difluorophenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy] rimidin-2-yl}pyrrolidin-3-ylamine hydrochloride

To a solution of 2-choro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidine (Preparation 2, 54mg, 0.15mmol) and [(3 ?,45)-4-(2,4- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 34, 54mg, 0.18mmol) in DMSO (0.63mL), under argon, was added DBU (47μΙ, 0.20mmol) and the reaction was heated to 100°C for 16 h. The mixture was cooled to r.t. and partitioned between EtOAc and brine. The organic phase was separated, washed with brine (3 x 150mL), dried (MgS0₄) and concentrated in vacuo. Purification by column chromatography (IH:EtOAc, 60:40) afforded the intermediate product ((3i?,45)-4-(2,4-difiuorophenyl)-l-{5- [l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3- yl)carbamic acid tert-butyl ester: RT = 4.47 min; m/z (ES⁺) = 600.3 [M+ H]⁺

To a solution of the product in DCM (5mL) was added TFA (lmL) and the reaction was stirred at r.t. until complete. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. Removal of the solvent in vacuo afforded the title compound as the free amine, which was re-dissolved in Et₂0 (3mL). A solution of HC1 in dioxane (4M) was added and the solvent was removed in vacuo to afford the title compound: RT = 2.77 min; m/z (ES⁺) = 500.2 [M+ H] .

The following Examples were prepared by reacting the appropriate 2-choropyrimidine building block with the appropriate amine building block employing a similar procedure to that outlined in Example 13:

Example 18: (3R,4S)-l-{5-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidin-2-yl}-4- 2,4,5-trifluorophenyl)pyrrolidin-3-ylamine

To a solution of 2-choro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidine (Preparation 2, 199mg, 0.56mmol) and [(3R,4S)-4-(2,4,5- trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 269mg, 0.85mmol) in DMSO (4mL), under argon, was added DBU (130μΙ_,, 0.89mmol) and the reaction was heated to 85°C for 144 h. The mixture was cooled to r.t. and diluted with EtOAc. The organic solution was washed with water, then brine, and dried (MgS0₄), before removal of the solvent in vacuo. Purification by column chromatography (IH:EtOAc, 1 : 1.5) afforded the intermediate product [(3i?,4S)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester: RT = 4.53 min; m/z (ES⁺) = 618.2 [M+ H]⁺

To a solution of the product in DCM (lOmL) was added TFA (2.5mL) and the reaction was stirred at r.t. until complete. The reaction solvent was concentrated in vacuo and the resulting residue was partitioned between EtOAc and 1M NaOH solution. The organic phase was separated and the aqueous phase extracted with EtOAc (x 3). All organic fractions were combined, washed with brine, dried (MgS0₄), and the solvent removed in vacuo.

Purification by column chromatography (DCM:MeOH, 20: 1), followed by crystallisation from EtOAc, afforded the title compound: RT = 2.77 min; m/z (ES⁺) = 500.2 [M+ H]⁺.

Example 19: ((3R,45)-4-(4-Chloro-2-fluorophenyl)-l-{5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperi in-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-ylamine

To a solution of 2-choro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidine (Preparation 2, 130mg, 0.37mmol) and [(tra/?s)-4-(4-chloro-2- fluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 45, HOmg, 0.0.35mmol) in DMSO (2mL), under argon, was added DBU (55μί, 0.37mmol) and the reaction was heated to 85°C for 120 h. The mixture was cooled to r.t. and diluted with EtOAc. The organic solution was washed with water, then brine, and dried (MgSC^), before removal of the solvent in vacuo. Purification by column chromatography (IH:EtOAc, 1 : 1.5) and further purification by chiral HPLC (MTBE:THF 80:20, 12ml/min, 235nm, RT = 14.2 min) afforded the intermediate product ((3i?,45)-4-(4-chloro-2-fluorophenyl)-l- {5-[l-(3- isopropyl-[l ,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3- yl)carbamic acid tert-butyl ester: RT = 4.64 min; mlz (ES ) = 616.3 [M + H]⁺

To a solution of the product in DCM (4mL) was added TFA (lmL) and the reaction was stirred at r.t. until complete. The solvent was concentrated in vacuo, and resulting residue partitioned between EtOAc and 1M NaOH solution. The organic phase was separated, washed with brine, dried (MgSC^), and the solvent removed in vacuo. Purification by column chromatography (DCM:MeOH, 40:3) afforded the title compound: RT = 2.93 min; mlz (ES⁺) = 516.2 [M + H]⁺.

Example 20: ((3S,4R)-4-(4-Chloro-2-fluorophenyl)-l-{5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-ylamine

The title compound was prepared from 2-choro-5-[l-(3-isopropyl-[l ,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2) and [(tra/?s)-4-(4-chloro-2- fluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 45) employing the procedure outlined in Example 19. Chiral HPLC: MTBE:THF 80:20, 12ml/min, 235nm, RT 9.1 min. LCMS : RT = 2.85 min; mlz (ES⁺) = 516.2 [M + H]⁺.

Example 21: 4-((R)-l-{6-[(3R,45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyridine-3-yloxy}ethyl)pi eridine-l-carboxylic acid isopropyl ester hydrochloride

The title compound was prepared by reacting 4-[l-(6-bromopyridin-3- yloxy)ethyl]piperidine-l-carboxylic acid isopropyl ester (Preparation 54) with [(3R,4S)-4- (2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48)

employing a similar method to that outlined in Example 3. At the end of the first step the reaction mixture was passed directly down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. To a solution of the residue in DCM (5mL) was added TFA (5mL) and the reaction was stirred at r.t. for 30 min. The crude reaction mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. Further purification by column chromatography (DCM:MeOH, 97.5:2.5) followed by chiral HPLC (MTBE:MeOH:BA 80:20:0.1, 13ml/min, 250nm, RT: 10.5 min) afforded the title compound as the free amine. The product was dissolved in Et₂0, and a few drops of a solution of HC1 in dioxane (4M) was added.

Removal of the solvent in vacuo afforded the title compound: RT = 2.54 min; mlz (ES ) =

Example 22: 4-((5)-l-{6-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyridin-3-yloxy}ethyl)piperidine-l-carbox lic acid isopropyl ester hydrochloride

The title compound was prepared employing the procedure outlined in Example 21: chiral HPLC: MTBE:MeOH:BA 80:20:0.1, 13ml/min, 250nm, RT: 14.4 min. LCMS: RT = 2.54 min; mlz (ES⁺) = 489.2 [M+ H]⁺.

Example 23: (3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy] -4-methylpyrimidin-2-yl}pyrrolidin-3-ylamine p- toluenesulfonic acid salt

To a solution of 2-chloro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]-4-methylpyrimidine (Preparation 57, 89mg, 0.25mmol) and [(3i?,45)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid fert-butyl ester (Preparation 48, 150mg, 0.50mmol) in DMSO (4mL) was added DBU (39μί, 0.25mmol) and the reaction was heated to 80°C in a sealed tube for 7 days. The mixture was diluted with EtOAc, washed with brine, dried (Na₂S0₄) and the solvent removed in vacuo to afford the intermediate product

((3i?,45)-4-(2,5-difluorophenyl)- 1 - {5-[l -(3 -isopropyl- [ 1 ,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]-4-methylpyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester: RT = 4.51 min; m/z (ES⁺) = 614.5 [M+ H]⁺.

To a solution of the product in DCM (5mL), cooled to 0°C, was added TFA (2mL) over 5 min, and the resulting mixture was stirred at this temperature for 2 h. Sat. NaHC0₃ solution was added to quench the reaction and the organic phase was separated, passed through a phase separator, and concentrated in vacuo. Purification by column

chromatography, followed by chiral HPLC, afforded the title compound as the free amine. To a solution of the product in MeOH was added a solution of TsOH (leq.) in MeOH, then removal of the solvent in vacuo afforded the title compound: RT = 2.87 min; m/z (ES ) =

Example 24: (3R,4S)-l-{5-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]- 4-methylpyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-ylamine p- toluenesulfonic acid alt

To a solution of 2-chloro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]-4-methylpyrimidine (Preparation 57, 83mg, 0.24mmol) and [(3i?,45)-4-(2,4,5- trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 150mg, 0.47mmol) in DMSO (4mL) was added DBU (36μΕ, 0.24mmol) and the reaction was heated to 80°C in a sealed tube for 7 days. The mixture was diluted with EtOAc, washed with brine, dried (MgS0₄) and the solvent removed in vacuo. Purification by preparative HPLC afforded the intermediate product [(3i?,45)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]-4-methylpyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester: RT = 4.53 min; mlz (ES⁺) = 632.26 [M+ H]⁺.

To a solution of the product in Et₂0 (5mL), under argon, was added HC1 in dioxane

(4M, 5mL), and the resulting mixture was stirred at r.t. for 16 h. The reaction solvent was concentrated in vacuo, then sat. NaHC0₃ solution and MeOH (2mL) were added. The mixture was extracted with DCM and the organic phase was dried (Na₂S0₄). Removal of the solvent in vacuo and purification by column chromatography (DCM:MeOH, 100:0, 98:2, 97:3, 90: 10) afforded the title compound as the free amine. To a solution of the product in MeOH was added a solution of TsOH (leq.) in MeOH, then removal of the solvent in vacuo afforded the title compound: RT = 2.95 min; mlz (ES⁺) = 532.2 [M+ H]⁺.

Example 25: (3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(5-isopropyl-[l,2,4]oxadiazol-3- yl)piperidin-4-ylmethoxy] rimidin-2-yl}pyrr olidin-3-ylamine hydrochloride

To a solution of 2-chloro-5-[l-(5-isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4- ylmethoxy]pyrimidine (Preparation 60, 249mg, 0.70mmol) and [(3i?,45)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 209mg, OJOmmol) in DMSO (1.4mL), under argon, was added DBU (104μΙ., 0.70mmol) and the reaction was heated to 100°C for 16 h. The mixture was cooled to r.t. and partitioned between EtOAc and brine. The organic phase was separated, dried (MgS0₄) and the solvent removed in vacuo. Purification by column chromatography (IH:EtOAc, 70:30) afforded the intermediate product ((3i?,45)-4-(2,5-difluorophenyl)-l-{5-[l-(5-isopropyl-[l,2,4]oxadiazol- 3-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester: RT = 4.69 min; mlz (ES⁺) = 600.2 [M+ H]⁺

To a solution of the product in DCM (8mL) was added TFA (2mL) and the reaction was stirred at r.t. for 1 h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected and concentrated in vacuo. Purification was repeated by passing the residue down an SCX(POH) cartridge. The basic fraction was collected and concentrated in vacuo to afford the title compound as the free amine. The product was re-dissolved in a small volume of Et₂0 and a solution of HC1 in dioxane (4M) was added. Removal of the solvent in vacuo afforded the title compound: RT = 2.79 min; mlz (ES⁺) = 500.2 [M+ H]⁺.

Example 26: (3R,4S)-l-{5-[l-(5-Chloropyrimidin-2-yl)piperidin-4- ylmethoxy]pyrimidin-2-yl}-4-(2,5-difluorophenyl)pyrrolidin-3-ylamine

A combination of (3i?,45)-4-(2,5-difluorophenyl)-l-[5-(piperidin-4- ylmethoxy)pyrimidin-2-yl]pyrrolidin-3-ylamine (Preparation 64, 21 mg, 0.05 mmol), 2,5- dichloropyrimidine (8 mg, 0.05 mmol) and triethylamine (30 μί, 0.2 mmol) in tert-butanol (1 mL) was heated in a microwave reactor at 110°C for 50 min. The mixture was cooled to r.t. and passed directly down an SCX(POH) cartridge, eluting with MeOH then 10% NH₄OH in MeOH. The basic fraction was collected and concentrated in vacuo to afford the title compound: RT = 2.93 min; mlz (ES⁺) = 502.2 [M+ H]⁺.

Example 27: 4-(5-{2-[(3R,4S)-3-Amino-4-(2-fluorophenyl)pyrrolidin-l-yl]pyrimidin-5- yloxymethyl}-[l,2,4]oxadiazol-3-yl)piperidine-l-carboxylic acid isopropyl ester p- toluenesulfonic acid salt

A combination of 4-[5-(2-chloropyrimidin-5-yloxymethyl)-[l,2,4]oxadiazol-3- yl]piperidine-l-carboxylic acid isopropyl ester (Preparation 68, 125mg, 0.33mmol),

[(tra/75)-4-(2-fluorophenyl)pyrrolidin-3-yl]carbamic acid-9H-fluoren-9-ylmethyl ester hydrochloride (Preparation 71, 143mg, 0.33mmol) and DIPEA (120μΕ, 0.69mmol), in tert- butanol (2mL), was heated to 80°C for 72 h. The reaction mixture was concentrated in vacuo and purified by column chromatography (DCM:MeOH, 94:6). Further purification by chiral HPLC (MTBE:MeOH:BA 80:20:0.1, 12ml/min, 250nm, RT = 24.9 min) afforded the title compound as the free amine. A solution of TsOH (leq.) in MeOH (2mL) was added to the product, then removal of the solvent in vacuo afforded the title compound: RT = 2.79 min; mlz (ES⁺) = 526.3 [M+ H]

Example 28 : 4-(5- {2- [(3R,4R)-3- Amino-4-(2,5-difluorophenyl)piperidin- 1-yl] pyrimidin- 5-yloxymethyl}-[l,2,4]oxadiazol-3-yl)piperidine-l-carboxylic acid isopropyl ester hydrochloride

To a solution of 4-(5-{2-[(3i?,4i?)-3-tert-butoxycarbonylamino-4-(2,5- difluorophenyl)piperidin- 1 -yl]pyrimidin-5-yloxymethyl} -[ 1 ,2,4]oxadiazol-3-yl)piperidine- 1 - carboxylic acid isopropyl ester (Preparation 69, 30mg, 0.05mmol) in DCM (8mL) was added TFA (2mL) and the reaction was stirred at r.t. for 1 h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH. The basic fraction was collected and concentrated in vacuo to afford the title compound as the free amine. The product was re-dissolved in Et₂0, then a solution of HC1 in dioxane (4M) was added. The solvent was removed in vacuo to afford the title compound: RT = 2.87 min; mlz (ES⁺) = 558.2 [ + H]⁺.

Example 29: {2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l-yl]pyrimidin-5- ylmethyl}- [1 -(3-isopr opyl- [ 1 ,2,4] oxadiazol-5- l)piperidin-4-yl] methylamine

To a solution of {(3i?,45)-4-(2,5-difluorophenyl)-l-[5-({[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]methylamino}methyl)pyrimidin-2-yl]pyrrolidin-3- yl}carbamic acid tert-butyl ester (Preparation 78, 49.3mg, 0.08mmol) in DCM (l .OmL) was added TFA (0.2mL) and the reaction was mixed at r.t. for 2h .

The reaction mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected. Removal of the solvent in vacuo afforded the title compound: RT = 2.27 min; mlz (ES⁺) = 513.2 [M+ H]⁺.

Example 30: {2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l-yl]pyrimidin-5- yl}-[l-(3-isopropyl-[l,2,4]oxadiazol-5- l)piperidin-4-ylmethyl]amine

The title compound was prepared from [(3i?,45)-4-(2,5-difluorophenyl)-l-(5-{[l-(3- isopropyl- [ 1 ,2,4]oxadiazol-5 -yl)piperidin-4-ylmethyl] amino } pyrimidin-2-yl)pyrrolidin-3 - yljcarbamic acid tert-butyl ester (Preparation 82) employing the procedure outlined in

Example 29: RT = 2.62 min; mlz (ES⁺) = 499.3 [M+ H]⁺. Example 31: (3R,4S)-4-(2,5-Difluorophenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yloxymethyl] rimidin-2-yl}pyrrolidin-3-ylamine

To a solution of ((3i?,45)-4-(2,5-difluorophenyl)-l-{5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yloxymethyl]pyrimidin-2-yl}pyrrolidin-3-yl)car^ acid tert-butyl ester (Preparation 85, 11.7mg, 0.02mmol) in DCM (250μί) was added TFA (50μί), and the mixture was stirred at r.t. for 80 min. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected and concentrated in vacuo. Further purification by column chromatography (EtOAc:MeOH, 100:0, 0: 100) afforded the title compound: RT = 2.57 min; mlz (ES⁺) = 500.3 [M+ H]⁺.

Example 32: (3R,4S)-l-{5-[l-(5-Chloropyrimidin-2-yl)-4-methoxypiperidin-4- ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluoro henyl)pyrrolidin-3-ylamine

To a solution of [(3i?,45)-l-{5-[l-(5-chloropyrimidin-2-yl)-4-methoxypiperidin-4- ylmethoxy]pyrimidin-2-yl} -4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 90, 4.9mg, O.Olmmol) in DCM (lmL) was added TFA (O.lmL) and the reaction was shaken at r.t. for 16 h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected and concentrated in vacuo to afford the title compound: RT = 2.98 min; mlz (ES⁺) = 550.5 [M+ H] .

Example 33: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]ethoxy}pyrimidin-2-yl)pyrrolidin-3-yl]-5,5-difluoropiperidin-2-one hydrochloride

To a solution of 2-chloro-5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrimidine (Preparation 63, 171mg, 0.49mmol) and [(3S,4S)-4-(5,5-Difluoro-2- oxopiperidin-l-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 93, 155mg, 0.49mmol) in DMSO (l .OmL), under argon, was added DBU (Ί4μΙ, 0.49mmol) and the reaction was heated to 80°C for 112 h. The reaction mixture was diluted with DCM (50mL), washed with brine (3 x 50mL), dried using a phase separator, and the solvent removed in vacuo. Purification by column chromatography (DCM:MeOH, 97.5: 1.5) afforded the intermediate product [(35^,,45)-4-(5,5-difluoro-2-oxopiperidin-l -yl)- 1 -(5- {(S)- 1 -[ 1 -(3- isopropyl- [ 1 ,2,4]oxadiazol-5 -yl)piperidin-4-yl] ethoxy } pyrimidin-2-yl)pyrrolidin-3 - yljcarbamic acid tert-butyl ester.

To a solution of the intermediate in DCM (5mL) was added TFA (lmL) and the reaction was stirred at r.t. for 30min. A further portion of TFA was added (lmL) and the reaction was stirred for a further 20min. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. Further purification by column chromatography (DCM:MeOH, 95:5, 90: 10) afforded the title compound as the free amine. The product was re-dissolved in Et₂0 (2mL) and a solution of HC1 in dioxane (4M, 5 drops) was added. Removal of the solvent in vacuo afforded the title compound: RT = 2.67 min; m/z (ES⁺) = 535.5 [M+ H] .

Example 34: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl] ethoxy pyrimidin-2-yl)pyrrolidin-3-yl] piperidin-2-one hydrochloride

To a solution of 2-chloro-5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrimidine (Preparation 63, 171mg, 0.49mmol) and [(35',45)-4-(2-oxopiperidin- l-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 20, 160mg, 0.56mmol) in DMSO (l .OmL), under argon, was added DBU (81 uL, 0.54mmol) and the reaction was heated to 80°C for 144 h. The reaction mixture was diluted with DCM (50mL), washed with brine (x 3), dried using a phase separator, and the solvent removed in vacuo. Purification by column chromatography (DCM:MeOH, 98:2) afforded the intermediate product (3S,4S)-l- (5- {(S)- 1 -[ 1 -(3-isopropyl-[l ,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidin-2-yl)-4-(2- oxopiperidin-l-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester. To a solution of the intermediate in DCM (5mL) was added TFA (lmL) and the reaction was stirred at r.t. for 30min. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. Purification was repeated by passing the residue down an SCX(POH) cartridge. The basic fraction was collected and concentrated in vacuo to afford the title compound as the free amine. The product was re-dissolved in Et₂0 (2mL) and a solution of HCl in dioxane (4M, 5 drops) was added. Removal of the solvent in vacuo afforded the title compound: RT = 2.57 min; mlz (ES⁺) = 499.3 [M+ H]⁺. Example 35: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]ethoxy} ridin-2-yl)pyrrolidin-3-yl]piperidin-2-one

A combination of 2-bromo-5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin- 4-yl]ethoxy}pyridine (Preparation 94, 200mg, 0.50mmol), [(35',45)-4-(2-oxopiperidin-l- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 20, 170mg, 0.61mmol), sodium tert-butoxide (170mg, 1.77mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-l- phosphabicyclo[3.3.3]undecane (17mg, 0.05mmol) in 1,4-dioxane (6mL) was degassed with argon for 10 min. tra(Dibenzylideneacetone)dipalladium (46mg, 0.05mmol) was added and the mixture was degassed with argon for a further 10 min before heating in a microwave reactor at 120°C for 2 x 30 min. The reaction mixture was filtered, washing with MeOH and the solvent removed in vacuo. Purification by preparative HPLC and column

chromatography (DCM:MeOH, 95:5), followed by further purification by chiral HPLC (MeOH:THF:BA 80:20:0.1, 12ml/min, 250nm, RT = 13.0 min) afforded the title compound: RT = 1.83 min; mlz (ES⁺) = 498.5 [M+ H]⁺.

Example 36: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]ethoxy}pyrazin-2-yl)pyrrolidin-3-yl]piperidin-2-one

A combination of 2-bromo-5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin- 4-yl]ethoxy}pyrazine (Preparation 95, 200mg, 0.51mmol), [(35',45)-4-(2-oxopiperidin-l- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 20, 172mg, 0.61mmol), sodium tert-butoxide (170mg, 1.77mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-l- phosphabicyclo[3.3.3]undecane (17mg, 0.05mmol) in 1,4-dioxane (3mL) was degassed with argon for 10 min. tra(Dibenzylideneacetone)dipalladium (46mg, 0.05mmol) was added and the mixture was degassed with argon for a further 10 min before heating in a microwave reactor at 120°C for 2 x 30 min. The reaction mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected. Removal of the solvent in vacuo afforded the intermediate product [(35',45)-l-(5-{(5)-l-[l-(3-Isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrazin-2-yl)-4-(2-oxopiperidin-l-yl)pyrrolidin- 3-yl]carbamic acid tert-butyl ester.

To a solution of the product in DCM (5mL) was added TFA (lmL) and the reaction was stirred at r.t. for 20 min. A further portion of TFA (lmL) was added and stirring continued for 20 min. The reaction mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The residue was passed down an SCX(POH) cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. Further purification by preparative HPLC (basic method), SCX cartridge, preparative HPLC

(standard method) then SCX cartridge, with removal of the solvent in vacuo between each purification step, afforded the title compound: RT = 2.63 min; m/z (ES ) = 499.4 [M+ H]⁺.

Example 37: (3R,45)-4-(2,5-Difluorophenyl)-l-(5-{(S)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl] ethoxy rimidin-2-yl)pyrrolidin-3-ylamine hydrochloride

To a solution of 2-chloro-5-{(i?)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrimidine (Preparation 102, 182mg, 0.54mmol) and [(3i?,45)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 160mg, 0.54mmol) in DMSO (l . lmL), under argon, was added DBU (81 μΙ_,, 0.49mmol) and the reaction was heated to 80°C for 72 h. The reaction mixture was diluted with DCM (50mL), washed with brine (x 3), dried using a phase separator, and the solvent removed in vacuo. Purification by column chromatography (IH:EtOAc, 60:40) afforded the intermediate product (3i?,45)-4-(2,5-difiuorophenyl)- 1 -(5- {(S)- 1 -[ 1 -(3-ethyl-[ 1 ,2,4]oxadiazol-5- yl)piperidin-4-yl]ethoxy}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester: RT = 4.39 min; m/z (ES⁺) = 600.5 [M+ H]⁺.

To a solution of the product in DCM (5mL) was added TFA (lmL) and the reaction was stirred at r.t. for 20 min. A further portion of TFA (lmL) was added and stirring continued for 20 min. The reaction mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The residue was passed down an SCX(POH) cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected. Removal of the solvent in vacuo afforded the title compound as the free amine: The product was re-dissolved in Et₂0 (2mL) and a solution of HCl in dioxane (4M, 5 drops) was added. Removal of the solvent in vacuo afforded the title compound: RT = 2.70 min; m/z (ES⁺) = 500.3 [M+ H]⁺.

The following examples were prepared by reacting the appropriate chloropyrimidine building block with the desired pyrrolidine building block employing the procedure outlined in Example 37:

Ex. Structure Name LCMS

(3R,4S)-l-(5-{(S)-l-

[l-(3-Ethyl-

[l,2,4]oxadiazol-5- RT = 2.70 yl)piperidin-4- min; m/z

38 yl]ethoxy}pyrimidin- (ES⁺) =

2-yl)-4-(2,4,5- 518.3 [M + trifluorophenyl)pyrroli H]⁺.

din-3-yl amine

hydrochloride

Example 40: (3R,45)-4-(2,5-Difluorophenyl)-l-(5-{l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]-2-methox ethoxy}pyrimidin-2-yl)pyrrolidin-3-ylamine

The title compound was prepared from [(3i?,45)-4-(2,5-difluorophenyl)-l-(5-{ l-[l -

(3-isopropyl-[l ,2,4]oxadiazol-5-yl)piperidin-4-yl]-2-methoxyethoxy}pyrimidin-2- yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 108) employing the procedure outlined in Example 29: RT = 2.76 min; m/z (ES⁺) = 544.3 [M + H]⁺. Example 41: (3R,45)-4-(2,5-Difluorophenyl)-l-(5-{(S)-l-[l-(3-isopropyl-

[l,2,4]oxadiazol-5-yl)piperidin-4-yl]-2-methoxyethoxy}pyrimidin-2-yl)pyrrolidin-3- ylamine

The title compound was prepared via chiral HPLC separation of (3i?,45)-4-(2,5- difluorophenyl)- 1 -(5- { 1 -[1 -(3-isopropyl-[ 1 ,2,4]oxadiazol-5-yl)piperidin-4-yl]-2- methoxyethoxy}pyrimidin-2-yl)pyrrolidin-3-ylamine (Example 40): MTBE:MeOH:THF:n- butylamine 80: 15:5:0.1, l .OmL/min, 250nm.

Example 42: (3R,4S)-4-(2,5-Difluorophenyl)-l-(5-{(R)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]-2-methoxyethoxy}pyrimidin-2-yl)pyrrolidin-3- ylamine

The title compound was prepared via chiral HPLC separation of (3i?,45)-4-(2,5- difluorophenyl)- 1 -(5- { 1 -[1 -(3-isopropyl-[ 1 ,2,4]oxadiazol-5-yl)piperidin-4-yl]-2- methoxyethoxy}pyrimidin-2-yl)pyrrolidin-3-ylamine (Example 40): MTBE:MeOH:THF:n- butylamine 80: 15:5:0.1, l .OmL/min, 250nm.

The following examples were prepared by reacting the appropriate tert-butyl carbamate-containing building block with TFA employing the procedure outlined in

Example 29:

Example 47: (3R,4S)-l-{5-[l-(3-Ethyl-[l,2,4]triazolo[4,3-c]pyrimidin-7-yl)piperidin-4- ylmethoxy]pyrimidin-2- l}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-ylamine

The title compound was prepared from [(3i?,45)-l-{5-[l-(3-ethyl-[l,2,4]triazolo[4,3- c]pyrimidin-7-yl)piperidin-4-ylmem^

3-yl]carbamic acid tert-butyl ester (Preparation 127) employing the procedure outlined in Example 29. Further purification by preparative HPLC (basic method) afforded the title compound: RT = 2.57 min; m/z (ES⁺) = 554.3 [M+ H]⁺. Example 48: (3R,45)-4-(2,5-Difluorophenyl)-l-(5-{(S)-l-[l-(5-isopropylpyrimidin-2- yl)piperidin-4-yl]ethox rimidin-2-yl)pyrrolidin-3-ylamine

2-Chloro-5-isopropylpyrimidine (19mg, 0.12mmol) and DBU (37μί, 0.25mmol) were added to a solution of (3i?,45)-4-(2,5-difluorophenyl)-l-[5-((5)-l-piperidin-4-yl- ethoxy)pyrimidin-2-yl]pyrrolidin-3-ylamine (Preparation 121, 50mg, O.lmmol) in DMSO

(lmL, lOmmol) and the reaction was heated in a microwave reactor at 100°C for 30 min.

The mixture was partitioned between DCM and water, and passed through a phase separator.

The aqueous phase was washed with further DCM. The organic fractions were combined, concentrated in vacuo, and purified by preparative HPLC. Fractions containing the desired product were passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected. Removal of the solvent in vacuo afforded the title compound: RT = 2.92 min; m/z (ES⁺) = 524.3 [M+ H]⁺.

Example 49: 4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyrimidin-5-yloxy}eth l)piperidine-l-carboxylic acid propyl ester

Pyridine (14μΙ_^, 0.17mmol) and n-propylchloroformate (19μΙ_^, 0.17mmol) were added to a stirred solution of {(3i?,45)-4-(2,5-difluorophenyl)-l-[5-((5)-l-piperidin-4- ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid 9H-fluoren-9-ylmethyl ester

(Preparation 119, 35mg, 0.06mmol) in DCM (l .OmL) and the reaction continued to stir at r.t. for 16 h. The mixture was washed with water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and Piperidine (200μί, 2.00mmol) was added. The reaction was stirred at r.t. for a further 16 h. The mixture was washed with water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and concentrated in vacuo. Purification by preparative HPLC (basic method) afforded the title compound: RT = 2.87 min; mlz (ES⁺) = 490.2 [M + H]⁺.

Example 50: 4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyrimidin-5-yloxy}eth l)piperidine-l-carboxylic acid cyclopropylmethyl ester

Triphosgene (12mg, 0.04mmol) was dissolved in DCM (0.25mL, 3.9mmol) and cooled to 0°C. To the solution was added a mixture of cyclopropylmethanol (9.6μί, 0.12mmol) and pyridine (9.7μΙ., 0.12mmol) in DCM (0.25mL), drop-wise, and the reaction was allowed to warm to r.t.. After 1 h, a solution of {(3i?,45)-4-(2,5-difluorophenyl)-l-[5- ((iS)- 1 -piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid 9H-fluoren-9- ylmethyl ester (Preparation 119, 25mg, 0.04mmol) and pyridine (9.ΊμΙ_^, 0.12mmol) in DCM (0.5mL) was added, drop-wise, and the reaction was stirred at r.t. for 16 h. The mixture was washed with water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and Piperidine (200μΙ_^, 2mmol) was added. The reaction was stirred at r.t. for 16 h. The mixture was washed with water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined, concentrated in vacuo and purified by preparative HPLC (basic method) to afford the title compound: RT = 2.90 min; mlz (ES⁺) = 502.2 [M + U]⁺. Example 51: (3R,4S)-4-(2,5-Difluorophenyl)-l-(5-{(S)-l-[l-(5-fluoropyrimidin-2- yl)piperidin-4-yl]ethoxy}pyrimidin-2-yl)pyrrolidin-3-ylamine formic acid salt

The title compound was prepared by reacting {(3i?,4S)-4-(2,5-difluorophenyl)-l-[5- ((5)-l-piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid 9H-fluoren-9- ylmethyl ester (Preparation 119) with 2-chloro-5-fluoropyrimidine employing a procedure similar to that outlined in Example 48, but after work-up the crude residue was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. Further purification by preparative HPLC afforded the title compound as the formate salt: RT = 2.97 min; mlz (ES⁺) = 500.1 [M+ H]⁺.

Example 52: 4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyrimidin-5-yloxy}eth l)piperidine-l-carboxylic acid cyclopentyl ester

Cyclopentanol (19.8μί, 0.22mmol) and 2,6-lutidine (25μΙ,, 0.22mmol) were added to a solution of triphosgene (22mg, 0.07mmol) in DCM (lmL), and the mixture was stirred at r.t. for 30 min. In a separate vessel, a solution of {(3i?,4S)-4-(2,5-difluorophenyl)-l-[5-((S)- 1 -piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid 9H-fluoren-9-ylmethyl ester acetate (Preparation 118, 50mg, 0.07mmol) in DCM (2mL) was washed with sat. NaHCC>3 solution (lmL) and passed through a phase separator to afford a solution of

{(3i?,45)-4-(2,5-difluorophenyl)-l-[5-((5)-l-piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrol^ 3-yl} carbamic acid 9H-fluoren-9-ylmethyl ester as the free base. The cyclopentanol mixture was added to the solution of {(3i?,45)-4-(2,5-difluorophenyl)-l-[5-((5)-l-piperidin-4- ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid 9H-fluoren-9-ylmethyl ester, followed by 2,6-lutidine (8.4μΙ,, 0.07mmol), and the reaction was stirred at r.t. for 30 min. The mixture was washed with water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and piperidine (200μΙ,, 2mmol) was added. After stirring at r.t. for 60 h, the mixture was washed with water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and concentrated in vacuo.

Purification by preparative HPLC (basic method) afforded the title compound: RT = 2.94 min; mlz (ES⁺) = 516.4 [M+ H]⁺. Example 53: 4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyrimidin-5-yloxy}eth l)piperidine-l-carboxylic acid butyl ester

A solution of {(3i?,45)-4-(2,5-difiuorophenyl)-l-[5-((5)-l-piperidin-4- ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid 9H-fluoren-9-ylmethyl ester acetate (Preparation 118, 50mg, 0.07mmol) in DCM (2mL) was washed with sat. NaHC0₃ solution (lmL) and passed through a phase separator, washing with DCM (0.5mL), to afford a solution of {(3i?,45)-4-(2,5-difluorophenyl)- 1 -[5-((5)- 1 -piperidin-4-ylethoxy)pyrimidin-2- yl]pyrrolidin-3-yl}carbamic acid 9H-fluoren-9-ylmethyl ester as the free base, n- Butylchloroformate (30.5 μΐ,, 0.24mmol) and 2,6-lutidine (9.2μΙ,, 0.08mmol) were added to the solution and the reaction was stirred at r.t. for 60 min.

The mixture was partitioned between DCM and water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined, piperidine (200μί, 2mmol) was added, and the mixture was stirred at r.t. for 16 h. The mixture was washed with water and passed through a phase separator. The aqueous phase was washed with further DCM, then the organic fractions were combined and concentrated in vacuo. Purification by preparative HPLC (basic method) afforded the title compound: RT = 2.97 min; mlz (ES⁺) = 504.2 [M+ H]⁺.

Example 54: 4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyrimidin-5-yloxy}eth l)piperidine-l-carboxylic acid isobutyl ester

The title compound was prepared from {(3i?,45)-4-(2,5-difluorophenyl)-l-[5-((5)-l- piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid 9H-fluoren-9-ylmethyl ester acetate (Preparation 118) and isobutylchloro formate employing the procedure outlined in Example 53: RT = 2.87 min; mlz (ES⁺) = 504.2 [M + H]⁺.

Example 55: 4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl]pyrimidin-5-yloxy}eth l)piperidine-l-carboxylic acid cyclobutyl ester

Cyclobutanol (17mg, 0.24 mmol) and 2,6-lutidine (28μί, 0.24mmol) were added to a solution of triphosgene (24mg, 0.08mmol) in DCM (1 mL) and the mixture was shaken at r.t. for 30 min. In a separate vessel, a solution of {(3i?,4S)-4-(2,5-difluorophenyl)-l-[5-((S)-l- piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid 9H-fluoren-9-ylmethyl ester acetate (Preparation 118, 50mg, 0.07mmol) in DCM was washed with sat. NaHC0₃ solution and passed through a phase separator to afford a solution of {(3i?,45)-4-(2,5- difluorophenyl)- 1 -[5-((5)- 1 -piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid 9H-fluoren-9-ylmethyl ester as the free base. The cyclobutanol mixture was added to the solution of {(3i?,45)-4-(2,5-difluorophenyl)- 1 -[5-((5)- 1 -piperidin-4-ylethoxy)pyrimidin-2- yl]pyrrolidin-3-yl} carbamic acid 9H-fluoren-9-ylmethyl ester and the reaction was shaken at r.t. for 60 min. The mixture was washed with water, passed through a phase separator, and the aqueous phase was washed with further DCM. The organic fractions were combined, piperidine (200 uL, 2 mmol) was added, and the reaction was shaken at r.t. for 16 h. The mixture was washed with water and passed through a phase separator. The aqueous was washed with further DCM, and the organic fractions were combined and concentrated in vacuo. Purification by preparative HPLC (basic method) afforded the title compound: RT = 2.87 min; mlz (ES⁺) = 502.2 [M + H]⁺.

The following examples were prepared by reacting {(3i?,45)-4-(2,5-difluorophenyl)- 1 -[5-((iS)- 1 -piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid 9H-fluoren-9- ylmethyl ester acetate (Preparation 118) with the appropriate alcohol employing the procedure outlined in Example 55:

Example 64: (3R,4S)-4-(2,5-Difluorophenyl)-l-(5-{(S)-l-[l-(5-ethylpyrimidin-2- yl)piperidin-4-yl]ethox }pyrimidin-2-yl)pyrrolidin-3-ylamine

To a combination of {(3i?,45)-4-(2,5-difluorophenyl)-l -[5-((5)-l-piperidin-4- ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid 9H-fluoren-9-ylmethyl ester

(Preparation 119, 50mg, 0.08mmol ) and 2-chloro-5-ethylpyrimidine (1 lOmg, 0..08mmol) in DMSO (lmL) was added DBU (36μΙ_^, 0.24mmol) and the reaction was heated in a microwave reactor at 100°C for 30 min. The mixture was partitioned between DCM and water, and passed through a phase separator. The aqueous phase was washed with further DCM. The organic fractions were combined, concentrated in vacuo, and purified by preparative HPLC. Fractions containing the desired product were combined, concentrated in vacuo, and purified further by preparative HPLC (basic method) to afford the title compound: RT = 2.82 min; m/z (ES⁺) = 510.3 [M + H]⁺.

Example 65: {6-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l- yl] pyrimidin-5-yloxy} eth l)piperidin- 1-yl] pyridazin-3-yl} dimethylamine

The title compound was prepared by reacting {(3i?,45)-4-(2,5-difluorophenyl)-l-[5- ((iS)- 1 -piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid 9H-fluoren-9- ylmethyl ester (Preparation 119) with (6-chloropyridazin-3-yl)dimethylamine employing the procedure outlined in Example 48: RT = 2.85 min; m/z (ES⁺) = 524.3 [M + H]⁺.

Example 66: (3R,45)-4-(2,5-Difluorophenyl)-l-(5-{(S)-l-[l-(5-propylpyrimidin-2- yl)piperidin-4-yl]ethox rimidin-2-yl)pyrrolidin-3-ylamine

The title compound was prepared by reacting {(3i?,45)-4-(2,5-difluorophenyl)-l-[5- ((iS)- 1 -piperidin-4-ylethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid 9H-fluoren-9- ylmethyl ester (Preparation 119) with 2-chloro-5-propylpyrimidine employing a procedure similar to that outlined in Example 48, but after heating the reaction in a microwave reactor at 100°C for 30 min, a further portion of 2-chloro-5-propylpyrimidine (leq.) was added, and the reaction was heated at 150°C for 30 min: RT = 2.97 min; mlz (ES⁺) = 524.3 [M+ H]⁺.

Example 67: {2-[(3R,4S)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l-yl]pyrimidin-5- yl}- {(5)- 1- [l-(3-isopr op l- [ 1 ,2,4] oxadiazol-5-yl)piperidin-4-yl] ethyl} amine

To a solution of [(3i?,45)-4-(2,5-difiuorophenyl)-l-(5-{(5)-l-[l-(3-isopropyl- [1 ,2,4]oxadiazol-5 -yl)piperidin-4-yl]ethylamino } pyrimidin-2-yl)pyrrolidin-3 -yl] carbamic acid tert-butyl ester (Preparation 130, 6mg, O.Olmmol) in DCM (200μί, 3.0mmol) was added TFA (30uL, 0.4mmol) and the reaction was stirred at r.t. for 2.5 h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The material was further purified by preparative HPLC, and the fractions containing product were concentrated in vacuo. The material was passed down an SCX cartridge again, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo to afford the title compound: RT = 2.57 min; mlz (ES⁺) = 513.3 [M+ H]⁺. Example 68: (3R,45)-l-{5-[l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidin-2- -4-(2,4,5-trifluorophenyl)pyrrolidin-3-ylamine hydrochloride

To a solution of [(3i?,45)-l-{5-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidin-2-yl} -4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 131, 171mg, 0.28mmol) in DCM (5mL) was added TFA and the reaction was stirred for 20 min. A further portion of TFA was added and stirring continued for 20 min. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The material was then passed down an SCX(POH) cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The resulting residue was purified by column chromatography (DCM:MeOH, 98:2), followed by preparative HPLC, and the fractions containing product were concentrated in vacuo. The residue was again passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo to afford the title compound as the free amine.

To a solution of the compound in Et₂0 (2mL) was added a solution of HC1 in dioxane (4M, 5 drops). Removal of the solvent in vacuo afforded the title compound: RT = 2.70 min; mlz (ES⁺) = 504.2 [M+ H]⁺.

Example 69: (3R,45)-l-{5-[l-(5-Isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4- ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-ylamine p- toluenesulfonic aci alt

To a solution of [(3i?,45)-l-{5-[l-(5-isopropyl-[l,2,4]oxadiazol-3-yl)piperidin-4- ylmethoxy]pyrimidin-2-yl} -4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid fert-butyl ester (Preparation 132, 103mg, 0.17mmol) in DCM (5mL) was added TFA (ImL) and the reaction was stirred at r.t. for 20 min. A further portion of TFA (ImL) was added and stirring continued for 20 min. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. To a solution of the product in a combination of MeOH (2mL) and EtOAc (2mL) was added TsOH (25mg, 0.13mmol). Removal of the solvent in vacuo afforded the title compound: RT = 2.87 min; mlz (ES⁺) = 518.2 [M+ H]⁺. Example 70: (3R,45)-l-(5-{(S)-l-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrimidin-2-yl -4-pyridin-2-ylpyrrolidin-3-ylamine hydrochloride

To a solution of 2-chloro-5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrimidine (Preparation 63, 81mg, 0.23mmol) and ((tra/?s)-4-pyridin-2- ylpyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 136, 61mg, 0.23mmol) in DMSO (0.5mL) was added DBU (39μΙ., 0.23mmol) and the reaction was heated to 100°C for 48 h. The mixture was diluted with DCM, washed with brine (x 3) and passed through a phase separater before removal of the solvent in vacuo. Purification by column

chromatography (IH:EtOAc, 20:80) and further purification by chiral HPLC

(MTBE:MeCN:MeOH, 70:20: 10, 15mL/min, 250nm, RT = 11.46 min) afforded the intermediate compound [(3R, 4S)- 1 -(5- {(S)- 1 -[ 1 -(3 -isopropyl-[ 1 ,2,4]oxadiazol-5- yl)piperidin-4-yl]ethoxy}pyrimidin-2-yl)-4-pyridin-2-ylpyrrolidin-3-yl]carbamic acid tert- butyl ester.

To a solution of the product in dioxane (0.1 mL) was added a solution of HC1 in dioxane (4M, O.lmL) and the reaction was stirred at r.t. for 16 h. Removal of the solvent in vacuo afforded the title compound: RT = 2.52 min; mlz (ES⁺) = 479.3 [M+ H]⁺.

Example 71: (3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(2-isopropyl-2H-tetrazol-5- yl)piperidin-4-ylmethox ]pyrimidin-2-yl}pyrrolidin-3-ylamine hydrochloride

To a solution of ((3i?,45)-4-(2,5-difluorophenyl)-l-{5-[l-(2-isopropyl-2H-tetrazol-5- yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 143, 1 lOmg, 0.18mmol) in DCM (5mL) was added TFA (lmL) and the reaction was stirred at r.t. until complete. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected. Removal of the solvent in vacuo afforded the title compound as the free amine, which was re-dissolved in DCM (5mL). A solution of HC1 in dioxane (4M, 230μί, 0.92mmol)) was added and the mixture was stirred for 30 min. Removal of the solvent in vacuo afforded the title compound: RT = 2.85 min; mlz (ES⁺) = 500.2 [M+ H]⁺.

Example 72: (3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(5-isopropyl-[l,3,4]oxadiazol-2- yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-ylamine

To a solution of ((3i?,4S)-4-(2,5-difluorophenyl)-l-{5-[l-(5-isopropyl- [l,3,4]oxadiazol-2-yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbami acid tert-butyl ester (Preparation 144, 19mg, 0.03mmol) in DCM (2.5mL) was added TFA (0.5mL) and the reaction was stirred at r.t. until complete. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected. Removal of the solvent in vacuo afforded the title compound: RT = 2.62 min; m/z (ES⁺) = 500.3 [M+ H]

The following examples were prepared by reacting the appropriate tert-butyl carbamate-containing building block with TFA employing the procedure outlined in

Example 72:

Example 81: (3R,4S)-4-(2,5-Difluorophenyl)-l-(5-{l-[5-(2-methoxy-l-methylethyl)- [l,2,4]oxadiazol-3-yl]pi eridin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-ylamine

To a solution of 3-methoxy-2-methylpropionic acid (Preparation 146, 8.4mg, 0.07mmol) in DMF (1.5mL) was added ((3^4S)-4-(2,5-difluorophenyl)-l-{5-[l-(N- hydroxycarbamimidoyl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbam acid tert-butyl ester (Preparation 145, 30mg, 0.05mmol), followed by HOBt (12mg, 0.08mmol), and finally EDCI (16mg, 0.08mmol). The reaction was allowed to stir at r.t. for 16 h before being heated to 80°C for 3 h. The solvent was concentrated in vacuo and the resulting residue was partitioned between DCM and water. The organic phase was separated, washed with sat. NaHCC"3 solution, and the solvent removed in vacuo to afford the intermediate product [(3i?,45)-4-(2,5-difiuorophenyl)-l -(5- { 1 -[5-(2-methoxy-l -methylethyl)- [l,2,4]oxadiazol-3-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester.

To a solution of the intermediate in DCM (lmL) was added TFA (0. lmL) and the reaction was stirred at r.t. for 2h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The residue was purified by MDP (acidic conditions), and the fractions containing product were passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH. The basic fraction was collected and concentrated in vacuo to afford the title compound: RT = 2.80 min; m/z (ES⁺) = 530.2 [M+ H]⁺.

Example 82: (3R,45)-l-(5-{l-[5-(l,l-Difluoroethyl)-[l,2,4]oxadiazol-3-yl]piperidin-4- ylmethoxy}pyrimidin-2- l)-4-(2,5-difluorophenyl)pyrrolidin-3-ylamine

To a solution of [(3i?,45)-l-(5-{l-[5-(l,l-difluoroethyl)-[l,2,4]oxadiazol-3- yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 147, 38mg, 0.06mmol) in DCM (2mL) was added TFA (0.2mL) and the reaction was stirred at r.t. for 2 h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. Purification by SCX cartridge was repeated to afford the title compound: RT = 2.87 min; mlz (ES⁺) = 522.5 [M+ H]⁺. Example 83: (3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(3-isobutyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethox ]pyrimidin-2-yl}pyrrolidin-3-ylamine hydrochloride

To a combination of [(3i?,45)-l-[5-(l-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]- 4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141, 50mg, O. lOmmol) and N-hydroxy-3-methylbutyramidine (14mg, 0.12mmol) in EtOH (2mL) was added a solution of Zinc(II)chloride in Et₂0 (1M, 0.12mL, 0.12mmol) and the reaction was stirred at r.t. for 90min. To the mixture was added cone. HC1 (12M, 44μΕ, 0.53mmol) and stirring continued at r.t. for 90 min, before heating the reaction in a microwave reactor at 100°C for 30 min. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The residue was further purified by MDP (basic conditions) to afford the title compound as a free amine. The non-basic fraction from SCX purification was concentrated in vacuo and purified by MDP (basic conditions) to afford a further amount of the title compound as the free amine.

The whole reaction procedure was repeated, but the crude mixture was purified directly by MDP (basic conditions) to afford a third amount of the title compound as the free amine.

The products were combined in DCM (5mL) and a solution of HC1 in dioxane (4M, ll^^L, 0.78mmol) was added. The reaction was stirred at r.t. for 30 min, before removal of the solvent in vacuo to afford the title compound: RT = 2.84 min; mlz (ES⁺) = 514.3 [M + H]⁺. Example 84: (3R,4S)-4-(2,5-Difluorophenyl)-l-(5-{l-[3-((S)-l-methoxyethyl)-

[l,2,4]oxadiazol-5-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-ylamine hydrochloride

To a combination of [(3i?,45)-l-[5-(l-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-

4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141, 150mg, 0.29mmol) and (S)-N-hydroxy-2-methoxypropionamidine

(Preparation 148, 46mg, 0.35mmol) in EtOH (3mL) was added a solution of

Zinc(II)chloride in Et₂0 (1M, 0.35mL, 0.35mmol) and the reaction was stirred at r.t. for 60 min. To the mixture was added cone. HCl solution (12M, 0.13mL, 1.6mmol), and stirring continued at r.t. for 5min before heating the reaction in a microwave reactor at 80°C for 30min. The solvent was removed in vacuo and crude material purified by preparative HPLC (basic method). Further purification by MDP (basic conditions) afforded the title compound as the free amine. To a solution of the product in DCM (5mL) was added a solution of HCl in dioxane (4M, 0.2mL, 0.9mmol). The reaction was stirred at r.t. for 30min before removal of the solvent in vacuo to afford the title compound: RT = 2.62 min; m/z (ES ) = 516.1 [M + H]⁺.

Example 85: (3R,45)-l-(5-{l-[3-(l,l-Difluoroethyl)-[l,2,4]oxadiazol-5-yl]piperidin-4- ylmethoxy}pyrimidin-2- l)-4-(2,5-difluorophenyl)pyrrolidin-3-ylamine hydrochloride

To a combination of [(3i?,45)-l-[5-(l-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]- 4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141, 150mg, 0.29mmol) and 2,2-difluoro-N-hydroxypropionamidine (Preparation 149, 43mg, 0.35mmol) in EtOH (3mL) was added a solution of Zinc(II)chloride in Et₂0 (1M, 0.35mL, 0.35mmol) and the reaction was stirred at r.t. for 60 min. To the mixture was added a solution of HCl in dioxane (4M, 0.36mL, 1.4mmol) and the reaction was heated in a microwave reactor at 80°C for 30min before increasing the temperature to 100°C for a further 30 min. A second portion of HCl in dioxane (4M, 0.36mL, 1.4mmol) was added and the reaction was heated in a microwave reactor at 120°C for 30 min. The solvent was removed in vacuo and the resulting residue was partitioned between DCM and sat. NaHC0₃ solution. The organic phase was separated, dried (MgS0₄), and the solvent was removed in vacuo. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The material was purified by preparative HPLC, and the fractions containing product were concentrated in vacuo. The material was passed down an SCX cartridge for a second time, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo to afford the title compound as the free amine.

To a solution of the product in DCM (2mL) was added a solution of HC1 in dioxane

(0.36mL) and the reaction was stirred at r.t. for 30 min. Removal of the solvent in vacuo afforded the title compound: RT = 2.86 min; mlz (ES⁺) = 522.6 [M+ H]⁺.

Example 86: (3R,45)-4-(2,5-Difluorophenyl)-l-{5-[l-(5-ethyl-[l,2,4]oxadiazol-3- yl)piperidin-4-ylmethox ] pyrimidin-2-yl}pyrr olidin-3-ylamine

To a solution of ((3i?,45)-4-(2,5-difiuorophenyl)-l-{5-[l-(5-ethyl-[l,2,4]oxadiazol-3- yl)piperidin-4-ylmethoxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester (Preparation 150, 25mg, 0.04mmol) in DCM (2mL) was added TFA (0.15mL) and the reaction was stirred at r.t. for 90 min The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The resulting product was stirred in a combination of MeCN and water (1 : 1, 2mL), containing HC0₂H ( 1 drop), for 10 mins, and purification by SCX was repeated to afford the title compound: RT = 2.77 min; mlz (ES ) = 486.3 [M+ H]⁺.

The following examples were prepared by reacting the corresponding Boc-protected building block with TFA, employing the procedure outlined in Example 86:

Example 94: (3R,4S)-4-(2,5-Difluorophenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yloxy]pyrimidin-2- l}pyrrolidin-3-ylamine

To a combination of 2-chloro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yloxy]pyrimidine (containing 40% 2-bromo-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yloxy]pyrimidine, Preparation 158, 55mg, 0.16mmol) and [(3i?,45)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 59mg, 0.20mmol) in DMSO (0.33mL) was added DBU (25 uL, 0.16mmol) and the reaction was heated to 80°C for 16 h. The mixture was diluted with DCM, washed with brine, and concentrated in vacuo. Purification by column chromatography (IH:EtOAc, 1 : 1) afforded the intermediate product ((3i?,45)-4-(2,5-difluorophenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)piperidin-4-yloxy]pyrimidin-2-yl}pyrrolidin-3-yl)carbamic acid tert-butyl ester: RT = 4.37 min; m/z (ES⁺) = 586.2 [M+ H]⁺.

To a solution of the product in DCM (lOmL) was added TFA (2mL) and the reaction was stirred at r.t. for 30 min. The reaction mixture was passed directly down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo to afford the title compound: RT = 2.72 min; m/z (ES ) = 486.2 [M+ H]⁺. Example 95: (3R,45)-4-(2,5-Difluorophenyl)-l-(5-{l-[3-(2-methoxyethyl)-

[l,2,4]oxadiazol-5-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-ylamine hydrochloride

To a solution of 3-methoxypropionitrile (1.07mL, 11.8mml) in EtOH (7mL) was added a solution of hydroxylamine (50% in water, 3. lmL, 51.2mmol) and the reaction was heated to reflux for 16 h. The solvent was removed in vacuo, azeotroping with toluene, to afford the intermediate product N-Hydroxy-3-methoxypropionamidine. To a portion of the intermediate (41mg, 0.4mmol) and [(3i?,45)-l-[5-(l- cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141, 150mg, 0.29mmol) in EtOH (2.5mL) was added a solution of Zinc(II)chloride in Et₂0 (1M, 0.35mL, 0.35mmol) and the reaction was stirred at r.t. for 60 min. To the mixture was added cone. HC1 solution (12M, 0.13mL, 1.6mmol), and the reaction was heated in a microwave reactor at 80°C for 30min. The solvent was removed in vacuo and the resulting residue was partitioned between DCM and sat. NaHC0₃ solution. The organic phase was separated, and the aqueous phase was extracted with DCM. Organic fractions were combined, concentrated in vacuo, and purified by MDP (basic conditions) to afford the title compound as the free amine.

To a solution of the product in DCM (5mL) was added a solution of HC1 in dioxane (4M, 0.36mL, 1.4mmol) and the reaction was stirred at r.t. for 30 min. Removal of the solvent in vacuo afforded the title compound: RT = 2.52 min; m/z (ES⁺) = 516.3 [M+ H]⁺. Example 96: (3R,4S)-4-(2,5-Difluorophenyl)-l-{5-[l-(3-methoxymethyl-[l,2,4]oxadiazol- 5-yl)piperidin-4-ylmethox ]pyrimidin-2-yl}pyrrolidin-3-ylamine hydrochloride

To a solution of N-hydroxy-2-methoxyacetamidine (Preparation 167, 36mg, 0.35mmol) and [(3i?,45)-l-[5-(l-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141, 150mg,

0.29mmol) in EtOH (2.5mL) was added a solution of Zinc(II)chloride in Et₂0 (1M, 0.35mL, 0.35mmol) and the reaction was stirred at r.t. for 60 min. To the mixture was added cone. HC1 solution (12M, 0.13mL, 1.6mmol), and the reaction was heated in a microwave reactor at 80°C for 30min. The solvent was removed in vacuo and the resulting residue was partitioned between DCM and sat. NaHC0₃ solution. The organic phase was separated, and the aqueous phase was extracted with DCM. Organic fractions were combined, concentrated in vacuo, and purified by MDP (basic conditions) to afford the title compound as the free amine. To a solution of the product in DCM (5mL) was added a solution of HC1 in dioxane (4M, 0.36mL, 1.4mmol) and the reaction was stirred at r.t. for 30 min. Removal of the solvent in vacuo afforded the title compound: RT = 2.55 min; m/z (ES⁺) = 502.3 [M+ H]⁺. The following examples were prepared by reacting [(3i?,45)-l-[5-(l-cyanopiperidin- 4-ylmethoxy)pyrimidin-2-yl]-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141) with the appropriate amidine intermediate employing the procedure outlined in Example 96:

Example 101: (3R,4S)-l-{5-[l-(3-Difluoromethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidin-2- l}-4-(2,5-difluorophenyl)pyrrolidin-3-ylamine

To a solution of 2,2-difluoro-N-hydroxyacetamidine (Preparation 169, 38mg, 0.35mmol) and [(3i?,45)-l-[5-(l-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141, 150mg, 0.29mmol) in EtOH (2.5mL) was added a solution of Zinc(II)chloride in Et₂0 (1M, 0.35mL, 0.35mmol) and the reaction was stirred at r.t. for 60 min. To the mixture was added cone. HC1 solution (12M, 0.13mL, 1.6mmol), and the reaction was heated in a microwave reactor at 80°C for 30min. The solvent was removed in vacuo and the resulting residue was partitioned between DCM and sat. NaHCC"3 solution. The organic phase was separated, and the aqueous phase was extracted with DCM. Organic fractions were combined, concentrated in vacuo, and purified by MDP (basic conditions). Fractions containing the product were concentrated in vacuo and further purified by MDP (acidic conditions). Fractions containing the product were passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. Trituration with Et₂0 afforded the title compound: RT = 2.70 min; m/z (ES⁺) = 508.2 [M+ H]⁺.

Example 102: (3R,45)-4-(2,5-Difluorophenyl)-l-(5-{l-[3-(l-methylcyclopropyl)- [l,2,4]oxadiazol-5-yl]pi eridin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-ylamine

To a solution of N-hydroxy-1 -methyl cyclopropanecarboxamidme (Preparation 170, 40mg, 0.35mmol) and [(3i?,45)-l-[5-(l-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141, 150mg, 0.29mmol) in EtOH (3.5mL) was added a solution of Zinc(II)chloride in Et₂0 (1M, 0.35mL, 0.35mmol) and the reaction was stirred at r.t. for 90 min. To the mixture was added cone. HC1 solution (12M, 0.12mL, 1.4mmol), and the reaction was heated in a microwave reactor at 80°C for 30min. The solvent was removed in vacuo and the resulting residue was partitioned between DCM and sat. NaHCOs solution. The organic phase was separated, and the aqueous phase was extracted with DCM. Organic fractions were combined, concentrated in vacuo, and purified by MDP (acidic conditions). Fractions containing product were collected and the solvent removed in vacuo to afford the title compound: RT = 2.89 min; mlz

Example 103 : (3R,45)-4-(2,5-Difluor ophenyl)- 1-{5- [ l-(3-ethoxymethyl- [1 ,2,4] oxadiazol- 5-yl)piperidin-4-ylmethox ]pyrimidin-2-yl}pyrrolidin-3-ylamine formate salt

2-Ethoxy-N-hydroxyacetamidine (Preparation 173) was reacted with [(3i?, S)-l-[5- (1 -cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5-difluorophenyl)pyrrolidin-3- yljcarbamic acid tert-butyl ester (Preparation 141) employing the procedure outlined in Example 102. Removal of the solvent in vacuo afforded the title compound as the formate salt: RT = 2.65 min; mlz (ES⁺) = 516.5 [M+ H]⁺. Example 104: (3R,45)-4-(2,5-Difluorophenyl)-l-(5-{l-[(R)-3-(tetrahydrofuran-2-yl)- [l,2,4]oxadiazol-5-yl]piperidin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-ylamine formate salt

(i?)-N-Hydroxytetrahydrofuran-2-carboxamidine (Preparation 174) was reacted with [(3i?,45)-l-[5-(l-cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141) employing a similar method to that outlined in Example 102. Purification by MDP (acidic conditions) was carried out twice to afford the title compound as the formate salt: RT = 2.63 min; mlz (ES⁺) = 528.5 [Μ+ ηγ. Example 105: (3R,4S)-4-(2,5-Difluorophenyl)-l-(5-{l-[3-(l-fluoro-l-methylethyl)- [l,2,4]oxadiazol-5-yl]pi eridin-4-ylmethoxy}pyrimidin-2-yl)pyrrolidin-3-ylamine

The title compound was prepared by reacting 2-fluoro-N-hydroxy-2- methylpropionamidine (Preparation 171) with [(3 ?,45)-l-[5-(l-cyanopiperidin-4- ylmethoxy)pyrimidin-2-yl]-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141) employing a similar procedure to that outlined in Example 102, but purification was carried out by MDP (basic conditions): RT = 2.75 min; m/z (ES ) = 518.2 [M+ H]⁺.

Example 106 : (3R,45)-1 -{5- [ l-(3-tert-Butyl- [ 1 ,2,4] oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidin-2- l}-4-(2,5-difluorophenyl)pyrrolidin-3-ylamine

The title compound was prepared by reacting N-hydroxy-2,2- dimethylpropionamidine with [(3R,4S)- 1 -[5-(l -cyanopiperidin-4-ylmethoxy)pyrimidin-2-yl]- 4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 141) employing a similar procedure to that outlined in Example 102, but purification was carried out by MDP (basic conditions): RT = 2.87 min; m/z (ES⁺) = 514.2 [M+ H]⁺. Example 107: 2-[(3R,45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l-yl]-5-[l-(3- isopropyl-[l,2,4]oxadiazol-5- l)piperidin-4-ylmethoxy]nicotinonitrile

To a combination of [(l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]methanol (Preparation 1, 23mg, O.lOmmol) and [(3i?,4S)-l-[3-cyano-5-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)pyridin-2-yl]-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 176, 109mg, 0.21mmol) in DCM (lOmL) was added

Triethylamine (72μΙ_^, 0.52mmol), followed by copper(II)acetate monohydrate (22mg, 0.1 lmmol). The flask was sealed and the reaction was stirred at r.t. for 5 days. TFA (5mL) was added directly to the reaction and stirring continued for 1 h. The reaction was poured directly onto a pre-activated (1M HCl then MeOH) SCX cartridge, eluting with MeOH then 7.5% NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. The resulting residue was purified by column chromatography (IH:EtOAc:MeOH, 80:20:0 - 0:100:0, then 0:95:5) and the fractions containing product were combined and concentrated in vacuo. Further purification by preparative HPLC (basic method) afforded the title compound: RT = 2.97 min; mlz (ES⁺) = 524.3 [M+ H]⁺. Example 108: 5-[(3R,45)-3-Amino-4-(2,5-difluorophenyl)pyrrolidin-l-yl]-2-[l-(3- isopropyl-[l,2,4]oxadiazol-5- l)piperidin-4-ylmethoxy]nicotinonitrile

To an oven dried sealable tube equipped with magnetic stirrer, under an atmosphere of argon, was added [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 61.7mg, 0.21mmol), 5-bromo-2-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy]nicotinonitrile (Preparation 177, 70.0mg, 0.2mmol), sodium tert- butoxide (19.9mg, 0.21mmol) and biphenyl-2-yl(di-fert-butyl)phosphine (10.3mg,

0.03mmol), followed by toluene (2mL). The resulting solution was stirred vigorously and bubbled with argon for 20 min. bis(Dibenzylideneacetone)palladium (7.89mg, 0.0 lmmol) was then added and the tube sealed securely before heating to 75°C for 19 h. The reaction mixture was poured directly onto a pre-activated (1M HCl then MeOH) SCX cartridge, eluting with MeOH then 7.5% NH₄OH in MeOH, and both fractions were collected and concentrated in vacuo. To a solution of the residue in DCM (lOmL) was added TFA (5mL) and the reaction was stirred at r.t. for 40 min. The crude mixture was passed directly down a pre-activated (1M HCl then MeOH) SCX cartridge, eluting with MeOH then 7.5% NH₄OH in MeOH, and the basic fraction was collected and concentrated in vacuo. Further purification by preparative HPLC (basic method) afforded the title compound: RT =

2.95 min; mlz (ES⁺) = 524.3 [M+ H]⁺. Example 109: (4-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxymethyl}-piperidin-l-yl)-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- methanone

To a solution of [(3i?,45)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazole-5-carbonyl)- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3

acid tert-butyl ester (Preparation 179, 35mg, 53.6μηιο1) in DCM (2.0mL) was added TFA (0.2mL, 2mmol) and the resulting solution was stirred at r.t. for 2 h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected, concentrated in vacuo and purified by preparative HPLC (basic method) to afford the title compound: RT = 2.75 min; m/z (ES⁺) = 546.23 [M+ H]⁺.

Example 110 : l-(4- {2- [(3R,45)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- 1-yl] - pyrimidin-5-yloxymethyl -piperidin-l-yl)-3-methyl-butan-l-one

To a solution of [(3i?,45)-l-{5-[l-(3-methyl-butyryl)-piperidin-4-ylmethoxy]- pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 93, 25mg, 42.6μιηο1) in DCM (2.0mL) was added TFA (0.2mL, 2mmol) and the resulting solution was stirred at r.t. for 2 h. The crude mixture was passed down an SCX cartridge, eluting with MeOH then NH₄OH in MeOH, and the basic fraction collected and concentrated in vacuo to afford the title compound: RT = 2.62 min; m/z (ES ) = 492.26 [M +

H]⁺. Example 111: (3R,4S)-l-(5-{(S)-l-[l-(Butane-l-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro- henyl)-pyrrolidin-3-ylamine hydrochloride

To a solution of [(3R,4S)-l-(5-{(S)-l-[l-(¾utane-l-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 186, 60mg, 90μηιο1) in DCM (2mL) was added TFA (0.2mL) and the resulting reaction mixture stirred at RT for 4 h. The crude mixture was passed down an SCX cartridge, eluting with DCM, then MeOH then 3.5M NH₃ in MeOH, and the basic fraction collected and concentrated in vacuo. The product was dissolved in DCM (3mL) and 4M HCl in dioxane (31 uL, 124μιηο1) was added. The resulting reaction mixture was stirred at r.t. for 0.5 h before removing the solvent in vacuo to afford the title compound: RT = 2.93 min; m/z

Example 112: (3R,45)-l-(5-{(S)-l-[l-(2-Methyl-propane-l-sulfonyl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4- 2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was prepared from [(3R,4S)- 1 -(5- {(S)- 1-[1 -(2 -methyl-propane- 1- sulfonyl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3- yl]-carbamic acid tert-butyl ester (Preparation 187) employing the procedure outlined in Example 111: RT = 2.92 min; m/z (ES⁺) = 542.13 [M+ H]⁺.

Example 113: (3R,45)-l-(5-{(S)-l-[l-(Propane-2-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro- henyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was prepared from [(3R,4S)- 1 -(5- {(S)- 1 -[ 1 -(propane-2-sulfonyl)- piperidin-4-yl]-ethoxy} -pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 188) employing the procedure outlined in Example 111 : RT = 2.80 min; mlz (ES⁺) = 528.12 [M + H]⁺.

Example 114: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl] -ethoxy}- rimidin-2-yl)-pyrrolidin-3-yl] -5-fluoro-lH-pyridin-2-one

To a solution of 2-chloro-5- {(5)-l-[l-(3-ethyl-[l ,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrimidine (Preparation 102, HOmg, 325μmol) and l-((trans)-4-amino- pyrrolidin-3-yl)-5-fluoro-lH-pyridin-2-one (Preparation 191, 32.0mg, 0.162mmol) in DMSO (lmL) was added DBU (32μί, 210μmol) and the resulting reaction mixture was heated under microwave irradiation at 120°C for 65 minutes. The reaction mixture was partitioned between DCM and water and passed through a phase separator. The organics were concentrated in vacuo and the crude product was purified by preparative HPLC and loaded onto an SCX cartridge. The cartridge was eluted with methanol, then 3.5M NH₃ in MeOH, and the basic fraction collected and concentrated in vacuo to afford l-[(trans)-4- amino-1 -(5- {(S)- 1 -[ 1 -(3 -ethyl- [1 ,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy} -pyrimidin-2- yl)-pyrrolidin-3-yl]-5-fluoro-lH-pyridin-2-one. Purification by chiral HPLC

(MTBE:MeOH:THF:n-butylamine 50:30:20:0.1 , 12mL/min, 250nm) afforded the title compound: RT = 2.45 min; m/z (ES⁺) = 499.19 [M+ H]⁺.

Example 115: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-ethoxy}-pyrimidin-2- l)-pyrrolidin-3-yl]-lH-pyridin-2-one

1 -[(Trans)-4-amino- 1 -(5- {(S)- 1 -[ 1 -(3-ethyl-[l ,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-lH-pyridin-2-one was synthesised from l-((trans)- 4-amino-pyrrolidin-3-yl)-lH-pyridin-2-one (Preparation 192) and 2-chloro-5- {(5)-l-[l-(3- ethyl-[l ,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation 102) employing a procedure similar to that outlined in Example 114. Purification by chiral HPLC (MeOH:THF:n-butylamine 80:20:0.1 , 13mL/min, 250nm) afforded the title compound: RT =2.37min; m/z (ES⁺) = 481.19 [M+ H]⁺.

Example 116: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-ethoxy}- rimidin-2-yl)-pyrrolidin-3-yl]-4-methyl-lH-pyridin-2-one

1 -[(Trans)-4-amino- 1 -(5- {(S)- 1 -[ 1 -(3-ethyl-[l ,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-4-methyl-lH-pyridin-2-one was synthesized from l-((trans)-4-amino-pyrrolidin-3-yl)-4-methyl-lH-pyridin-2-one (Preparation 193) and 2- chloro-5-{(5)-l-[l -(3-ethyl-[l ,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine

(Preparation 102) employing a procedure similar to that outlined in Example 114.

Purification by chiral HPLC (MeOH:THF:n-butylamine 80:20:0.1 , 13mL/min, 250nm) followed by further purification by preparative HPLC afforded the title compound: RT = 2.47min; m/z (ES⁺) = 495.25 [M+ H]⁺.

Example 117: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-ethoxy}- rimidin-2-yl)-pyrrolidin-3-yl]-5-methyl-lH-pyridin-2-one

1 -[(Trans)-4-amino- 1 -(5- {(S)- 1 -[ 1 -(3-ethyl-[l ,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl] -5 -methyl- lH-pyridin-2-one was synthesized from l-((trans)-4-amino-pyrrolidin-3-yl)-5-methyl-lH-pyridin-2-one (Preparation 194) and 2- chloro-5-{(5)-l-[l -(3-ethyl-[l ,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine

(Preparation 102) employing a procedure similar to that outlined in Example 114.

Purification by chiral HPLC (MeOH:MTBE:THF:n-butylamine 60:20:20:0.1 , 13mL/min, 250nm) followed by further purification by preparative HPLC afforded the title compound: LCMS: RT = 2.45min; m/z (ES⁺) = 495.24 [M+ H]⁺. Example 118: l-((3S,4S)-4-Amino-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin- 4-ylmethoxy]-pyrimidin-2- l}-pyrrolidin-3-yl)-5-fluoro-lH-pyridin-2-one

1 -((Trans)-4-amino- 1 - {5 -[ 1 -(3-isopropyl-[ 1 ,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy] - pyrimidin-2-yl}-pyrrolidin-3-yl)-5-fluoro-lH-pyridin-2-one was synthesized from l-((trans)- 4-amino-pyrrolidin-3-yl)-5-fluoro-lH-pyridin-2-one (Preparation 195) and 2-choro-5-[l-(3- isopropyl-[l ,2,4]oxadiazol-5-yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2)

employing a procedure similar to that outlined in Example 114. Purification by chiral HPLC (MTBE:MeOH:THF:n-butylamine 50:40:10:0.1, 14mL/min, 250nm) afforded the title compound: LCMS: RT = 2.43 min; m/z (ES⁺) = 499.25 [M+ H]⁺.

Example 119: (3R,45)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(3-isopropyl-

[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrazin-2-yl)-pyrrolidin-3-ylamine hydrochloride

2-Bromo-5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrazine (Preparation 95, 150mg, 380μmol), [(3R,4S)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 140mg, 460μιηο1), sodium tertiary butoxide (l lOmg, l . lmmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza- l-phosphabicyclo[3.3.3]undecane (13mg, 38μmol) were combined in toluene (2mL) in a sealed tube and degassed with argon for 10 min. Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (20mg, 19μιηο1) was added and the reaction mixture degassed with argon for a further 5 min prior to heating at 120°C for 1 h under microwave irradiation. The reaction mixture was cooled to r.t., loaded onto an SCX cartridge, then eluted with MeOH followed by NH₃ in MeOH (7M) and the basic fractions concentrated in vacuo. The remainder was dissolved in DCM (4mL), TFA (lmL) was added and the resulting reaction mixture was stirred at r.t. for 30 min. The reaction mixture was loaded onto an SCX cartridge, then eluted with MeOH followed by NH₃ in MeOH (7M) and the basic fractions concentrated in vacuo. Purification by preparative HPLC (basic method) afforded (3R,4S)-4- (2,5-difluoro-phenyl)-l-(5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrazin-2-yl)-pyrrolidin-3-yl amine, which was dissolved in DCM (lmL) prior to the addition of HC1 in dioxane (4M). Removal of the solvent in vacuo afforded the title compound: RT = 3.25min; mlz (ES⁺) = 514.1 [M+ H]⁺.

Example 120: (3R,45)-4-(2,5-Difluoro-phenyl)-l-(6-{(5)-l-[l-(3-isopropyl-

[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyridazin-3-yl)-pyrrolidin-3-ylamine hydrochloride

3-Chloro-6-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}- pyridazine (Preparation 197, 115mg, 327μmol), [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin- 3-yl]carbamic acid tert-butyl ester (Preparation 48, 117mg, 392μmol) and 1,8- diazabicyclo[5.4.0]undec-7-ene (59.7mg, 392μmol) in DMSO (654μΕ) in a sealed tube were heated at 80°C for 72 h and at 100°C for 24 h. Upon cooling, the reaction mixture was poured into DCM (200mL), washed with brine (200mL) and concentrated in vacuo. The remainder was redissolved in DCM (6mL), TFA (2mL) was added and the resulting reaction mixture was stirred at r.t. for 1 h. The reaction mixture was loaded onto an SCX cartidge and eluted with MeOH, followed by NH₃ in MeOH (7M). The basic fractions were concentrated in vacuo and the remainder redissolved in MeOH and loaded onto a phosphonic acid SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M). The basic fractions were concentrated in vacuo and purified by column chromatography (DCM:MeOH; 96:4) to afford (3i?,45)-4-(2,5-difluoro-phenyl)- 1 -(6- {(S)- 1 -[ 1 -(3-isopropyl-[ 1 ,2,4]oxadiazol-5-yl)- piperidin-4-yl]-ethoxy}-pyridazin-3-yl)-pyrrolidin-3-ylamine. The product was dissolved in Et₂0 (2mL) and HC1 in 1,4-Dioxane (4M, 0.3mL) was added. The solvent was removed in vacuo to afford the title compound: RT = 2.55min; mlz (ES ) = 514.2 [M+ H]⁺. Example 121: (3R,4S)-4-(2,5-Difluoro-phenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)-piperidin-4-ylmethoxy]-4-methoxy-pyrimidin-2-yl}-pyrrolidin-3-ylamine hydrochloride

To a solution of ((3i?,45)-4-(2,5-difluoro-phenyl)-l-{5-[l-(3-isopropyl-

[l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-4-methoxy-pyrimidin-2-yl}-pyrrolid^ carbamic acid tert-butyl ester (Preparation 200, 68.7mg, 109μηιο1) in DCM (5mL) was added TFA (lmL) and the resulting reaction mixture was stirred at r.t. for 30 min. Further TFA (lmL) was added and the reaction mixture stirred at r.t. for 1 h. The reaction mixture was loaded onto an SCX cartidge and eluted with MeOH followed by NH₃ in MeOH (7M). The basic fractions were concentrated in vacuo and purified by column chromatography (DCM:MeOH; 195:5) to afford (3i?,45)-4-(2,5-difluoro-phenyl)-l-{5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-4-methoxy-pyrimidin-2-yl}-pyrrolidin-3- ylamine. The product was redissolved in DCM (2mL) and HC1 in 1,4-dioxane (4M, 0.2mL) was added. The solvent was removed in vacuo to afford the title compound: RT = 2.67min; m/z (ES⁺) = 530.3 [M+ H]

Example 122: (3R,45)-4-(2,5-Difluoro-phenyl)-l-(5-{(5)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyridin-2-yl)-pyrrolidin-3-ylamine hydrochloride

Toluene (2mL) was added to 2-bromo-5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-yl]ethoxy}pyridine (Preparation 94, 150mg, 380μιηο1), [(3i?,45)-4-(2,5- difluorophenyl)pyrrolidin-3-yl] carbamic acid tert-butyl ester (Preparation 48, 150mg, 0.49mmol), sodium tertiary butoxide (HOmg, l .lmmol) and 2,8,9-triisobutyl -2,5,8,9- tetraaza -1-phosphabicyclo [3.3.3]undecane (14mg, 0.041mmol) and the resulting reaction mixture was degassed with argon for 10 min.Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (20mg, 19μιηο1) was added and the reaction mixture degassed with argon for a further 5 min prior to heating at 120°C for 1 h under microwave irradiation. Upon cooling, the reaction mixture was loaded onto an SCX cartridge and eluted with MeOH followed by NH₃ in MeOH (7M). The basic fractions were concentrated in vacuo, redissolved in DCM (lOmL) and TFA (2mL) was added. The resulting reaction mixture was stirred at r.t for 30 min, loaded onto an SCX cartridge and eluted with MeOH followed by N¾ in MeOH (7M). The basic fractions were concentrated in vacuo and the remainder purified by preparative HPLC (basic method) to afford (3i?,45)-4-(2,5-difluoro-phenyl)-l-(5- {(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyridin-2-yl)- pyrrolidin-3-ylamine. The product was dissolved in DCM and HC1 in 1,4-dioxane (4M) was added. Removal of the solvent in vacuo afforded the title compound: RT = 2.54min; mlz (ES⁺) = 513.29 [M+ H]

Example 123: 4-((S)-l-{2-[(3S,4S)-3-Amino-4-(2-oxo-piperidin-l-yl)-pyrrolidin-l-yl]- pyrimidin-5-yloxy}-ethyl)- iperidine-l-carboxylic acid isopropyl ester

To a solution of 4-((5)-l-{2-[(35',45)-3-tert-butoxycarbonylamino-4-(2-oxo- piperidin- 1 -yl)-pyrrolidin- 1 -yl] -pyrimidin-5 -yloxy } -ethyl)-piperidine- 1 -carboxylic acid isopropyl ester (Preparation 202, 57mg, 99μιηο1) in DCM (lmL) was added HC1 in 1, 4- dioxane (4M, O.lmL) and the resulting reaction mixture was stirred at r.t. for 16 h. The solvent was removed in vacuo to afford the title compound: RT = 2.62min; mlz (ES⁺) = 475.2 [M+ H]⁺.

Example 124: 2-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-ethanol

hydrochloride

To a solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2- yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 205, 150mg, 0.28mmol) and 3,N-dihydroxy-propionamidine (35mg, 0.34mmol) in EtOH (15mL) was added zinc dichloride in Et₂0 (1M, 0.34mL, 0.34mmol) and the resulting reaction mixture was stirred at r.t. for 3 h. HCl in 1,4-dioxane (4M, 0.35mL, 1.4mmol) was added and the reaction mixture heated at 110°C for 30 min under microwave irradiation. The reaction mixture was loaded onto an SCX cartridge and eluted with MeOH followed by NH₃ in MeOH (3.5M, 3.5mL), then the basic frations were concentrated in vacuo and purified by preparative HPLC. The product was loaded onto a phosphonic acid SCX cartridge and eluted with MeOH followed by NH₃ in MeOH (3.5M, 2.5mL). The basic fractions were

concentrated in vacuo, redisoolved in DCM (lmL) and HCl in 1, 4-dioxane was added. The resulting reaction mixture was stirred at r.t. for 30 min and the solvent removed in vacuo to afford the title compound: RT = 2.43min; mlz (ES⁺) = 516.13 [M+ H]⁺.

Example 125: l-{5-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-ethanol

hydrochloride

The title compound was synthesized from [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4- yl)-ethoxy]-pyrimidin-2-yl} -4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 205, 150mg, 0.28mmol) and 2,N-dihydroxy-propionamidine (35mg, 0.34mmol) employing a procedure similar to that outlined in Example 124: RT = 2.48min; mlz (ES⁺) = 516.5 [M+ H]⁺.

Example 126: l-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- l-yl]-pyrimidin-5-yloxy -ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-ethanol

To a solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2- yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 206, 50mg, 0.09mmol) and 2,N-dihydroxy-propionamidine (1 lmg, 0.1 lmmol) in EtOH was added molecular sieves (lg) and zinc dichloride in Et₂0 (0.1 lmL, 0.1 lmmol) and the resulting reaction mixture was stirred at r.t. for 2 h. HCl in 1 ,4-dioxane (4M, 0.1 lmL, 0.46mmol) was added and the reaction mixture heated at 110°C for 30 min under microwave irradiation. The reaction mixture was loaded onto an SCX cartridge and eluted with MeOH followed by NH₃ in MeOH (3.5M, 2.4mL), then the basic frations were concentrated in vacuo and purified by preparative HPLC. The product was loaded onto an SCX cartridge and eluted with MeOH followed by NH₃ in MeOH (3.5M, 2.4mL). The basic fractions were concentrated in vacuo to afford the title compound: RT = 2.57min; mlz (ES⁺) = 534.21 [M +

H]⁺.

Example 127: 2-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-ethanol hydrochloride

The title compound was synthesised from [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4- yl)-ethoxy]-pyrimidin-2-yl} -4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 206, 150mg, 0.28mmol) and 3,N-dihydroxy-propionamidine (34mg, 0.33mmol) employing a procedure similar to that outlined in Example 124: RT = 2.52min; mlz (ES⁺) = 534.14 [M+ H]⁺.

Example 128: (R)-l-{5-[4-((5)-l-{2-[(3R,45)-3-Amino-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-ethanol hydrochloride

(R)- 1 - {5-[4-((S 1 - {2-[(3i?,45)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l -yl]- pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-ethanol was isolated from 1 - {5-[4-((S)-l - {2-[(3i?,45)-3-amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l -yl]-pyrimidin-5- yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-ethanol (Example 126, 145mg, 0.272mmol) by chiral HPLC (MTBE:MeOH:THF:BA 60:20:20:0.1, 12mL/min, 250nM). The product (66.8mg, 0.125mmol) was dissolved in DCM (0.5mL), HC1 in Et₂0 (2M, 80μΕ, 0.160mmol) was added and the resulting reaction mixture was stirred at r.t. for 10 min. The solvent was removed in vacuo to afford the title compound: RT = 0.75 min; mlz (ES⁺) = 534.40 [M+ ] (LCMS Method-6).

Example 129: (5)-l-{5-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-ethanol hydrochloride

The title compound was synthesized froml-{5-[4-((5)-l-{2-[(3i?,45)-3-amino-4- (2,4,5 -trifluoro-phenyl)-pyrrolidin- 1 -yl] -pyrimidin-5 -yloxy } -ethyl)-piperidin- 1 -yl] - [l,2,4]oxadiazol-3-yl}-ethanol (Example 126, 145mg, 0.272mmol) employing the procedure outlined in Example 128: RT = 0.77 min; m/z (ES⁺) = 534.40 [M+ H]⁺ (LCMS Method-6).

Example 130: 4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxy}-ethyl)-piperidine-l-sulfonic acid isopropyl-methyl-amide

hydrochloride

To a solution of [(3i?,45)-l-[5-((5)-l-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5- trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 75mg, 0.14mmol) in DCE (5mL) was added triethylamine (40μί, 0.29mmol) and methyl(propan-2- yl)sulfamyl chloride (30mg, 0.17 mmol) and the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was diluted with DCM (lOmL) and H₂0 (lOmL) and the organics separated, concentrated in vacuo and purified by peparative HPLC. The product was dissolved in DCM (2mL), HC1 in Et₂0 (2M, 72μΙ,, 0.14mmol) was added and the resulting reaction mixture was stirred at r.t. for 30 min. The solvent was removed in vacuo to afford the title compound: RT = 2.87 min; m/z (ES⁺) = 557.14 [M+ H]⁺. Example 131: (3R,4S)-4-(2-Fluoro-5-methoxy-phenyl)-l-{5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-pi eridin-4-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-ylamine

To a solution of (tra/?5)-4-(2-Fluoro-5-methoxy-phenyl)-pyrrolidin-3-ylamine

(Preparation 209, 43mg, 200μηιο1) and 2-choro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2, 69mg, 200μηιο1) in MeCN (2mL) was added DIPEA (53μί, 310μηιο1) and the resulting reaction mixture was heated at 170°C for 30 min under microwave irradiation. The solvent was removed in vacuo and the residue was purified by MDP (acidic method). Purification by chiral HPLC (IH : EtOH : THF : B A

50:30:20:0.1, 12mL/min, 250nM, RT = 21.6 min) afforded the title compound: RT = 2.84 min; mlz (ES⁺) = 512.5 [M+ H]⁺.

Example 132: (3S,4R)-4-(2-Fluoro-5-methoxy-phenyl)-l-{5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-pi eridin-4-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-ylamine

To a solution of (tra/?5)-4-(2-Fluoro-5-methoxy-phenyl)-pyrrolidin-3-ylamine

(Preparation 209, 43mg, 200μιηο1) and 2-choro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2, 69mg, 200μιηο1) in MeCN (2mL) was added DIPEA (53μΙ_^, 310μιηο1) and the resulting reaction mixture was heated at 170°C for 30 min under microwave irradiation. The solvent was removed in vacuo and the residue was purified by MDP (acidic method). Purification by chiral HPLC (IH : EtOH : THF : B A

50:30:20:0.1, 12mL/min, 250nM, RT = 12.8 min) afforded the title compound: RT = 2.70 min; mlz (ES⁺) = 512.24 [M+ H]⁺. Example 133: (3S,45)-l-(5-{(S)-l-[l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4-(4-ethyl-pyrazol-l-yl)-pyrrolidin-3-ylamine

A solution of 2-chloro-5-{(5)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrimidine (Preparation 102, 130mg, 380μηιο1), (tra/?s)-4-(4-ethyl-pyrazol-l- yl)-pyrrolidin-3-ylamine (Preparation 214, 34mg, 190μηιο1) and DBU (37μί, 240μηιο1) in DMSO (lmL) were heated at 120°C for 65 min under microwave irradiation. The reaction mixture was diluted with DCM and H₂0, and the organics separated and concentrated in vacuo. The remainder was purified by preparative HPLC, then loaded onto an SCX cartridge, eluting with MeOH followed by NH₃ in MeOH. The basic fractions were concentrated in vacuo and purified by chiral HPLC (MeCN:THF:BA 70:30:0.1, 15mL/min, 250nM, RT = 12.8 min). The crude product was loaded onto an SCX cartridge, eluting with MeOH followed by NH₃ in MeOH. The basic fractions were concentrated in vacuo to afford the title compound: RT = 2.65 min; mlz (ES⁺) = 482.22 [M+ H]⁺.

Example 134: 2-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-propan-2-ol tosylate

To a solution of [(3i?,45)-l-[5-((5)-l-{l-[3-(l-hydroxy-l-methyl-ethyl)- [l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 217, 0.178g, 0.275mmol) in DCM (4mL) was added TFA (lmL) and the resulting reaction mixture was stirred at r.t. for 90 min. The solvent was removed in vacuo and the remainder was partitioned between DCM (15mL) and saturated aqueous NaHC0₃ solution (lOmL). The aqueous layer was separated and extracted with DCM (15mL). The combined organic layers were concentrated in vacuo, re-dissolved in DCM (3mL) and TsOH (47mg, 0.25mmol) in MeOH (0.5mL) was added. The solvent was removed in vacuo to afford the title compound: RT = 0.77 min; mlz (ES⁺) = 548.45 [M+ H]⁺ (LCMS - Method 6). Example 135 : (3R,4S)-1 -{5- [ l-(3-Isopropyl- [ 1 ,2,4] oxadiazol-5-ylmethyl)-azetidin-3- ylmethoxy]-pyrimidin-2- l}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine

To a solution of [(3R,4S)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-ylmethyl)-azetidin- 3-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 219, 14mg, 23μηιο1) in DCM (lmL) was added TFA (0.2mL) and the resulting reaction mixture was stirred at r.t. for 1 h. The reaction mixture was added to an SCX cartridge and eluted with MeOH followed by NH₃ in MeOH (3.5M). The basic fractions were concentrated in vacuo to afford the title compound: RT = 2.15 min; mlz (ES ) = 504.17 [ + H]⁺.

Example 136: (3S,45)-l-{5-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4- ylmethoxy]-pyrimidin-2- l}-4-(4-methyl-pyrazol-l-yl)-pyrrolidin-3-ylamine

A solution of 2-chloro-5-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- ylmethoxy]pyrimidine (Preparation 53, 0.1 lg, 0.32mmol), (tra/?s)-4-(4-methyl-pyrazol-l- yl)-pyrrolidin-3-ylamine (Preparation 221, 35mg, 0.21mmol) and DBU (40μί, 0.268mmol) in DMSO (1.5mL) were heated at 120°C for 60 min under microwave irradiation. Upon cooling, the reaction mixture was loaded onto a phosphonic acid SCX cartridge and eluted with MeOH, followed by triethylamine in MeOH (3%), followed by NH₃ in MeOH (10%). The basic fractions were concentrated in vacuo and purified by chiral HPLC

(MeCN:THF:BA 80:20:0.1, 15mL/min, 250nM, RT = 13.3 min) to afford the title compound: RT = 1.92 min; mlz (ES⁺) = 468.40 [M+ H]⁺. Example 137: 4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxy}-ethyl)- iperidine-l-sulfonic acid ethyl-methyl-amide hydrochloride

The title compound was synthesised from [(3R,4S)-l-[5-((S)-l-piperidin-4-yl- ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 75mg, 0.14mmol) and ethyl(methyl)sulfamyl chloride (0.027 g, 0.17 mmol) employing a procedure similar to that outlined in Example 30: RT = 2.80 min; m/z (ES⁺) = 543.12 [ + H]⁺. Example 138: (3R,45)-4-(2,5-Difluoro-phenyl)-l-[5-((S-l-{l-[3-((S)-l-methoxy-ethyl)- [l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-ylamine hydrochloride

To a solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2- yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 205, 120mg, 0.230mmol) and (5)-N-hydroxy-2-methoxypropionamidine (Preparation 148, 33 mg, 0.27mmol) in EtOH (6mL) was added zinc dichloride in Et₂0 (1M, 0.27mL, 0.27mmol) and the resulting reaction mixture was stirred at r.t. for 3 h. HC1 in 1 ,4-dioxane (4M,

0.28mL, l . lmmol) was added and the reaction mixture heated at 100°C fo 30 min under microwave irradiation. The reaction mixture was loaded onto an SCX cartridge and eluted with MeOH (3.5mL) followed by NH₃ in MeOH (3.5M, 2.5mL) and the basic fractions concentrated in vacuo. The residue was purified by preparative HPLC, then loaded onto an SCX cartridge and eluted with MeOH (3.5mL) followed by NH₃ in MeOH (3.5M, 2.5mL) and the basic fractions concentrated in vacuo. The remainder was dissolved in DCM (3mL), HC1 in 1 ,4-dioxane (4M, 0.14mL) was added and the resulting mixture stirred at r.t. for 30 min. Removal of the solvent in vacuo afforded the title compound: RT = 2.72 min; m/z (ES ) = 530.26 [ + H]⁺.

The following examples were prepared by reaction of the appropriate (l-cyano-piperidin-4- yl-ethoxy)-pyrimidin-2-yl building block with the appropriate amidoxime building block employing a procedure similar to that outlined in Example 138:

Example 168: (3R,4S)-4-(2,5-Difluoro-phenyl)-l-[5-((S)-l-{l-[(S)-3-(tetrahydro-furan-3- yl)-[l,2,4]oxadiazol-5-yl]- iperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-ylamine

To a solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2- yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 205, 240mg, 0.45mmol) and N-hydroxytetrahydrofuran-3-carboxamidine (Preparation 168, 71mg, 0.54mmol) in EtOH (12mL) was added zinc dichloride in Et₂0 (1M, 0.54mL, 0.54mmol) and the resulting reaction mixture was stirred at r.t. for 3 h. HC1 in 1,4-dioxane (4M, 0.57mL, 2.3mmol) was added and the resulting reaction mixture heated at 100°C for 30 min under microwave irradiation. Upon cooling, the reaction mixture was added to an SCX cartridge and eluted with MeOH (3 x 5mL) followed by NH₃ in MeOH (3.5M, 2 x 5mL) and the basic fractions concentrated in vacuo and purified by preparative HPLC. The purified product was added to an SCX cartridge and eluted with MeOH (3 x 5mL) followed by N¾ in MeOH (3.5M, 2 x 5mL) and the basic fractions concentrated in vacuo to afford (3R,4S)-4- (2,5-difluoro-phenyl) -[5-((S)-l-{l-[3-(tetrahydro-furan-3-yl)-[l,2,4]oxadiazol-5-yl]- piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-ylamine. The product was purified by chiral HPLC (MeOH:IH:THF:BA; 50:25:25:0.1, 15ml/min, 250nm), then dissolved in DCM (3mL) and HC1 in 1,4-dioxane (4M, 3mL) was added. The resulting reaction mixture was stirred at r.t. for 30 min, prior to removal of the solvent in vacuo. The residue was purified by preparative HPLC and added to an SCX cartridge, eluting with MeOH followed by N¾ in MeOH (3.5M). The basic fractions were concentrated in vacuo to afford the title compound: RT = 2.60 min; mlz (ES⁺) = 542.31 [M+ H]⁺.

Example 169: (3R,45)-4-(2,5-Difluoro-phenyl)-l-[5-((S)-l-{l-[(R)-3-(tetrahydro-furan- 3-yl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin-4-yl}-ethoxy)-pyrimidin-2-yl] -pyrr olidin-3- ylamine

The title compound was synthesised from [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4- yl)-ethoxy]-pyrimidin-2-yl} -4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 205, 240mg, 0.45mmol) and N-hydroxytetrahydrofuran-3- carboxamidine (Preparation 168, 71mg, 0.54mmol) employing the procedure outlined in Example 168: RT = 2.60 min; mlz (ES⁺) = 542.32 [M+ H]⁺.

Example 170: (3R,45)-4-(2,5-Difluoro-phenyl)-l-[5-((S)-l-{l-[(R)-3-(tetrahydro- 2-yl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin-4-yl}-ethoxy)-pyrimidin-2-yl] -pyrr olidin-3 ylamine

To a solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2- yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 205, 150mg, 0.28mmol) and (i?)-N-hydroxy-tetrahydro-furan-2-carboxamidine (44mg,

0.34mmol) in EtOH (12mL) was added molecular sieves (lg) followed by zinc dichloride in Et₂0 (1M, 0.34mL, 0.34mmol) and the resulting reaction mixture was stirred at r.t. for 2 h. HC1 in 1,4-dioxane (4M, 0.35mL, 1.4mmol) was added and the reaction mixture heated at 110°C under microwave irradiation for 30 min. The reaction mixture was added to an SCX cartridge and eluted with MeOH (4 x 5mL) followed by NH₃ in MeOH (3.5M, 2 x 5mL) and the basic fractions concentrated in vacuo and purified by preparative HPLC. The purified product was added to an SCX cartridge and eluted with MeOH (3 x 5mL) followed by NH₃ in MeOH (3.5M, 2 x 5mL) and the basic fractions concentrated in vacuo to afford the title compound: RT = 2.62 min; mlz (ES⁺) = 542.17 [M+ H]⁺.

Example 171: (3R,45)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(5-ethyl-[l,2,4]oxadiazol-3- yl)-piperidin-4-yl]-ethox -pyrimidin-2-yl)-pyrrolidin-3-ylamine hydrochloride

To a solution of [(3i?,45)-4-(2,5-difluoro-phenyl)-l-(5-{(5)-l-[l-(N- hydroxycarbamimidoyl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 226, 102mg, 0.181mmol) and propanoic acid (24.2mg, 0.326mmol) in DMF (4mL) was added HOBt (55.5mg, 0.362mmol) and EDCI (69.4mg, 0.362mmol) and the resulting reaction mixture was stirred at r.t. for 1 h, at 80°C for 3 h and at r.t. for 72 h. The reaction mixture was partitioned between DCM and water and the organics separated, concentrated in vacuo and purified by preparative HPLC. The product was dissolved in DCM (2mL), TFA (0.2mL, 2mmol) was added and the reaction mixture stirred at r.t. for 3 h. The reaction mixture was added to a phosphonic acid SCX cartridge and eluted with MeOH (4 x 4mL) followed by NH₃ in MeOH (3.5M, 3 x 3mL) and the basic fractions concentrated in vacuo. The remainder was dissolved in DCM and HC1 in 1, 4- dioxane 0.02mmol) was added and the reaction mixture stirred at r.t. for 20 min. The solvent was removed in vacuo, azeotroping with Et₂0, to afford the title compound: RT = 2.85 min; mlz (ES⁺) = 500.15 [M+ H]⁺.

Example 172: (3R,45)-l-(5-{(S)-l-[l-(5-Ethyl-[l,2,4]oxadiazol-3-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4- 2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was synthesised from [(3i?,45)-l-(5-{(5)-l-[l-(N- hydroxycarbamimidoyl)-piperidin-4-yl]-ethoxy} -pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 227, 105mg, 0.181mmol) employing a procedure similar to that outlined in Example 171: RT = 2.84 min; mlz (ES ) =

Example 173: (3R,45)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(4-methyl-thiazol-2-yl)- piperidin-4-yl]-ethoxy}-p rimidin-2-yl)-pyrrolidin-3-ylamine

To a solution of [(3i?,45)-4-(2,5-difluoro-phenyl)-l-(5-{(5)-l-[l-(4-methyl-thiazol-2- yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 228, 8mg, ΙΟμιηοΙ) in DCM (2mL) was added TFA (O.lmL, lmmol) and the resulting reaction mixture was stirred at r.t. for 3 h. The reaction mixture was added to an SCX cartridge eluting with MeOH (2 x 4mL) followed by NH₃ in MeOH (2 x 4mL) and the basic fractions were concentrated in vacuo to afford the title compound: RT = 2.34 min; mlz (ES⁺) = 501.23 [Μ+ ηγ. Example 174: (3R,4S)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(3-ethyl-[l,2,4]thiadiazol- 5-yl)-piperidin-4-yl]-ethox -pyrimidin-2-yl)-pyrrolidin-3-ylamine hydrochloride

A solution of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 204, 75mg, 0.15mmol) and 5-bromo-3-ethyl-l ,2,4-thiadiazole (170mg, 0.89mmol) was heated at 140°C for 30 min under microwave irradiation. Purification by preparative HPLC afforded

[(3i?,45)-4-(2,5-difluoro-phenyl)- 1 -(5- {(S)- 1 -[ 1 -(3 -ethyl-[ 1 ,2,4]thiadiazol-5-yl)-piperidin-4- yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. The intermediate was dissolved in DCM (2mL), TFA (0.2mL, 2mmol) was added and the resulting reaction mixture was stirred at r.t. for 3 h. The reaction mixture was added to a phosphonic acid SCX cartridge eluting with MeOH (4 x 4mL) followed by NH₃ in MeOH (3.5M, 3 x 3mL) and the basic fractions were concentrated in vacuo. The remainder was dissolved in DCM, HC1 in 1 ,4-dioxane (4M, IQuL, 40μιηο1) was added and the reaction mixture stirred at r.t. for 20 min. Removal of the solvent in vacuo, azeotroping with Et₂0, afforded the title compound: RT = 2.80 min; m/z (ES⁺) = 516.13 [M+ H]⁺.

Example 175: (3R,45)-l-(5-{(S)-l-[l-(3-Ethyl-[l,2,4]thiadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4- 2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was synthesised from [(3i?,45)-l-[5-((5)-l-piperidin-4-yl- ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 170mg, 0.86mmol) employing a procedure similar to that outlined in Example 174: RT = 2.75 min; m/z (ES⁺) = 534.10 [M+ H]⁺. Example 176: (3R,4S)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(2-ethyl-2H-tetrazol-5-yl)- piperidin-4-yl]-ethoxy}-pyrimidin-2- l)-pyrrolidin-3-ylamine dihydrochloride

To a solution of [(3i?,45)-4-(2,5-difluoro-phenyl)-l-(5-{(5)-l-[l-(3-ethyl-lH-tetrazol- 5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 230, 40mg, 0.07mmol) in DCM (5mL) was added TFA (0.5mL) and the resulting reaction mixture was stirred at r.t. for 3 h. The reaction mixture was added to an SCX cartridge eluting with MeOH (3 x 4mL) followed by NH₃ in MeOH (3.5M, 3 x 4mL) and the basic fractions were concentrated in vacuo. The remainder was dissolved in DCM (3mL), HC1 in Et₂0 (2M, 80μί, 0.2mmol) was added and the reaction stirred at r.t for 20 min. Removal of the solvent in vacuo afforded the title compound: RT = 2.77 min; m/z (ES )

Example 177: (3R,45)-l-(5-{(S)-l-[l-(2-Ethyl-2H-tetrazol-5-yl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifl ro-phenyl)-pyrrolidin-3-ylamine dihydrochloride

The title compound was synthesised from [(3i?,45)-l-(5-{(5)-l-[l-(2-Ethyl-2H- tetrazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- 3-yl]-carbamic acid tert-butyl ester (Preparation 232, 30mg, 0.05mmol) employing a procedure similar to that outlined in Example 176: RT = 2.75 min; m/z (ES⁺) = 518.12 [M+ H]⁺.

Example 178: (3R,45)-l-(5-{(S)-l-[l-(Propane-l-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro- henyl)-pyrrolidin-3-ylamine hydrochloride

To a solution of [(3i?,45)-l-[5-((5)-l-piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5- trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 75mg, 0.14mmol) and triethylamine 40μί, 0.29mmol) in DCM (4mL) was added n-propyl sulfonyl chloride (24mg, 0.17mmol) and the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was partitioned between DCM (lOmL) and water (8mL) and the organics separated and concentrated in vacuo. Purification by preparative HPLC afforded [(3R,4S)-l- (5- {(S)- 1 -[ 1 -(propane- 1 -sulfonyl)-piperidin-4-yl]-ethoxy} -pyrimidin-2-yl)-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. The product was dissolved in DCM (2mL), TFA (0.2mL, 2.0mmol) was added and the resulting reaction mixture was stirred at r.t. for 3 h. The reaction mixture was added to an SCX cartridge eluting with MeOH (3 x 4mL) followed by NH₃ in MeOH (3.5M, 3 x 3mL) and the basic fractions were concentrated in vacuo. The remainder was dissolved in DCM (2mL) and HC1 in 1,4-dioxane (25μί, O.lOmmol) was added. The reaction mixture was stirred at r.t for 20 min and the solvent removed in vacuo to afford the title compound: RT = 2.75 min; m/z (ES ) = 528.11 [M+ H]⁺.

The following examples were prepared by reacting [(3i?,45)-l-[5-((5)-l-piperidin-4- yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 185) with the appropriate sulfonyl chloride building block employing a procedure similar to that outlined in Example 178:

Example 186: (3R,4S)-l-(5-{(S)-l-[l-((R)-Butane-2-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifl ro-phenyl)-pyrrolidin-3-ylamine hydrochloride

(3R,4S)-1 -(5- {(S)- 1 -[ 1 -(Butane-2-sulfonyl)-piperidin-4-yl]-ethoxy} -pyrimidin-2-yl)- 4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine was syntheised from [(3i?,4»S)- 1 - [5 -((JS - 1 - piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-frifluoro-phenyl)-pyrrolidin-3- acid tert-butyl ester (Preparation 185, 75mg, 0.14mmol) and sec-butylsulfonyl chloride (27mg, 0.17 mmol) employing a procedure similar to that outlined in Example 178. The product was purified by chiral HPLC (MeOH:THF:BA; 75:25:0.1, 13ml/min, 250nm), then added to an SCX cartridge eluting with MeOH (3 x 4mL) followed by NH₃ in MeOH (3.5M, 3 x 3mL) and the basic fractions were concentrated in vacuo. The remainder was dissolved in DCM (2mL) and HC1 in 1,4-dioxane (4M, ΙΟμί, 40μιηο1) was added. The reaction was stirred at r.t. for 20 min, the solvent removed in vacuo and the remainder added to a phosphonic acid SCX cartridge, eluting with MeOH (3 x 3mL) followed by N¾ in MeOH (3.5M, 3 x 3mL). The methanolic fractions were concentrated in vacuo to afford the title compound: RT = 2.92 min; mlz (ES⁺) = 542.13 [M+ H]⁺.

Example 187: (3R,45)-l-(5-{(S)-l-[l-((S)-Butane-2-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine

The title compound was syntheised from [(3 ?,45)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 75mg, 0.14mmol) and sec-butylsulfonyl chloride (27mg, 0.17 mmol) employing the procedure outlined in Example 186: RT = 2.90 min; mlz (ES ) = 542.13 [M + H]⁺. Example 188: (3R,4S)-l-(5-{(S)-l-[l-((R)-Pentane-2-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro- henyl)-pyrrolidin-3-ylamine hydrochloride

(3i?,45)-l-(5-{(5)-l-[l-(Pentane-2-sulfonyl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-y^^ 4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine was syntheised from [(3i?,4»S)- 1 - [5 -((JS - 1 - piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-frifluoro-phenyl)-pyrrolidin-3- acid tert-butyl ester (Preparation 185, 75mg, 0.14mmol) and 2-pentyl sulfonyl chloride (0.029 g, 0.17 mmol) employing a procedure similar to that outlined in Example 178. The product was purified by chiral HPLC (MeOH:THF:BA; 75:25:0.1, 13ml/min, 250nm), then added to an SCX cartridge eluting with MeOH (3 x 4mL) followed by NH₃ in MeOH (3.5M, 3 x 3mL) and the basic fractions were concentrated in vacuo. The remainder was dissolved in DCM (2mL) and HC1 in 1,4-dioxane (4M, ΙΟμί, 40μιηο1) was added. The reaction mixture was stirred at r.t. for 20 min, the solvent removed in vacuo and the remainder added to a phosphonic acid SCX cartridge, eluting with MeOH (3 x 3mL) followed by N¾ in MeOH (3.5M, 3 x 3mL). The methanolic fractions were concentrated in vacuo to afford the title compound: RT = 2.97 min; mlz (ES⁺) = 556.16 [M+ H]⁺.

Example 189: (3R,45)-l-(5-{(S)-l-[l-((S)-Pentane-2-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifl ro-phenyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was syntheised from [(3 ?,45)-l-[5-((5)-l-piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 75mg, 0.14mmol) and 2-pentyl sulfonyl chloride (0.029 g, 0.17 mmol) employing the procedure outlined in Example 188: RT = 3.05 min; m/z (ES⁺) = 556.15 [M + H]⁺. Example 190: (3R,4S)-l-[5-((S)-l-{l-[(S)-(Tetrahydro-furan-3-yl)sulfonyl]-piperidin-4- yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine

hydrochloride

(3i?,45)-l-(5-{(5)-l-[l -(Tetrahydro-furan-3-sulfonyl)-piperidin-4-yl]-ethoxy}- pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine was syntheised from

[(3i?,45)-l-[5-((5)-l -piperidin-4-yl-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-frifluoro-phenyl^ pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 75mg, 0.14mmol) and tetrahydrofuran-3-sulfonyl chloride (29mg, 0.17 mmol) employing a procedure similar to that outlined in Example 178. The product was purified by chiral HPLC

(MTBE : MeCN : : THF : B A; 40:30:30:0.1 , 14ml/min, 250nm), then added to an SCX cartridge eluting with MeOH (3 x 4mL) followed by NH₃ in MeOH (3.5M, 3 x 3mL) and the basic fractions were concentrated in vacuo. The remainder was dissolved in DCM (2mL) and HCl in 1 ,4-dioxane (4M, 10uL, 40μιηο1) was added. The reaction was stirred at r.t. for 20 min, the solvent removed in vacuo and the remainder added to a phosphonic acid SCX cartridge, eluting with MeOH (3 x 3mL) followed by NH₃ in MeOH (3.5M, 3 x 3mL). The methanolic fractions were concentrated in vacuo to afford the title compound: RT = 2.67 min; m/z (ES ) = 556.1 1 [M + H]⁺. Example 191: (3R,45)-l-[5-((S)-l-{l-[(R)-(Tetrahydro-furan-3-yl)sulfonyl]-piperidin-4- yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine

hydrochloride

The title compound was syntheised from [(3R,4S)-l-[5-((S)-l -piperidin-4-yl-ethoxy)- pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 185, 75mg, 0.14mmol) and tetrahydrofuran-3-sulfonyl chloride (29mg, 0.17 mmol) employing the procedure outlined in Example 190: RT = 2.68 min; m/z (ES ) = 556.12 [M + H]⁺. Example 192 : (3R,4S)-1 -{5- [ l-(6-Ethyl-pyridazin-3-yl)-piperidin-4-ylmethoxy] - pyrimidin-2-yl}-4-(2,4,5-trifl ro-phenyl)-pyrrolidin-3-ylamine

To a solution of [(3i?,45)-l-{5-[l-(6-Ethyl-pyridazin-3-yl)-piperidin-4-ylmethoxy]- pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 234, 22mg, 36μΙ.) in DCM (2mL) was added TFA (0.2mL, 2mmol) and the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (3.5M) and the basic fractions concentrated in vacuo to afford the title compound: RT = 2.18 min; m/z (ES ) =

Example 193: (3R,45)-l-{5-[(S)-l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-3- ylmethoxy]-pyrimidin-2-yl}-4- 2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine

The title compound was isolated from (3i?,45)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)piperidin-3-ylmethoxy]pyrimidin-2-yl}-4-(2,4,5-trifluorophenyl)pyrrolidin-3-ylamine (Example 46) via chiral HPLC (MTBE:MeOH:BA; 80:20:0.1, 13ml/min, 250nm, RT = 15.7 min): RT = 2.75 min; m/z (ES⁺) = 518.25 [M+ H]⁺. The stereochemistry of * centre has been arbitrarily assigned.

Example 194 : (3R,45)-1 -{5- [ l-(3-Isopr opyl- [ 1 ,2,4] oxadiazol-5-yl)-piperidin-4- ylmethoxy]-pyrimidin-2- l}-4-phenyl-pyrrolidin-3-ylamine

To a solution of (trans)-4-phenyl-pyrrolidin-3-yl-ammonium (Preparation 237, 50mg, 0.3mmol) in MeCN (2mL) was added 2-chloro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2, 83mg, 0.25mmol) followed by DIPEA (64μΙ_^, 0.37mmol) and the resulting reaction mixture was heated at 170°C for 30min under microwave irradiation. The solvent was removed in vacuo and the remainder purified by preparative HPLC. The crude product was loaded onto an SCX cartridge eluting with MeOH, followed by NH₃ in MeOH (3.5M) and the basic fractions concentrated in vacuo. Purification by chiral HPLC (MTBE :MeOH:THF :BA; 65:30:5:0.1, 13ml/min, 250nm, RT = 17.0 min), afforded the title compound: RT = 2.68 min; mlz (ES⁺) = 464.26 [M+ H]⁺.

Example 195: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-ethoxy}-pyridin-2-yl)-pyrrolidin-3-yl]-5,5-difluoro-piperidin-2-one hydrochloride

2-Bromo-5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyridine (Preparation 94, 50mg, O.lmmol), [(3S,4S)-4-(5,5-difluoro-2- oxopiperidin-l-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 93, 48mg,

0.15mmol), sodium tertiary butoxide (42mg, 0.44mmol) and 2,5,8,9-tetraaza-2,8,9-trimethyl- l-phosphabicyclo[3.3.3]undecane (2.7mg, 13μιηο1) were dissolved in 1,4-dioxane (2mL) and the resulting reaction mixture was degassed with argon for 10 min.

Tris(dibenzylideneacetone)dipalladium (12mg, 13μιηο1) was added and the reaction mixture was degassed with argon for a further 10 min. The reaction mixture was heated at 120°C for 60 min under microwave irradiation prior to filtration through celite. The filtrate was concentrated in vacuo, dissolved in DCM (5mL) and TFA (ImL) was added. The resulting reaction mixture was stirred at r.t. for 30 min, further TFA (ImL) was added and the reaction mixture stirred at r.t. for a further 20 min. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M) and the basic fractions concentrated in vacuo. The remainder was loaded onto a phosphonic acid SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M) and the basic fractions concentrated in vacuo. The remainder was purified by column chromatography (DCM:MeOH, 95:5), dissolved in Et₂0, and HC1 in 1,4-dioxane (5 drops) added. The solvent was removed in vacuo and the remainder purified by chiral HPLC (MTBE : THF : MeOH : B A; 55 :25 :20:0.1 , 12ml/min, 250nm, RT = 12.9 min) to afford the title compound: RT = 2.45 min; mlz (ES ) = 534.27 [M+ H]⁺.

Example 196: (3R,4S)-l-(5-{(S)-l-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrazin-2-yl)-4- 2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was synthesized from 2-bromo-5-{(5)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrazine (Preparation 95, 300mg, 0.8mmol), and [(3i?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

(Preparation 39, 290mg, 0.91mmol) employing a procedure similar to that outlined in

Example 119: RT = 2.92 min; mlz (ES⁺) = 532.53 [M+ H]⁺.

Example 197: (3R,45)-l-(2-{(S)-l-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-5-yl)-4- 2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

A solution of 5-Bromo-2-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4- yl]-ethoxy}-pyrimidine (Preparation 238, 177mg, 0.447mmol), [(3R,4S)-4-(2,4,5- trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 170mg, 0.54mmol), sodium tertiary butoxide (52mg, 0.54mmol) and 2-(di-t- butylphosphino)biphenyl (27mg, 89μmol) in toluene was degassed with argon for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (20mg, 22μιηο1) was added and the reaction mixture was degassed with argon for a further 10 min and heated at 75°C for 96 h. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo and the remainder purified by preparative HPLC. The product was dissolved in DCM (5mL) and TFA (lmL) added. The reaction mixture was stirred at r.t. for 30 min, further TFA (lmL) was added and stirring at r.t. continued for 20 min. The reaction mixture was loaded onto an SCX cartridge and eluted with MeOH followed by NH₃ in MeOH (7M) and the basic fractions concentrated in vacuo. The remainder was dissolved in Et₂0 and HC1 in 1,4- dioxane (4M, 5 drops) added. The solvent was removed in vacuo to afford the title compound: RT = 2.82 min; mlz (ES⁺) = 532.51 [M+ H]⁺.

Example 198: (3R,45)-l-(5-{(S)-l-[l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4- 4-methyl-pyridin-2-yl)-pyrrolidin-3-ylamine hydrochloride

2-Chloro-5-{(5)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrimidine (Preparation 102, 30.4mg, 90μmol), [(3i?,4S)-4-(4-methyl-pyridin-2- yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 243, 31.3mg, 113μιηο1) and DBU (13.7mg, 90μιηο1) in DMSO (lmL) were heated in a sealed tube at 80°C for 96 h.

Upon cooling, the reaction mixture was diluted with DCM (50mL), washed with brine (3 x 50mL) and concentrated in vacuo. The remainder was purified by column chromatography (DCM:MeOH; 97.5:2.5) to afford [(tra/75)-l-(5-{(5)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-ethoxy} -pyrimidin-2-yl)-4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. The intermediate was dissolved in DCM (5mL), TFA (lmL) was added and the resulting reaction mixture was stirred at r.t for 20 min. Further TFA (lmL) was added and the reaction mixture stirred at r.t. for 20 min. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M). The basic farctions were concentrated in vacuo, dissolved in Et₂0 (2mL) and HC1 in Et₂0 (5 drops) was added. The solvent was removed in vacuo to afford the title compound: RT = 0.70 min; mlz (ES⁺) = 479.50 [M+ H]⁺ (LCMS - Method 6).

Example 199: (3R,4S)-4-(2,5-Difluoro-phenyl)-l-(6-{(S)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyridin-3-yl)-pyrrolidin-3-ylamine dihydrochloride

To [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 78.9mg, 0.264mmol), 5-bromo-2-{(S)-l-[l-(3-isopropyl-[l,2,4]oxadiazol- 5 -yl)-piperidin-4-yl]-ethoxy} -pyridine (Preparation 244, 87.1mg, 0.220mmol), sodium tertiary butoxide (25.4mg, 0.264mmol) and biphenyl-2-yl(di-tert-butyl)phosphine (13.2mg, 44.1 μηιο1) in a sealed tube was added toluene (2mL, 20mmol). The reaction mixture was degassed with argon for 15 min prior to the addition of bis(dibenzylideneacetone)palladium (lO.lmg, 11.ΟμιηοΙ). The reaction mixture was degassed for a further 5 min and heated at 80°C for 40 h. Upon cooling, the reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M). The fractions were concentrated in vacuo, dissolved in DCM (8mL) and TFA (2mL) was added. The resulting reaction mixture was stirred at r.t. for 1 h. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M). The basic fractions were concentrated in vacuo and the remainder purified by column chromatography (DCM:MeOH; 98:2). The product was dissolved in Et₂0 (2mL) and HC1 in 1, 4-dioxane (0.2mL) was added. Removal of the solvent in vacuo afforded the title compound: RT = 2.80 min; mlz (ES⁺) = 513.3 [M+ H]⁺.

Example 200: (3R,45)-4-(2,5-Difluoro-phenyl)-l-(6-{(5)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-4-methyl-pyridin-3-yl)-pyrrolidin-3- ylamine dihydrochloride

The title compound was synthesised from [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin- 3-yl]carbamic acid tert-butyl ester (Preparation 48, 71.6mg, 0.24mmol)), and 5-bromo-2- {(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-4-methyl-pyridine (Preparation 245, 81.9mg, 0.20mmol) employing a procedure similar to that outlined in Example 199: RT = 2.65 min; mlz (ES⁺) = 527.3 [M+ H]⁺.

Example 201: (3R,45)-4-(2,5-Difluoro-phenyl)-l-(2-{(S)-l-[l-(3-isopropyl-

[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-5-yl)-pyrrolidin-3-ylamine dihydrochloride

The title compound was synthesised from 5-bromo-2-{(5)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidine (Preparation 238, HOmg, 0.28mmol) and [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 48, 99.4mg, 0.333mmol) employing a procedure similar to that outlined in Example 197: RT = 2.79 min; mlz (ES⁺) = 514.6 [M+ H]⁺. Example 202: (3R,4R)-4-(2,5-Difluoro-phenyl)-l-(5-{(5)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5- yl)-piperidin-4-yl]-ethox -pyrimidin-2-yl)-piperidin-3-ylamine hydrochloride

The title compound was synthesised from [(3i?,4i?)-4-(2,5-difluoro-phenyl)-l-(5- {(5)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-piperidin- 3-yl]-carbamic acid tert-butyl ester (Preparation 246, 85.0mg, 0.138mmol) employing a procedure similar to that outlined in Example 176: RT = 0.83 min; mlz (ES⁺) = 514.4 [M + H]⁺ (LCMS Method - 6).

Example 203: (3R,45)-l-(5-{(S)-l-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4- 4-methyl-pyridin-2-yl)-pyrrolidin-3-ylamine hydrochloride

A solution of [(3i?,45)-l-(5-{(5)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin- 4-yl]-ethoxy} -pyrimidin-2-yl)-4-(4-methyl-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert butyl ester (Preparation 247, 50mg, 84μιηο1) in HC1 in 1,4-dioxane (4M, 5mL, 20mmol) was stirred at r.t. for 16 h. The solvent was removed in vacuo, azeotroping with DCM (2 x) and Et₂0 (2 x) to afford the title compound: RT = 2.52 min; mlz (ES⁺) = 493.32 [M+ H]⁺.

Example 204: (3R,45)-4-(2,5-Difluoro-phenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)-piperidin-4-ylmethoxy]-6-methyl-pyridin-2-yl}-pyrrolidin-3-ylamine

dihydrochloride

A solution of ((3i?,45)-4-(2,5-difluoro-phenyl)-l-{5-[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)-piperidin-4-ylmethoxy]-6-methyl-pyridin-2-yl} -pyrrolidin-3-yl)-carbamic acid tert- butyl ester (Preparation 249, 40.0mg, 65.3μηιηιο1) in HC1 in 1,4-Dioxane (4M, lO.OmL, 40.0mmol) was stirred at r.t. for 2 h. The solvent was removed in vacuo and the remainder triturated with Et₂0 to afford the title compound: RT = 2.59 min; m/z (ES⁺) = 513.53 [M + H]⁺.

Example 205: (3R,45)-4-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxymeth l}-l-(5-chloro-pyrimidin-2-yl)-piperidin-3-ol

To a solution of [(3i?,45)-l-{5-[(3i?,45)-l-(5-chloro-pyrimidin-2-yl)-3-hydroxy- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 259, 55mg, 89μmol) in DCM (8mL) was added TFA (1.5mL) dropwise at 0°C. The resulting reaction mixture was stirred at r.t. for 2 h, then loaded onto an SCX cartridge eluting with MeOH, followed by NH₃ in MeOH (10%). The basic fractions were concentrated in vacuo to afford the title compound: RT = 2.68 min; m/z

Example 206: (3S,4R)-4-{2-[(3R,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxymeth l}-l-(5-chloro-pyrimidin-2-yl)-piperidin-3-ol

The title compound was synthesized from [(3i?,45)-l-{5-[(3S,4R)-l-(5-chloro- pyrimidin-2-yl)-3-hydroxy-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 260, 54mg, 87μιηο1) employing a procedure similar to that outlined in Example 205: RT = 2.70 min; m/z (ES ) = 518.21 [M + H]⁺.

Example 207: (3R,4S)-l-{5-[(3S,4R)-l-(5-Chloro-pyrimidin-2-yl)-3-methoxy-piperidin- 4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-ylamine

To a solution of (3_lS,4i?)-4-{2-[(3i?,45)-3-amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5-yloxymethyl}-l-(5-chloro-pyrimidin-2-yl)-piperidin-3-ol (Example 206, 62mg, O. lOmmol) in THF (lmL) was added NaH (60% dispersion in mineral oil, 6.0mg, 0.15mmol) and the resulting reaction mixture was stirred at r.t. for 10 min. Methyl iodide (50μί, 0.80mmol) was added and the reaction mixture stirred at r.t for 16 h. Further sodium hydride (60% dispersion in mineral oil, 6.0mg, 0.15mmol) and methyl iodide (50μί, 0.80mmol) were added and the reaction mixture stirred at r.t. for 2 h. Water was added cautiously to the reaction mixture and the product extracted into EtOAc (3 x). The combined organic extracts were wahed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by preparative HPLC afforded [(3 ?,45)-l-{5-[(35',4i?)-l-(5-chloro-pyrimidin-2- yl)-3-methoxy-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3- yl]-carbamic acid tert-butyl ester. The product was dissolved in DCM (5.0mL), cooled to 0°C and TFA (0.5mL) was added dropwise. The resulting reaction mixture was stirred at r.t. for 2 h, then loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (10%). The basic fractions were concentrated in vacuo and triturated with IH:Et₂0 (9: 1) to afford the title compound: RT = 2.98 min; mlz (ES⁺) = 532.15 [M+ H]⁺.

The following examples were prepared by reaction of the appropriate 4-{2-[(3R,4S)- 3-amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxymethyl}-l-(5-chloro- pyrimidin-2-yl)-piperidin-3-ol building block (Example 205 or Preparation 261 or

Preparation 262) with methyl iodide employing a procedure similar to that outlined in

Example 207:

Example 211: (3R,4S)-1 -{5- [(3R,4S)- l-(3-Isopropyl- [ 1 ,2,4] oxadiazol-5-yl)-3-methoxy- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

To a solution of [(3R,4S)-l-{5-[(3R,4S)-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-3- methoxy-piperidin-4-ylmethoxy]-pyri^

yl]-carbamic acid tert-butyl ester (Preparation 270, 28mg, 0.043mmol) in DCM (5mL) was added TFA (1.OmL) and the resulting reaction mixture stirred at r.t. for 2 h. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (10%) and the basic fraction concentrated in vacuo. The remainder was dissolved in DCM (lmL) and HC1 in Et₂0 (2mL) was added and the reaction mixture stirred for 5 min. The solvent was removed in vacuo to afford the title compound: RT = 0.85 min; mlz (ES⁺) = 548.49 [M+ H]⁺ (LCMS Method-6). Example 212: (3R,45)-l-{5-[(3S,4R)-l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-3-methoxy- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was synthesized from [(3R,4S)-l-{5-[(3S,4R)-l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-3-methoxy-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5- trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 271, 30mg, 0.046mmol) employing a procedure similar to that outlined in Example 211: RT = 0.83 min; mlz (ES⁺) = 548.53 [M+ H]⁺ (LCMS Method-6). Example 213: (3R,4S)-l-(5-{(S)-l-[l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4-(2-fluoro-5-fluorometh l-phenyl)-pyrrolidin-3-ylamine

To a solution of [(3 ?,45)-4-(2-fluoro-5-fluoromethyl-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester (Preparation 278, lO.lmg, 32.3 μί) and 2-chloro-5-{(5)-l-[l- (3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation 102, 10.9mg, 32.3μηιο1) in DMSO (0.2mL) in a sealed tube was added DBU (5uL, 32.3mmol) and the resulting reaction mixture was stirred at 80°C for 84 h. The reaction mixture was poured into water (25mL) and extracted with EtOAc (3 x 40mL). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purifictaion by column chromatography (DCM:MeOH; 99: 1 to 97: 1) afforded [(3R,4S)-l-(5-{(S)-l-[l-(3- ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2-fluoro-5- fluoromethyl-phenyl)-pyrrolidin-3-yl] -carbamic acid fert-butyl ester. The product was dissolved in 1,4-dioxane (ImL), cooled to 0°C and HCl in 1,4-dioxane was added (4M, ImL). The resulting reaction mixture was stirred at 0°C for 1 h, prior to the addition of further HCl in 1,4-dioxane (4M, ImL). After stirring at r.t. for 4 h, the reaction mixture was concentrated in vacuo, the remainder dissolved in DCM (50mL) and washed with saturated aqueous Na₂C0₃ solution (50mL), dried (MgS0₄), filtered and concentrated in vacuo.

Purification by column chromatography (DCM:MeOH; 97:3) afforded the title compound: RT = 0.82 min; mlz (ES⁺) = 514.48 [M+ H]⁺ (LCMS Method-6).

Example 214: (3R,4S)-4-(2,4-Difluoro-5-methyl-phenyl)-l-(5-{(5)-l-[l-(3-ethyl-

[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-ylamine hydrochloride

To a solution of 2-chloro-5-{(5)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethoxy}pyrimidine (Preparation 102, lOOmg, 0.3mmol) in DMSO (2mL) was added [(3i?,45)-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 292, 0.139g, 0.444mmol) and DBU (44.3 μ, 0.296mmol) and the resulting reaction mixture was stirred at 85°C for 89 h. Upon cooling, the reaction mixture was partitioned between EtOAc (50mL) and water (30mL) and the organic layer was separated, washed with brine (30mL) and concentrated in vacuo. The reminder was purified by preparative HPLC to afford [(5R,4S)-4-(2,4-difluoro-5-methyl-phenyl)-l-(5-{(S)-l-[l-(3- ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester. The compound was dissolved in DCM (5mL), TFA (500μί, 6mmol) was added and the resulting reaction mixture was stirred at r.t. for 3 h. The solvent was removed in vacuo and the remainder purified by preparative HPLC. The product was loaded onto an SCX cartridge in MeOH and eluted with MeOH, followed by NH₃ in MeOH (2M). The basic fractions were concentrated in vacuo, the remainder dissolved in DCM and HC1 in 1,4-dioxane (ΙΟΟμί) was added. The solvent was removed in vacuo, azeotroping with MeOH (2 x 2mL) to afford the title compound: RT = 0.83 min; mlz (ES⁺) = 514.49 [M + H]⁺ (LCMS Method-6). Example 215: (3R,45)-l-(5-{(S)-l-[(3R,4S)-l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-3- methoxy-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- 3-ylamine hydrochloride

To a solution of 2-chloro-5-{(5)-l-[(cz5)-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-3- methoxy-piperidin-4-yl]-ethoxy}-pyrimidine (Preparation 298, 50mg, O. lmmol) and

[(3i?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 62.1mg, 0.196mmol) in DMSO (lmL) was added DBU (19.6μί, 0.131mmol) and the resulting reaction mixture was heated at 85°C for 89 h. Upon cooling, the reaction mixture was partitioned between EtOAc (50mL) and water (30mL) and the organic layer was separated, washed with brine (30mL) and concentrated in vacuo. Purification by preparative HPLC afforded [(3R,4S)- 1 -(5- {(S)-l -[(cis)- 1 -(3-isopropyl-[ 1 ,2,4]oxadiazol-5-yl)-3-methoxy- piperidin-4-yl]-ethoxy} -pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. Purification by chiral HPLC (MTBE:MeOH; 90:10, 15ml/min, 250nm) afforded [(3R,4S)- 1 -(5- {(S)- 1 -[(3R,4S)- 1 -(3-isopropyl-[ 1 ,2,4]oxadiazol-5-yl)-3-methoxy- piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyiTolidin-3-yl]-carbamic acid tert-butyl ester. The product was dissolved in DCM (lmL) and HC1 in 1,4-dioxane (4M, ΙΟΟμί) was added. The reaction mixture was allowed to stand at r.t. for 3 h and the solvent removed in vacuo, azeotroping from MeOH (3 x 1 mL), to afford the title compound: RT = 0.84 min; mlz (ES⁺) = 562.50 [M + H]⁺ (LCMS Method-6). Example 216: (3R,45)-l-(5-{(S)-l-[(3S,4R)-l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-3- methoxy-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- 3-ylamine hydrochlorid

The title compound was prepared from 2-chloro-5- {(5)-l -[(cz^'s)-l-(3-isopropyl- [l ,2,4]oxadiazol-5-yl)-3-methoxy-piperidin-4-yl]-ethoxy}-pyrimidine (Preparation 298, 50mg, O. lmmol) and [(3 ?,45)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert- butyl ester (Preparation 39) employing the procedure outlined in Example 215: RT = 0.83 min; mlz (ES⁺) = 562.51 [M + H]⁺ (LCMS Method-6).

Example 217: (3R,45)-1 -{5- [ l-(3-Ethyl- [ 1 ,2,4] oxadiazol-5-yl)-4-methoxy-piperidin ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine

hydrochloride

To a solution of 2-chloro-5-[l -(3-ethyl-[l ,2,4]oxadiazol-5-yl)-4-methoxy-piperidin- 4-ylmethoxy]-pyrimidine (Preparation 303, 0.103g, 0.29mmol) and [(3R,4S)-4-(2,4,5- trifluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 39, 0.138g, 0.435mmol) in DMSO (2mL) was added DBU (48μί, 0.319mmol). The resulting reaction mixture was heated to 85°C and stirred for 19 h. Upon cooling, the reaction mixture was partitioned between EtOAc (20mL) and water (lOmL), then the organic layer separated, washed with brine and concentrated in vacuo. The remainder was purified by preparative

HPLC, then dissolved in 1 ,4-dioxane (2mL) prior to the addition of HC1 in 1 ,4-dioxane (4M, 2mL, 8mmol). The reaction mixture was stirred at r.t. for 4 h and the solvent removed in vacuo. The remainder was purified by preparative HPLC and the crude product partitioned between DCM (20mL) and saturated aqueous NaHC0₃ solution (lOmL). The organic layer was separated, concentrated in vacuo and the remainder dissolved in DCM (lmL) prior to the addition of HC1 in 1,4-dioxane (4M, ΙΟΟμί). The solvent was removed in vacuo, azeotroping with MeOH (2 x 2mL), to afford the title compound: RT = 0.77 min; mlz (ES ) = 534.50 [M+ H]⁺ (LCMS Method-6).

Example 218: (3R,45)-1 -{5- [ l-(3-Ethyl- [ 1 ,2,4] oxadiazol-5-yl)-4-fluoro-piperidin-4- ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine

hydrochloride

The title compound was synthesized from 2-chloro-5-[l-(3-ethyl-[l,2,4]oxadiazol-5- yl)-4-fluoro-piperidin-4-ylmethoxy]-pyrimidine (Preparation 306, 0.137g, 0.401mmol) employing a procedure similar to that outlined in Example 217: RT = 0.79 min; mlz (ES ) = 522.48 [M+ H]⁺ (LCMS Method-6).

Example 219: (3R,45)-4-(2,5-Difluoro-phenyl)-l- {6- [1 -(3-isopr opyl- [ 1 ,2,4] oxadiazol-5- yl)-piperidin-4-ylmethox ]-pyridin-3-yl}-pyrrolidin-3-ylamine

The title compound was synthesized from ((3S,4R)-4-(2,5-difluoro-phenyl)-l-{6-[l- (3-isopropyl-[ 1 ,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-pyridin-3-yl} -pyrrolidin-3-yl)- carbamic acid tert-butyl ester (Preparation 308, 60mg, O.lmmol) employing a procedure similar to that outlined in Example 205: RT = 2.80 min; mlz (ES⁺) = 499.31 [M+ H]⁺.

Example 220: 2-[(3R,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-5-{(S)-l-[l- (3-ethyl-[l,2,4]oxadiazol-5- l)-piperidin-4-yl]-ethoxy}-pyrimidine-4-carbonitrile

To a solution of [(3i?,45)-l-(4-cyano-5-hydroxy-pyrimidin-2-yl)-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 314, 20.0mg,

47.9μηιο1) and methanesulfonic acid (i?)-l-[l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin-4- yl]ethyl ester (Preparation 101, 17.4mg, 57.5μmol) in DMF (3mL) was added potassium carbonate (18.7mg, 0.12mmol) and the resulting reaction mixture was heated at 90°C for 66 h. Upon cooling, the reaction mixture was partitioned between H₂0 (20mL) and EtOAc

(50mL). The layers were separated and the aqueous extracted with EtOAc (2 x 20mL). The combined organic extracts were washed with brine (50mL), dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by column chromatography

(DCM:MeOH; 1 :0 to 5:95) and the crude product dissolved in DCM (lOmL). TFA (5mL) was added and the reaction mixture stirred at r.t .for 30 min. The reaction mixture was added to an SCX cartridge, eluting with MeOH, followed by ammonium hydroxide in methanol (7.5%). The basic fractions were concentrated in vacuo and purified by preparative HPLC (Basic method) to afford the title compound: RT = 2.88 min; mlz (ES⁺) = 525.26 [M+ H]⁺. Example 221: 2-[(3R,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-5-[l-(3- isopropyl-[l,2,4]oxadiazol-5- l)-piperidin-4-ylmethoxy]-pyrimidine-4-carbonitrile

The title compound was synthesized from [(3i?,45)-l-(4-cyano-5-hydroxy-pyrimidin- 2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 314, 25mg, 59.9μιηο1) and methanesulfonic acid-l-(3-ethyl-[l,2,4]oxadiazol-5-yl)piperidin- 4-ylmethyl ester (Preparation 52, 21.8mg, 0.0719mmol) employing a procedure similar to that outlined in Example 220: RT = 2.92 min; mlz (ES⁺) = 525.23 [M+ H]⁺.

Example 222: (3R,4S)-4-(2-Fluoro-5-methyl-phenyl)-l-(5-{(S)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-pi eridin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-ylamine

To a solution of [(3i?,45)-4-(2-fiuoro-5-methyl-phenyl)-l-(5-{(5)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 315, 45mg, 74μηιο1) in MeOH (lmL) was added HC1 in Et₂0 (2M, 5mL) and the resulting reaction mixture was stirred at r.t. for 120 h. The solvent was removed in vacuo and the remainder purified by preparative HPLC (Basic method) to afford the title compound: RT = 2.88 min; mlz (ES⁺) = 510.33 [M+ H]⁺.

Example 223: (3R,45)-l-(5-{l-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-2- methoxy-ethoxy}-pyrimi in-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3yl-amine

The title compound was synthesized from [(3 ?, S)-l-(5-{l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-2-methoxy-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 317, 466mg,

0.704mmol) employing a procedure similar to that outlined in Example 205: RT = 2.84 min; mlz (ES⁺) = 562.21 [M+ H]⁺. Example 224: (3R,45)-l-(5-{(R)-l-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- 2-methoxy-ethoxy}-pyrimi in-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine

The title compound was synthesised from (3i?,45)-l-(5-{l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-2-methoxy-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-3yl-amine (Example 223) via chiral HPLC (MTBE:MeOH:BA;

50:50:0.1, 17ml/min, 250nm): RT = 2.84 min; mlz (ES⁺) = 562.21 [M+ H]⁺.

Example 225: (3R,45)-l-(5-{S)-l-[l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- 2-methoxy-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine

The title compound was synthesised from (3i?,45)-l-(5-{l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-2-methoxy-ethoxy}-pyrimidin-2-yl)-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-3yl-amine (Example 223) via chiral HPLC (MTBE:MeOH:BA;

50:50:0.1, 17ml/min, 250nm): RT = 2.84 min; mlz (ES⁺) = 562.21 [M+ H]⁺.

Example 226: 4-((R)-l-{2-[(3R,45)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxy}-2-m thoxy-ethyl)-piperidine-l-carboxylic acid benzyl ester

The title compound was synthesised from 4-((i?)-l-{2-[(3i?,45)-3-fert- butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-2- methoxy-ethyl)-piperidine-l-carboxylic acid benzyl ester (Preparation 322, 6.3mg, 9.2μmol) employing a procedure similar to that outlined in Example 205: RT = 0.90 min; mlz (ES⁺) = 586.5 [M+ H]⁺ (LCMS Method-6). The stereochemistry of * centre has been arbitrarily assigned.

Example 227: l-((lS,25)-2-Amino-4-{5-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin- 4-ylmethoxy] -4-methyl-p rimidin-2-yl}-cyclopentyl)-5,5-difluoro-piperidin-2-one

To a solution of ((15',25)-2-(5,5-difluoro-2-oxo-piperidin-l-yl)-4-{5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-4-methyl-pyrimidin-2-yl}-cyclopentyl)- carbamic acid tert-butyl ester (Preparation 323, 150mg, 0.24mmol) in DCM (2mL) was added HC1 in dioxane (4M, 5mL) and the resulting reaction mixture stirred at r.t. for 16 h. The solvent was removed in vacuo and the remainder dissolved in DCM and basified with aqueous NaOH (2M). The organic layer was separated, dried (MgS0₄), filtered and concentrated in vacuo. Purification by preparative HPLC afforded the title compound: RT = 2.70 min; mlz (ES⁺) = 535.16 [M+ H]⁺. Example 228: (3R,4S)-4-(2,5-Difluoro-phenyl)-l-(5-{(S)-l-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-4-methyl-pyrimidin-2-yl)-pyrrolidin-3- ylamine hydrochloride

To a solution of [(3i?,45)-4-(2,5-dfluoro-phenyl)-l-(5-{(5)-l-[l-(3-isopropyl-

[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy} -4-methyl-pyrimidin-2-yl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester (Preparation 324,125mg, 0.199mmol) in DCM (1.5mL) was added HCl in 1,4-dioxane (4M, 5mL) and the resulting reaction mixture was stirred at r.t. for 16 h. The solvent was removed in vacuo and the residue triturated with Et₂0 to afford the title compound: RT = 3.12 min; m/z (ES⁺) = 528.36 [M+ H]⁺.

Example 229: (3R,45)-4-(5-Chloro-2-fluoro-phenyl)-l-{5-[l-(3-isopropyl-

[l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-ylamine tosylate

To a solution of (3i?,45)-4-(5-chloro-2-fluoro-phenyl)-pyrrolidin-3-ylamine

(Preparation 326, 210mg, 0.98mmol) and 2-choro-5-[l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)piperidin-4-ylmethoxy]pyrimidine (Preparation 2, 220mg, 0.67mmol) in DMSO (2mL) was added DBU (99.8μί, 0.667mmol) and the resulting reaction mixture was stirred at 90°C for 120 h. Upon cooling, the reaction mixture was added to water (200mL) and brine

(lOOmL) and extracted with EtOAc (4 x lOOmL). The combined organic extracts were washed with brine, dried (MgS0₄), filtered and reduced in vacuo to ~50mL. Oi-tertiary-butyl dicarbonate (500mg, 2.29mmol) was added and the reaction mixture stirred at r.t. for 16 h. The solvent was removed in vacuo and the residue purified by column chromatography (IH:EtOAc; 3:2). Purification by chiral HPLC (MeOH:IH:THF; 80: 17:3, 12ml/min, 250nm, RT = 4.55 min) afforded ((3i?,45)-4-(5-chloro-2-fluoro-phenyl)-l-{5-[l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester. To a solution of this compound in DCM (8mL) was added TFA (2mL) and the reaction mixture was stirred at r.t. for 2h. The solvent was removed in vacuo and the residue dissolved in EtOAc, washed with NaOH solution (50mL) and brine (50mL), dried (MgS0₄), filtered and concentrated in vacuo. The remainder was dissolved in EtOAc (2mL) and MeOH (lmL) and TsOH (30mg, 0.16mmol) was added. The solvent was removed in vacuo to afford the title compound: RT = 2.84 min; mlz (ES ) = 516.2 [M+ H]⁺.

Example 230: (3R,4S)-4-(2,5-Difluoro-phenyl)-l-{5-[l-(5-methoxy-pyrimidin-2-yl)- piperidin-4-ylmethoxy]- rimidin-2-yl}-pyrrolidin-3-ylamine

To a solution of (3i?,45)-4-(2,5-difluorophenyl)-l-[5-(piperidin-4- ylmethoxy)pyrimidin-2-yl]pyrrolidin-3-ylamine (Preparation 64, 45mg, 0.12mmol) in DMSO (lmL) was added 2-chloro-5-methoxypyrimidine (50mg, 0.35 mmol) and DBU (21mg, 0.14mmol). The resulting reaction mixture was heated under microwave irradiation at 100°C for 90 min.Upon cooling, the reaction mixture was diluted with DCM and washed with water. The organic extract was loaded onto a phosphonic acid SCX cartridge, eluting with MeOH, followed by NEt₃/MeOH (2%). The basic fraction was concentrated in vacuo and purified by preparative HPLC to afford the title compound: RT = 2.72 min; mlz (ES ) =

The following examples were prepared by reacting (3i?,45)-4-(2,5-difluorophenyl)-l- [5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]pyrrolidin-3-ylamine (Preparation 64) with the appropriate chloro or bromo heteroaryl building block employing a procedure similar to that outlined in Example 230:

Example 235: (3R,4S)-l-[5-(l-Benzothiazol-2-yl-piperidin-4-ylmethoxy)-pyrimidin-2- yl]-4-(2,5-difluoro-phen l)-pyrrolidin-3-ylamine

To a solution of {(3i?,45)-4-(2,5-difluorophenyl)-l-[5-(piperidin-4- ylmethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid tert-butyl ester (Preparation 140, 48.9mg, O. lmmol) in DMSO (lmL) was added 2-chloro-l,3-thiazole-5-carbonitrile (25.4mg, 0.15mmol) and DBU (22mg, 0.15mmol) and the resulting reaction mixture was heated under microwave irradiation at 100 °C for 30 min. The reaction mixture was diluted with DCM and washed with water. The organic extract was dried (MgSC^), filtered and concentrated in vacuo. The remainder wasa purified by preparative HPLC and dissolved in DCM (4 ml). TFA (1 ml) was added and the reaction mixture stirred at r.t. for 2 h, then loaded onto an SCX cartridge eluting with MeOH, followed by NH₃ in MeOH (10%). The basic fractions were concentrated in vacuo to afford the title compound: RT = 2.80 min; m/z (ES ) = 523.24 [M+ H]⁺.

Example 236: 2-(4-{2-[(3R,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxymeth l}-piperidin-l-yl)-thiazole-5-carbonitrile

The title compound was synthesized from {(3i?,45)-4-(2,5-difluorophenyl)-l-[5- (piperidin-4-ylmethoxy)pyrimidin-2-yl]pyrrolidin-3-yl}carbamic acid tert-butyl ester

(Preparation 140) and 2-chloro-l,3-thiazole-5-carbonitrile employing a procedure similar to that outlined in Example 235: RT = 2.75 min; m/z (ES⁺) = 498.16 [M+ H]⁺.

Example 237: 4-{2-[(3R,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxymethyl}-piperidine-l-carboxylic acid benzyl ester

The title compound was synthesised from 4-{2-[(3i?,45)-3-tert- butoxycarbonylamino-4-(2,5-difluorophenyl)pyrrolidin-l-yl]pyrimidin-5- yloxymethyl}piperidine-l-carboxylic acid benzyl ester (Preparation 139) employing a procedure similar to that outlined in Example 205: RT = 2.93 min; mlz (ES⁺) = 524.22 [M + H]⁺.

Example 238: 4-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxymeth l}-piperidine-l-carboxylic acid 2-isopropoxy-ethyl ester

To a solution of 2-isopropoxy-ethanol (0.3 mmol) in DCM (1ml) was added a solution of triphosgene (0.1 mmol) in DCM, followed by pyridine (0.41 mmol). After stirring at r.t. for 20 min the solution was added to a stirred solution of {(3i?,45)-4-(2,5- difluorophenyl)- 1 -[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid tert-butyl ester (Preparation 140, 48.9mg, 0.1 mmol) in DCM (1ml). The solution was stirred at r.t. for 16 h, diluted with DCM , washed with water, dried (MgS0₄), filtered and concentrated in vacuo. The reainder was purified by prepartive HPLC and dissolved in DCM (4 ml). TFA (1ml) was added and the reaction mixture stirred at r.t. for 2 h, prior to loading onto an SCX cartridge. The cartridge was eluted with MeOH, followed by NH₃ in MeOH (10%) and the basic fractions concentrated in vacuo to afford the title compound: RT = 2.72 min; mlz (ES⁺) = 520.25 [M + H]⁺.

Example 239: 4-{2-[(3R,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxymethyl}-piperidine-l-carboxylic acid (S)-2-methoxy-l-methyl-ethyl ester

The title compound was synthesized from {(3i?,45)-4-(2,5-difluorophenyl)-l-[5- (piperidin-4-ylmethoxy)pyrimidin-2-yl]pyrrolidin-3-yl} carbamic acid tert-butyl ester (Preparation 140) and (S)-l-methoxypropan-2-ol employing a procedure similar to that outlined in Example 238: RT = 2.67 min; mlz (ES⁺) = 506.24 [M+ H]⁺.

Example 240: (3R,4S)-l-(5-{(5)-l-[l-(3-Ethyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-ylamine

hydrochloride

The title compound was synthesised from [(3i?,45)-l-(5-{(5)-l-[l-(3-ethyl- [l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidin-2-yl)-4-(2-fluoro-5-methyl- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 237) employing a procedure similar to that outlined in Example 228: RT = 2.80 min; mlz (ES⁺) = 496.23 [M +

H]⁺.

Example 241: (3R,45)-l-(5-{2-[l-(5-Chloro-pyrimidin-2-yl)-piperidin-4-yl]-ethyl}- pyrimidin-2-yl)-4-(2,5-difluoro- henyl)-pyrrolidin-3-ylamine

To a solution of [(3i?,45)-l-(5-{2-[l-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]- ethyl} -pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 332, 69mg, 0.115mmol) in DCM (2mL) was added TFA (0.3mL) and the resulting reaction mixture was stirred at r.t for 90 min. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M) and the basic fraction concentrated in vacuo. The remainder was purified by column chromatography (DCM:MeOH; 97:3) and further purified by preparative HPLC. Purification by chiral HPLC (MTBE:MeOH:THF:BA; 60:20:20:0.1 , 12.5 ml/min, 250nm, RT = 8.3 min) afforded the title compound: RT = 3.02 min; mlz (ES⁺) =500.16 [M+ H]⁺. Example 242: (3R,4S)-4-(2,5-Difluoro-phenyl)-l-(5-{2-[l-(3-isopropyl-[l,2,4]oxadiazol- 5-yl)-piperidin-4-yl]-eth l}-pyrimidin-2-yl)-pyrrolidin-3-ylamine hydrochloride

To a solution of [(3i?,45)-l-{5-[2-(l-cyano-piperidin-4-yl)-ethyl]-pyrimidin-2-yl}-4- (2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 333, 69mg, 0.135mmol) in EtOH (5mL) was added N-hydroxyisobutyramidine (17mg,

0.162mmol) followed by dropwise addition of zinc dichloride in Et₂0(lM, 0.162mL, 0.162mmol) and the resulting reaction mixture was stirred at r.t. for 16 h. HC1 in 1,4- dioxane (4M, 0.168mL, 0.673mmol) was added and the reaction mixture heated at 70°C for 9 h. Upon cooling, the reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M) and the basic fractions were concentrated in vacuo. The remainder was purified by preparative HPLC and loaded onto a SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M) and the basic fractions were concentrated in vacuo. The remainder was dissolved in MeOH (lmL), HC1 in Et₂0 (2M, 50μί) was added and the solution was stirred at r.t. for 15 min. The solvent was removed in vacuo to afford the title compound: RT = 0.86 min; m/z (ES⁺) = 498.5 [M+ H]⁺ (LCMS Method-6).

Example 243: (3R,45)-l-{5-[(3S,4R)-3-Fluoro-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

To a solution of [(3i?,45)-l-{5-[(3^,4i?)-3-fluoro-l-(3-isopropyl-[l,2,4]oxadiazol-5- yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester (Preparation 337, 27mg, 0.042mmol) in DCM (2mL) was added TFA (98.2μΕ, 1.27mmol) and the resulting reaction mixture was stirred at r.t. for 6 h. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M) and the basic fractions were concentrated in vacuo. The remainder was dissolved in MeOH (lmL) and HC1 in Et₂0 (2M, 50μΕ) was added. After 10 min, the solvent was removed in vacuo to afford the title compound: RT = 0.87 min; m/z (ES⁺) = 536.4 [M+ ] (LCMS Method-6).

Example 244: (3R,45)-l-{5-[(3R,4S)-3-Fluoro-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was synthesized from [(3i?,45)-l-{5-[(3i?,45)-3-fluoro-l-(3- isopropyl-[l,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 336) employing a procedure similar to that outlined in Example 243: RT = 0.87 min; m/z (ES⁺) = 536.4 [M + H]⁺ (LCMS Method-6).

Example 245: (3R,45)-l-{5-[(3R,4R)-l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-3-methyl- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

To a solution of [(3 ?,45)-l-{5-[(cz5)-l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)-3-methyl- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 340, 92mg, 0.14mmol) in DCM (4mL) was added TFA (33.7μΙ.) and the resulting reaction mixture was stirred at r.t. for 4 h. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (7M) and the basic fractions were concentrated in vacuo. The remainder was dissolved in THF (2mL) and HC1 in Et₂0 (2M) was added. The solvent was removed in vacuo and the remainder purified by chiral HPLC (MeCN:MeOH:BA; 50:50:0.1, 15ml/min, 250nm). The compound was dissolved in MeOH (lmL), HC1 in Et₂0 (2M, 50μί) was added and the solution was stirred at r.t. for 15 min. The solvent was removed in vacuo to afford the title compound: RT = 0.91 min; m/z (ES⁺) = 532.4 [M+ H]⁺ (LCMS Method-6). Example 246: (3R,4S)-l-{5-[(3S,4S)-l-(3-Isopropyl-[l,2,4]oxadiazol-5-yl)-3-methyl- piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was synthesised from [(3i?,45)-l-{5-[(cz5)-l-(3-isopropyl- [l,2,4]oxadiazol-5-yl)-3-methyl-piperidin-4-ylmethoxy]-pyrimidin-2-yl}-4-(2,4,5-trifluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 340, 92mg, 0.14mmol) employing the procedure outlined in Example 245: RT = 0.90 min; m/z (ES ) = 532.4 [M + H]⁺ (LCMS Method-6).

Example 247: (3R,45)-l-[5-((S)-l-{l-[(R)-3-(Tetrahydro-furan-3-yl)-[l,2,4]oxadiazol-5- yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3- ylamine hydrochloride

The title compound was synthesised from [(3i?,45)-l-[5-((5)-l-{l-[(5)-3-(tetrahydro- furan-3-yl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-fri phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 341) employing a procedure similar to that outlined in Example 243: RT = 0.81 min; m/z (ES⁺) = 560.4 [M + H]⁺ (LCMS Method-6).

Example 248: (3R,45)-l-[5-((S)-l-{l-[(S)-3-(Tetrahydro-furan-3-yl)-[l,2,4]oxadiazol-5- yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3- ylamine hydrochloride

The title compound was synthesised from [(3i?,45)-l-[5-((5)-l-{l-[(i?)-3-(tetrahydro- furan-3-yl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-fri phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 342) employing a procedure similar to that outlined in Example 243: RT = 0.81 min; mlz (ES⁺) = 560.4 [M + H]⁺ (LCMS Method-6). Example 249: 2-{2-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5- loxy}-ethyl)-piperidin-l-yl]-oxazol-4-yl}-propan-2-ol tosylate

To a solution of 2-[4-((5)-l-{2-[(3i?,45)-3-tert-butoxycarbonylamino-4-(2,5-difluoro- phenyl)-pyrrolidin-l -yl]-pyrimidin-5-yloxy} -ethyl)-piperidin- 1 -yl]-oxazole-4-carboxylic acid ethyl ester (Preparation 343, 0.203g, 0.316mmol) in anhydrous THF (3mL), cooled to - 30°C under argon, was added methylmagnesium bromide (3M in Et₂0, 0.527mL, 1.58mmol) and the resulting reaction mixture was stirred at -30°C for 2 h. The reaction mixture was quenched with saturated aqueous NH₄C1 solution (5mL) and warmed to r.t. The reaction mixture was partitioned between EtOAc (25mL) and saturated aqueous NH₄CI solution (20mL). The organic layer was separated, washed with brine (25mL), passed through a hydrophobic frit and concentrated in vacuo. The remainder was purified by preparative HPLC and then dissolved in DCM (1.5mL). TFA (0.5mL, 6mmol) was added and the reaction mixture stirred at r.t. for 90 min. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH3 in MeOH (7M) and the basic fractions were concentrated in vacuo. The remainder was purified by column chromotogrpahy (DCM:7M NH₃/MeOH; 1 :99 to 2:99 to 3:99) and then dissolved in MeOH (lmL). TsOH (25mg, 0.13mmol) in MeOH (0.5mL) was added and the solvent removed in vacuo to afford the title compound: RT = 0.68 min; mlz (ES⁺) = 529.41 [M+ H]⁺ (LCMS Method-6). Example 250: (5)-2-{5-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-butan- 2-ol tosylate

To a solution of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-((5)-l-{l-[3-(l-hydroxy-l- methyl-propyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-py^ yl} -carbamic acid tert-butyl ester (Preparation 346, lOOmg, 0.156mmol) in DCM (2mL) was added TFA (0.5mL) and the resulting reaction mixture was stirred at r.t. for 1 h. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (2M) and the basic fractions were concentrated in vacuo. The remainder was purified by chiral HPLC (MeCN:MeOH:THF:BA; 60:20:20:0.05, 13ml/min, 250nm) and loaded in MeOH onto an SCX cartridge, eluting with MeOH, followed by NH₃ in MeOH (2M). The basic fractions were concentrated in vacuo, the remainder redissolved in MeOH and TsOH (1 equivalent) added. The solvent was removed in vacuo to afford the title compound: RT = 0.78 min; m/z (ES⁺) = 544.48 [M+ H]⁺ (LCMS Method-6).

Example 251: (R)-2-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-butan- 2-ol tosylate

The title compound was synthesized from {(3 ?,45)-4-(2,5-difluoro-phenyl)-l-[5-((5)- l-{l-[3-(l-hydroxy-l-methyl-propyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3-yl} -carbamic acid tert-butyl ester (Preparation 346)

employing the procedure outlined in Example 250: RT = 0.77 min; m/z (ES⁺) = 544.48 [M + H]⁺ (LCMS Method-6).

Example 252: (5)-l-{5-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-l- cyclopropyl-ethanol tos late

[(3R,4S)- 1 - [5 -((S)- 1 - { 1 - [3 -((S)- 1 -cyclopropyl- 1 -hydroxy-ethyl)- [ 1 ,2,4]oxadiazol-5 - yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-pyrrolodin-3-yl]- carbamic acid tert-butyl ester was isolated from [(3i?,45)-l-[5-((5)-l-{l-[3-(l-cyclopropyl-l- hydroxy-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,5- difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 347, 136mg, 0.208mmol) via chiral HPLC: (IH:MeOH:THF; 60:30: 10, 18ml/min, 250nm). The compound was dissolved in DCM (2mL), TFA (0.5mL) was added and the reaction mixture stirred at r.t. for 1 h. The reaction mixture was loaded onto an SCX cartridge, eluting with MeOH, followed by N¾ in MeOH (2M) and the basic fractions were concentrated in vacuo. The remainder was dissolved in MeOH and TsOH (1 equivalent) was added. The solvent was removed in vacuo to afford the title compound: RT = 0.80 min; mlz (ES⁺) = 556.45 [M + H]⁺ (LCMS Method-6). Example 253: (R)-l-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-l- cyclopropyl-ethanol tos late

The title compound was synthesised from [(3i?,45)-l-[5-((5)-l-{l-[3-(l-cyclopropyl- l-hydroxy-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,5- difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 347)

employing the procedure outlined in Example 252: RT = 0.80 min; mlz (ES⁺) = 556.45 [M + H]⁺ (LCMS Method-6). Example 254: 2-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-2-methyl-propan-l- ol hydrochloride

To a solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2- yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 205, 0.150g, 0.284mmol) and 3,N-dihydroxy-2,2-dimethyl-propionamidine (Preparation 349, 45.0mg, 0.340mmol) in EtOH (5mL) was added dropwise a solution of dichlorozinc

(38.7mg, 0.284mmol) in EtOH (lmL) and the resulting reaction mixture was stirred at r.t. for 3 h. HCl in 1,4-dioxane (4M, 0.2mL, 0.6mmol) was added and the reaction mixture heated at 80°C for 5 h. The solvent was removed in vacuo and the remainder neutralized with saturated aqueous NaHC0₃ solution and extracted with EtOAc (3 x 50mL). The combined organic extracts were washed with brine, dried (MgSC^), filtered and concentrated in vacuo and the remainder purified by preparative HPLC. The product was dissolved in MeOH (0.5mL) and HC1 in Et₂0 (2.5M, 25μί, 0.050mmol) was added. The reaction mixture was stirred at r.t. for 10 min and the solvent removed in vacuo to afford the title compound: RT = 0.79 min; mlz (ES⁺) = 544.45 [M+ H]⁺ (LCMS Method-6).

Example 255: 2-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-2-methyl-propan- l-ol hydrochloride

The title compound was synthesised from [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4- yl)-ethoxy]-pyrimidin-2-yl} -4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 206) and 3,N-dihydroxy-2,2-dimethyl-propionamidine

(Preparation 349) employing a procedure similar to that outlined in Example 254: RT = 0.80 min; mlz (ES⁺) = 562.44 [M+ H]⁺ (LCMS Method-6).

Example 256: 2-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5- loxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-propan-2-ol tosylate

The title compound was synthesised from {(3R,4S)-4-(2,5-difluoro-phenyl)-l-[5-((S)- l-{l-[3-(l-hydroxy-l-methyl-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 350)

employing a procedure similar to that outlined in Example 134: RT = 0.76 min; mlz (ES ) = 530.46 [M+ H]⁺ (LCMS Method-6). Example 257: 2-{5-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,4-difluoro-5-methyl-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}- propan-2-ol hydrochlori

The title compound was synthesized from {(3i?,45)-4-(2,4-difluoro-5-methyl- phenyl)- 1 -[5-((S)-l - { 1 -[3 -(1 -hydroxy- 1 -methyl-ethyl)- [ 1 ,2,4]oxadiazol-5 -yl] -piperidin-4- yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester (Preparation 354) employing a procedure similar to that outlined in Example 243: RT = 0.90 min; m/z (ES⁺) = 544.44 [M+ H]⁺ (LCMS Method-6).

Example 258: l-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-cyclopropanol hydrochloride

To a solution of 4-fiuoro-benzoic acid l-{5-[4-((5)-l-{2-[(3i?,45)-3-tert- butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)- piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-cyclopropyl ester (Preparation 358, 0.121g, 0.161mmol) in THF (5.0mL), MeOH (2.50mL) and H₂0 (2.50mL) was added lithium hydroxide monohydrate (27.1mg, 0.646mmol) and the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was acidified with 2M HCl and the solvent removed in vacuo. The remainder was dissolved in DCM (lOmL) and the resulting solution cooled to 0°C prior to the dropwise addition of TFA (1.5mL, 19mmol). The reaction mixture was stirred at r.t. for 2 h, diluted with DCM (lOOmL), washed with saturated aqueous NaHC0₃ solution (2 x), passed through a hydrophobic frit and concentrated in vacuo. The remainder was purified by column chromatography (DCM MeOH; 9: 1). The product was dissolved in MeOH (0.5mL), HCl in Et₂0 (2M, 21 xL, 54μιηο1) was added and the reaction mixture stirred at r.t. for 10 min. The solvent was removed in vacuo to afford the title compound: RT = 0.76 min; mlz (ES⁺) = 528.38 [M+ H]⁺ (LCMS Method-6). Example 259: 4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxy}-ethyl)- iperidine-l-carboxylic acid amide

To a solution of [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)-ethoxy]-pyrimidin-2- yl}-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 206, 0.250g, 0.457mmol) and 2,N-dihydroxy-propionamidine (57mg, 0.55mmol) in EtOH (17mL) was added a solution of zinc dichloride (62mg, 0.46mmol) in EtOH (17mL) and the resulting reaction mixture was stirred at r.t. for 4 h. HCl in 1,4-dioxane (4M, 0.572mL, 2.29mmol) was added and the reaction mixture heated at 80°C for 1 h. The solvent was removed in vacuo and the remainder neutralized with saturated aqueous NaHC0₃ solution and extracted into EtOAC (3 x 50mL). The combined organic extracts were washed with brine, dried (MgSC^), filtered and concentrated in vacuo. Purification by column

chromatography (DCM:MeOH; 9: 1 to 17:3) afforded the title compound: RT = 0.69 min; mlz (ES⁺) = 465.37 [M+ H]⁺ (LCMS Method-6).

Example 260: l-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-cyclobutanol tosylate

To a solution of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-((5)-l-{l-[3-(l-hydroxy- cyclobutyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}- carbamic acid tert-butyl ester tert-butyl (Preparation 362, 55mg, 0.086mmol) in 1,4- dioxane (ImL) was added HCl in 1,4-dioxane (4M, ImL, 8mmol) and the resulting reaction mixture was stirred at r.t. for 2 h. The solvent was removed in vacuo and the remainder partitioned between DCM (5mL) and saturated aqueous NaHC0₃ solution (3mL). The organic layer was separated, concentrated in vacuo and the remainder purified by preparative HPLC. The product was dissolved in DCM (ImL) and TsOH (7.2mg, 38μιηο1) in MeOH (0.5mL) was added. The solvent was removed in vacuo to afford the title compound: RT = 0.76 min; mlz (ES⁺) = 542.45 [M+ H]⁺ (LCMS Method-6). Example 261: l-{5-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-cyclobutanol hydrochloride

The title compound was synthesized from benzoic acid l-{5-[4-((5)-l-{2-[(3i?,45)-3- tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]-pyrimidin-5-yloxy}- ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-cyclobutyl ester (Preparation 363) employing a procedure similar to that outlined in Example 258: RT = 0.79 min; mlz (ES⁺) = 560.40 [M + H]⁺ (LCMS Method-6).

Example 262: (5)-l-{5-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}- propan-2-ol

A solution of 3-hydroxybutyronitrile (98.5mg, 11.6mmol) and hydroxylamine (50% aqueous solution, 0.85 lmL, 13.9mmol) in EtOH (20mL) was heated at 60°C for 5 h and at 70°C for 10 h. Further hydroxylamine (50% aqueous solution, 0.1 OmL, 1.63mmol) was added and the reaction mixture heated at 70°C for 10 h. The solvent was removed in vacuo and the remainder dissolved in EtOH (4mL). [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4-yl)- ethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 205, 0.1 Og, 0.189mmol) was added followed by zinc dichloride in Et₂0 (1M, 0.227mL, 0.227mmol) and the resulting reaction mixture stirred at r.t. for 2 h. Further zinc dichloride in Et₂0 (1M, 25μΙ_^, 25μmol) was added and the reaction mixture stirred at r.t. for 4.5 h. HCl in 1,4-dioxane (4M, 0.236mL, 0.946mmol) was added and the mixture heated at 60°C for 7 h. Upon cooling, the reaction mixture was partitioned between EtOAc and water and the organic layer passed through a hydrophobic frit and concentrated in vacuo. The remainder was purified by preparative HPLC, followed by further purification by chiral HPLC (MeOH : THF : IH : B A; 50:30:20:0.5, 16ml/min, 250nm). The compound was loaded onto an SCX cartridge, eluting with MeOH followed by NH₃ in MeOH (7M) and the basic fractions concentrated in vacuo to afford the title compound: RT = 0.75 min; mlz (ES ) = 530.42 [M+ H]⁺ (LCMS Method-6). The stereochemistry of * centre has been arbitrarily assigned. Example 263: l-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-2-methyl-propan-2- ol hydrochloride

The title compound was synthesised from [(3R,4S)-l-{5-[(S)-l-(l-cyano-piperidin-4- yl)-ethoxy]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 205) and 3,N-dihydroxy-3-methyl-butyramidine (Preparation 364) employing a procedure similar to that outlined in Example 254: RT = 0.77 min; mlz (ES ) = 544.44 [M+ H]⁺ (LCMS Method-6). Example 264: 2-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrimidin-5-yloxy}-eth l)-piperidin-l-yl]-tetrazol-2-yl}-2-methyl-propan-l-ol

The title compound was synthesised from {(3R,4S)-4-(2,5-difluoro-phenyl)-l-[5-((S)- 1 - { 1 -[2-(2-hydroxy-l , 1 -dimethyl-ethyl)-2H-tetrazol-5-yl]-piperidin-4-yl} -ethoxy)- pyrimidin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 367)

employing a procedure similar to that outlined in Example 205: RT = 0.82 min; mlz (ES ) = 544.42 [M+ H]⁺ (LCMS Method-6).

The following examples were prepared by deprotection of the appropriate tert-butoxy carbonyl protected intermediates (Preparation 374 or 375 or 376) employing a procedure similar to that outlined in Example 243:

Example 268: (S)-l-{5-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-l- cyclopropyl-ethanol hy rochloride

[(3R,4S)- 1 -[5 -((S)- 1 - { 1 -[3-((S 1 -Cyclopropyl- 1 -hydroxy-ethyl)-[ 1 ,2,4]oxadiazol-5- yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- carbamic acid tert-butyl ester (12.1mg, 18μηιο1) was isolated from [(3 ?,45)-l-[5-((5)-l-{l- [3-(l-cyclopropyl-l-hydroxy-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)- pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Prepartion 378) via chiral HPLC (MTBE:MeCN:MeOH; 70:20: 10, 14ml/min, 250nm) and dissolved in DCM (2mL). HC1 in Et₂0 (2M, 16.5μΕ, 33μmol) was added and the reaction mixture stirred at r.t. for 16 h. The solvent was removed in vacuo and the remainder triturated with Et₂0 to afford the title compound: RT = 0.83 min; m/z (ES⁺) = 574.5 [M+ H] (LCMS Method-6).

Example 269: (R)-l-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-l- cyclopropyl-ethanol hy rochloride

The title compound was synthesized from [(3 ?,45)-l-[5-((5)-l-{l-[3-(l-cyclopropyl- l-hydroxy-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5- trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Prepartion 378) employing the procedure outlined in Example 268: RT = 0.83 min; m/z (ES⁺) = 574.5 [M+ H]⁺ (LCMS Method-6). Example 270: (3R,4S)-4-(2,5-Difluoro-phenyl)-l-{5-[(lR,5S,9S)-7-(3-ethyl- [l,2,4]oxadiazol-5-yl)-3-oxa-7-aza-bicyclo[3.3.1]non-9-ylmethoxy]-pyrimidin-2-yl}- pyrrolidin-3-ylamine hydrochloride

(3^,45)-4-(2,5-ϋίΑηοΓθ-ρ1ΐ6η 1)-1-{5-[(ϋ?,5^,95)-7-(3-6 1-[1,2,4]οχα(1ίαζο1-5^1)- 3-oxa-7-aza-bicyclo[3.3.1 ]non-9-ylmethoxy]-pyrimidin-2-yl} -pyrrolidin-3-ylamine was isolated from ((3i?,45)-4-(2,5-difluoro-phenyl)-l-{5-[(li?,55)-7-(3-ethyl-[l,2,4]oxadiazol-5- yl)-3-oxa-7-aza-bicyclo[3.3.1 ]non-9-ylmethoxy]-pyrimidin-2-yl} -pyrrolidin-3-yl)-carbamic acid tert-butyl ester (Preparation 387) via chiral HPLC (MTBE:MeOH; 80:20, 13ml/min, 250nm) and dissolved in Et₂0 (lmL). HC1 in Et₂0 (2M, 29μί, 57μmol) was added and the reaction mixture stirred at r.t. for 16 h. The solvent was removed in vacuo to afford the title compound: RT = 0.73 min; mlz (ES⁺) = 528.4 [M+ H]⁺ (LCMS Method-6).

Example 271: (3R,45)-4-(2,5-Difluoro-phenyl)-l-{5-[(lR,5S,9R)-7-(3-ethyl- [l,2,4]oxadiazol-5-yl)-3-oxa-7-aza-bicyclo[3.3.1]non-9-ylmethoxy]-pyrimidin-2-yl}- pyrrolidin-3-ylamine hydrochloride

The title compound was synthesized from ((3i?,45)-4-(2,5-difluoro-phenyl)-l-{5- [(li?,55)-7-(3-ethyl-[l,2,4]oxadiazol-5-yl)-3-oxa-7-aza-bicyclo[3.3.1]non-9-ylmethoxy]- pyrimidin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (Preparation 387)

employing the procedure outlined in Example 270: RT = 0.73 min; mlz (ES ) = 528.4 [M H]⁺ (LCMS Method-6).

Example 272: (3R,45)-4-(2-Fluoro-phenyl)-l-[5-((S)-l-{l-[3-((S)-l-methoxy-ethyl)-

[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-ylamine hydrochloride

The title compound was synthesised from {(3R,4S)-4-(2-fluoro-phenyl)-l-[5-((S)-l- { 1 -[3-((iS)- 1 -methoxy-ethyl)-[ 1 ,2,4]oxadiazol-5-yl]-piperidin-4-yl} -ethoxy)-pyrimidin-2-yl]- pyrrolidin-3-yl} -carbamic acid tert-butyl ester (Preparation 396) employing a procedure similar to that outlined in Preparation 243: RT = 0.78 min; m/z (ES⁺) = 512.4 [M + H]⁺ (LCMS Method-6).

The following examples were prepared by deprotection of the appropriate tert-butoxy carbonyl protected intermediates (Preparation 397 or 400 or 403 or 404) employing a procedure similar to that outlined in Example 258:

Example 277: (l-{5-[4-((S)-l-{2-[(3R,4S)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}-cyclopropyl)- methanol hydrochlori

The title compound was synthesised from [(3i?,45)-l-{5-[(5)-l-(l-cyano-piperidin-4- yl)-ethoxy]-pyrimidin-2-yl} -4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester (Preparation 206) and N-hydroxy-l-hydroxymethyl-cyclopropanecarboxamidine (Preparation 405) employing a procedure similar to that outlined in Example 254: RT = 0.79 min; mlz (ES⁺) = 560.43 [M+ H]⁺ (LCMS Method-6).

Example 278: 2-{5-[4-((5)-l-{2-[(3R,4S)-3-Amino-4-(2-fluoro-5-methyl-phenyl)- pyrrolidin-l-yl]-pyrimidin-5-yloxy}-ethyl)-piperidin-l-yl]-[l,2,4]oxadiazol-3-yl}- propan-2-ol hydrochloride

To a solution of {(3i?,45)-4-(2-fluoro-5-methyl-phenyl)-l-[5-((5)-l-{l-[3-(l- hydroxy- 1 -methyl-ethyl)-[ 1 ,2,4]oxadiazol-5-yl]-piperidin-4-yl} -ethoxy)-pyrimidin-2-yl]- pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Preparation 407, 16mg, 26μmol)) in MeOH (0.25mL) was added HCl in Et₂0 (2M, ImL, 2mmol) and the resulting reaction mixture was stirred at r.t. for 16 h. The solvent was removed in vacuo to afford the title compound: RT = 0.79 min; mlz (ES⁺) = 526.5 [M + H]⁺ (LCMS Method-6).

Example 279: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(5-ethyl-pyrimidin-2-yl)-piperidin-4- yl]-ethoxy}-pyrimidin-2- l)-pyrrolidin-3-yl]-5-methyl-lH-pyridin-2-one

To a solution of 2-chloro-5-(15)- 1 -[ 1 -(5-ethylpyrimidin-2-yl)piperidin-4- yl]ethoxypyrimidine (Preparation 414, 123mg, 0.353mmol) and l-((tra/?5)-4-amino- pyrrolidin-3-yl)-5-methyl-lH-pyridin-2-one (Preparation 194, 40.0mg, 0.204mmol) in DMSO (lmL) was added DBU (50μί, 0.334mmol) and the resulting reaction mixture was heated under microwave irradiation at 120°C for 195 min. Upon cooling, the reaction mixture was poured into water and extracted with EtOAc (3 x). The combined organic extracts were dried in a phase separator and concentrated in vacuo. The remainder was dissolved in MeOH and loaded onto a phosphonic acid SCX cartridge eluting with MeOH followed by N¾ in MeOH. The basic fractions were concentrated in vacuo and purified by chiral HPLC (MeCN:THF:BA; 50:50:0.05, 16 ml/min, 250 nm, RT = 10.3 min) to afford the title compound: RT = 0.77 min; mlz (ES⁺) = 505.44 [M+ H]⁺ (LCMS Method-6). Example 280: l-[(3S,4S)-4-Amino-l-(5-{(5)-l-[l-(5-ethyl-pyrazin-2-yl)-piperidin-4-yl]- ethoxy}-pyrimidin-2-yl)- rrolidin-3-yl]-5-methyl-lH-pyridin-2-one

The title compound was synthesised from 2-chloro-5-{(S)-l-[l-(5-ethyl-pyrazin-2- yl)-piperidin-4-yl]-ethoxy}-pyrimidine (Preparation 415) and l-((trans)-4-ammo- pyrrolidin-3-yl)-5-methyl-lH-pyridin-2-one (Preparation 194) employing a procedure similar to that outlined in Example 279, replacing the chiral HPLC conditions as follows: (MeOH:THF:BA; 65:35:0.05, 15 ml/min, 250 nm, RT = 10.1 min): RT = 0.78 min; mlz (ES⁺) = 505.43 [M+ H]⁺ (LCMS Method-6). Example 281: l-[(3S,4S)-4-Amino-l-(5-{(S)-l-[l-(5-chloro-pyrimidin-2-yl)-piperidin-4- yl]-ethoxy}-pyrimidin-2- l)-pyrrolidin-3-yl]-5-methyl-lH-pyridin-2-one

The title compound was synthesized from 5-chloro-2-(4-(5)-l-[(2-chloropyrimidin-; yl)oxy] ethylpiperidin-l-yl)pyrimidine (Preparation 416) and l-((trans)-4-ammo- pyrrolidin-3-yl)-5-methyl-lH-pyridin-2-one (Preparation 194) employing a procedure similar to that outlined in Example 279, replacing the chiral HPLC conditions as follows: (MeCN:THF:BA; 50:50:0.05, 16 ml/min, 250 nm, RT = 12.5 min): RT = 0.87 min; mlz (ES⁺) = 511.37 [M+ H]⁺ (LCMS Method-6). Example 282: l-{(3S,4S)-4-Amino-l-[5-((S)-l-{l-[3-(l,l-difluoro-ethyl)-[l,2,4]oxadiazol-

5-yl]-piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-pyrrolidin-3-yl}-5-methyl-lH-pyridin-2- one

The title compound was synthesised from 2-chloro-5-((5)-l-{l-[3-(l,l-difluoro- ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-ethoxy)-pyrimidine (Preparation 418) and 1- ((tra/75)-4-amino-pyrrolidin-3-yl)-5 -methyl- lH-pyridin-2-one (Preparation 194) employing a procedure similar to that outlined in Example 279, replacing the chiral HPLC conditions as follows: (MeCN:THF:BA; 65:35:0.05, 15 ml/min, 250 nm, RT = 8.6 min): RT = 0.81 min; mlz (ES⁺) = 531.41 [M+ H]⁺ (LCMS Method-6).

Example 283: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-isopropyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-ethoxy}- rimidin-2-yl)-pyrrolidin-3-yl]-5-methyl-lH-pyridin-2-one

The title compound was synthesised from 2-chloro-5-{(5)-l-[l-(3-isopropyl-

[l,2,4]oxadiazol-5-yl)piperidin-4-yl]ethoxy}pyrimidine (Preparation 63) and \- trans)- - amino-pyrrolidin-3-yl)-5 -methyl- lH-pyridin-2-one (Preparation 194) employing a procedure similar to that outlined in Example 279, replacing the chiral HPLC conditions as follows: (MeOH:THF:BA; 85:15:0.05, 12 ml/min, 250 nm, RT = 16.0 min): RT = 0.79 min; mlz (ES⁺) = 509.46 [M + H]⁺ (LCMS Method-6).

Example 284: l-[(3S,4S)-4-Amino-l-(5-{(S)-l-[l-(3-trifluoromethyl-[l,2,4]oxadiazol-5- yl)-piperidin-4-yl]-ethox -pyrimidin-2-yl)-pyrrolidin-3-yl]-5-methyl-lH-pyridin-2-one

The title compound was synthesised from 2-chloro-5-{(S)-l-[l-(3-trifluoromethyl-

[l,2,4]oxadiazol-5-yl)-piperidin-4-yl]-ethoxy}-pyrimidine (Preparation 421) and \- trans)- 4-amino-pyrrolidin-3-yl)-5 -methyl- lH-pyridin-2-one (Preparation 194) employing a procedure similar to that outlined in Example 279, replacing the chiral HPLC conditions as follows: (MeOH:THF:BA; 85:15:0.05, 12 ml/min, 250 nm, RT = 12.9 min): RT = 0.87 min; mlz (ES⁺) = 535.43 [M+ H]⁺ (LCMS Method-6). Example 285: l-[(3S,45)-4-Amino-l-(5-{(S)-l-[l-(3-tert-butyl-[l,2,4]oxadiazol-5-yl)- piperidin-4-yl]-ethoxy}- rimidin-2-yl)-pyrrolidin-3-yl]-5-methyl-lH-pyridin-2-one

The title compound was synthesised from 5-{(S)-l-[l-(3-tert-butyl-[l,2,4]oxadiazol- 5-yl)-piperidin-4-yl]-ethoxy}-2-chloro-pyrimidine (Preparation 422) and 1 -((trans)-4- amino-pyrrolidin-3-yl)-5 -methyl- lH-pyridin-2-one (Preparation 194) employing a procedure similar to that outlined in Example 279, replacing the chiral HPLC conditions as follows: (MTBE :THF :MeOH:BA; 60:30: 10:0.05, 12 ml/min, 250 nm, RT = 11.5 min): RT = 0.85 min; mlz (ES⁺) = 523.45 [M+ H]⁺ (LCMS Method-6). Example 286: (3R,45)-l-[5-((S)-l-{l-[(S)-2-(Tetrahydro-furan-3-yl)-2H-tetrazol-5-yl]- piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was synthesized from [(3 ?,45)-l-[5-((5)-l-{l-[(5)-2-(tetrahydro- mran-3-yl)-2H-tetrazol-5-yl]-piperidin-4-yl}-e^

phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 423) employing the procedure outlined in Example 243: RT = 0.84 min; mlz (ES⁺) = 560.47 [M+ H]⁺ (LCMS Method-6). Example 287: (3R,4S)-l-[5-((S)-l-{l-[(R)-2-(Tetrahydro-furan-3-yl)-2H-tetrazol-5-yl]- piperidin-4-yl}-ethoxy)-pyrimidin-2-yl]-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-ylamine hydrochloride

The title compound was synthesized from [(3 ?,4S)-l-[5-((S)-l-{l-[(i?)-2-(tetrahyd mran-3-yl)-2H-tetrazol-5-yl]-piperidin-4-yl^

phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 424) employing the procedure outlined in Example 243: RT = 0.82 min; m/z (ES⁺) = 560.49 [M+ H]⁺ (LCMS Method-6).

The biological activity of the compounds of the invention may be tested in the following assay systems:

GPR119 Yeast Reporter Assay

Yeast Reporter Assay

The yeast cell-based reporter assays have previously been described in the literature (e.g. see Miret J. J. et al, 2002, J. Biol. Chem., 277:6881-6887; Campbell R.M. et al, 1999, Bioorg. Med. Chem. Lett., 9:2413-2418; King K. et al, 1990, Science, 250: 121-123); WO 99/14344; WO 00/12704; and US 6,100,042). Briefly, yeast cells have been engineered such that the endogenous yeast G-alpha (GPA1) has been deleted and replaced with G-protein chimeras constructed using multiple techniques. Additionally, the endogenous yeast GPCR, Ste3 has been deleted to allow for heterologous expression of a mammalian GPCR of choice. In the yeast, elements of the pheromone signaling transduction pathway, which are conserved in eukaryotic cells (for example, the mitogen-activated protein kinase pathway), drive the expression of Fusl . By placing β-galactosidase (LacZ) under the control of the Fusl promoter (Fuslp), a system has been developed whereby receptor activation leads to an enzymatic read-out.

Yeast cells were transformed by an adaptation of the lithium acetate method described by Agatep et al, (Agatep, R. et al, 1998, Transformation of Saccharomyces cerevisiae by the lithium acetate/single-stranded carrier DNA/polyethylene glycol (LiAc/ss- DNA/PEG) protocol. Technical Tips Online, Trends Journals, Elsevier). Briefly, yeast cells were grown overnight on yeast tryptone plates (YT). Carrier single-stranded DNA (10 μg), 2 μg of each of two Fuslp-LacZ reporter plasmids (one with URA selection marker and one with TRP), 2 μg of GPR119 (human or mouse receptor) in yeast expression vector (2 μg origin of replication) and a lithium acetate/ polyethylene glycol/ TE buffer was pipetted into an Eppendorf tube. The yeast expression plasmid containing the receptor/ no receptor control has a LEU marker. Yeast cells were inoculated into this mixture and the reaction proceeds at 30°C for 60min. The yeast cells were then heat-shocked at 42°C for 15 min. The cells were then washed and spread on selection plates. The selection plates are synthetic defined yeast media minus LEU, URA and TRP (SD-LUT). After incubating at 30°C for 2-3 days, colonies that grow on the selection plates were then tested in the LacZ assay.

In order to perform fluorimetric enzyme assays for β-galactosidase, yeast cells carrying the human or mouse GPR119 receptor were grown overnight in liquid SD-LUT medium to an unsaturated concentration (i.e. the cells were still dividing and had not yet reached stationary phase). They were diluted in fresh medium to an optimal assay concentration and 90 μΐ, of yeast cells added to 96-well black polystyrene plates (Costar).

Compounds, dissolved in DMSO and diluted in a 10% DMSO solution to 10X concentration, were added to the plates and the plates placed at 30°C for 4 h. After 4 h, the substrate for the β-galactosidase was added to each well. In these experiments, Fluorescein di (β-D- galactopyranoside) was used (FDG), a substrate for the enzyme that releases fluorescein, allowing a fluorimetric read-out. 20 μΐ_^ per well of 500μΜ FDG/2.5% Triton XI 00 was added (the detergent was necessary to render the cells permeable). After incubation of the cells with the substrate for 60 min, 20 μΐ, per well of 1M sodium carbonate was added to terminate the reaction and enhance the fluorescent signal. The plates were then read in a fluorimeter at 485/535nm.

A number of representative examples of the compounds of the invention, as well as pharmaceutically acceptable salts thereof, were tested and found to have activity in this assay, giving an increase in fluorescent signal of at least ~ 1.5 -fold that of the background signal (i.e. the signal obtained in the presence of 1% DMSO without compound); some of the examples gave an increase of at least 5 -fold. It was found that some of the examples tested were found to have a human yeast IC₅₀ value of less than 1 μΜ; other examples to have an IC₅₀ value of less than 10μΜ. On the basis of this data, and the additional data given below, it is expected that all of the compounds of the invention have at least comparable activity. cAMP Assay

A stable cell line expressing recombinant human GPR119 was established and this cell line was used to investigate the effect of compounds of the invention on intracellular levels of cyclic AMP (cAMP). The cell monolayers were washed with phosphate buffered saline and stimulated at 37°C for 30 min with various concentrations of compound in stimulation buffer plus 1% DMSO. Cells were then lysed and cAMP content determined using the Perkin Elmer AlphaScreen™ (Amplified Luminescent Proximity Homogeneous Assay) cAMP kit. Buffers and assay conditions were as described in the manufacturer's protocol.

A number of representative examples of compounds of the invention were tested and found to produce a concentration-dependent increase in intracellular cAMP levels and generally had an EC50 of <10 μΜ; some of the examples showed an EC50 of less than 1 μΜ in the cAMP assay.

DPP-IV Assay Method

DPP-IV activity was measured by monitoring the cleavage of the fluorogenic peptide substrate, H-Gly-Pro-7-amino-4-methylcoumarin (GP-AMC) whereby the product 7-amino- 4-methylcoumarin is quantified by fluorescence at excitation 380 nm and emission 460 nm. Assays were carried out in 96-well plates (Black OptiPlate-96F) in a total volume of 100 per well consisting of 50 mM Tris pH 7.6, 100 μΜ GP-AMC, 10-25 μΙΙ recombinant human DPP-IV and a range of inhibitor dilutions in a final concentration of 1% DMSO. Plates were read in a fluorimeter after 30 min incubation at 37°C. Recombinant human DPP-IV residues Asn29-Pro766 was purchased from BioMol.

All of Examples 1 to 287 above were tested and found to show activity in this assay having an IC50 of <20 μΜ. Some of the examples were found to have a DPP-IV EC50 value of less than 1 μΜ; others an EC50 value of less than 20μΜ. Activities of a representative group of compounds that were tested in the human yeast assay and the DPP-IV assay are shown in Table 1 below:

Table 1.

Activities of a representative group of compounds that were tested in the cAMP assay and the DPP-IV assay are shown in Table 2 below:

Table 2.

Example No. cAMP ECso cAMP ECso DPP-IV ICso DPP-IV ICso

<1μΜ between ΙμΜ <1μΜ between ΙμΜ

and 10μΜ and 20μΜ

109 + +

110 + +

112 + +

115 + +

124 + +

128 + +

130 + +

131 + +

133 + +

135 + +

140 + + Example No. cAMP ECso cAMP ECso DPP-IV ICso DPP-IV ICso

<1μΜ between ΙμΜ <1μΜ between ΙμΜ

and ΙΟμΜ and 20μΜ

158 + +

175 + +

176 + +

196 + +

197 + +

198 + +

200 + +

218 + +

223 + +

235 + +

242 + +

249 + +

280 + +

Metabolites

Metabolites of compounds of the invention can be identified through incubation in liver microsomes:

Compounds of interest are incubated at a concentration of 5 μΜ for 60 minutes at 37°C in rat, liver or human microsomes. A T=0 compound incubation is also prepared to determine the levels of parent prior to any metabolism. A matrix control is prepared to determine which compounds are matrix constituents, as well as a thermal stability control to ensure that any metabolites observed in the compound incubation are not a product of thermal instability. All solutions are extracted into MeCN and analysed by LC/MSMS with UV detection. Further MSMS analysis is performed for confirmation and structural elucidation of detected metabolites.

For example, Compound 1 below can be identified as a metabolite of Example 38 via this method. Compound 1 was synthesized and found to have an EC50 in the GPR119 cAMP assay of 9μΜ and an IC₅₀ in the DPP-IV assay of <1 μΜ. Compound 1 : 4-((5)-l-{2 (3i?,4_lS)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]- pyrimidin-5-yloxy} -ethyl)-piperidine- 1 -carboxylic acid propionyl-amide

Anti-diabetic effects of compounds of the invention in an in-vitro model of pancreatic beta cells (HIT-T15)

Cell Culture

HIT-T15 cells (passage 60) were obtained from ATCC, and were cultured in

RPMI1640 medium supplemented with 10% fetal calf serum and 30 nM sodium selenite. All experiments were done with cells at less than passage 70, in accordance with the literature, which describes altered properties of this cell line at passage numbers above 81 (Zhang HJ, Walseth TF, Robertson RP. Insulin secretion and cAMP metabolism in HIT cells. Reciprocal and serial passage-dependent relationships. Diabetes. 1989 Jan;38(l):44-8). cAMP assay

HIT-T15 cells were plated in standard culture medium in 96-well plates at 100,000 cells/ 0.1 mlV well and cultured for 24 h and the medium was then discarded. Cells were incubated for 15min at room temperature with ΙΟΟμΙ stimulation buffer (Hanks buffered salt solution, 5mM HEPES, 0.5mM IBMX, 0.1% BSA, pH 7.4). This was discarded and replaced with compound dilutions over the range 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 μΜ in stimulation buffer in the presence of 0.5% DMSO. Cells were incubated at room temperature for 30 min. Then 75 uL lysis buffer (5mM HEPES, 0.3% Tween-20, 0.1% BSA, pH 7.4) was added per well and the plate was shaken at 900 rpm for 20 min. Particulate matter was removed by centrifugation at 3000rpm for 5 min, then the samples were transferred in duplicate to 384-well plates, and processed following the Perkin Elmer AlphaScreen cAMP assay kit instructions. Briefly 25 reactions were set up containing 8 μΐ, sample, 5 μΐ, acceptor bead mix and 12 μΕ detection mix, such that the concentration of the final reaction components is the same as stated in the kit instructions. Reactions were incubated at room temperature for 150 min, and the plate was read using a Packard Fusion instrument.

Measurements for cAMP were compared to a standard curve of known cAMP amounts (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000 nM) to convert the readings to absolute cAMP amounts. Data was analysed using XLfit 3 software.

Representative compounds of the invention were found to increase cAMP at an EC50 of less than 10 μΜ. Compounds showing an EC50 of less than 1 μΜ in the cAMP assay may be preferred. Insulin secretion assay

HIT-T15 cells are plated in standard culture medium in 12-well plates at 106 cells/ 1 ml/ well and cultured for 3 days and the medium then discarded. Cells are washed x 2 with supplemented Krebs-Ringer buffer (KRB) containing 119 mM NaCl, 4.74 mM KC1, 2.54 mM CaCl₂, 1.19 mM MgS0₄, 1.19 mM KH₂P0₄, 25 mM NaHC0₃, 10 mM HEPES at pH 7.4 and 0.1% bovine serum albumin. Cells are incubated with 1ml KRB at 37°C for 30 min which is then discarded. This is followed by a second incubation with KRB for 30 min, which is collected and used to measure basal insulin secretion levels for each well.

Compound dilutions (0, 0.1, 0.3, 1, 3, 10 μΜ) are then added to duplicate wells in 1ml KRB, supplemented with 5.6 mM glucose. After 30 min incubation at 37°C samples are removed for determination of insulin levels. Measurement of insulin was done using the Mercodia Rat insulin ELISA kit, following the manufacturers' instructions, with a standard curve of known insulin concentrations. For each well, insulin levels are corrected by subtraction of the basal secretion level from the pre-incubation in the absence of glucose. Data is analysed using XLfit 3 software.

Compounds of the invention preferably increase insulin secretion at an EC50 of less than 10 μΜ.

Oral Glucose Tolerance Tests

The effects of compounds of the invention on oral glucose (Glc) tolerance may be evaluated in male Sprague-Dawley rats. Food is withdrawn 16 h before administration of Glc and remains withdrawn throughout the study. Rats have free access to water during the study. A cut is made to the animals' tails, then blood (1 drop) is removed for measurement of basal Glc levels 60 min before administration of the Glc load. Then, the rats are weighed and dosed orally with test compound or vehicle (20% aqueous hydroxypropyl-y^- cyclodextrin) 45 min before the removal of an additional blood sample and treatment with the Glc load (2 g kg ¹ p.o.). Blood samples are taken from the cut tip of the tail 5, 15, 30, 60, 120, and 180 min after Glc administration. Blood glucose levels are measured just after collection using a commercially available glucose-meter (OneTouch® UltraTM from

Lifescan). Compounds of the invention preferably statistically reduce the Glc excursion at doses <100 mg kg^-1.

The effects of compounds of the invention on oral glucose (Glc) tolerance were evaluated in male C57B1/6 mice or male DIO C57BL/6J mice or male oblob mice. Food was withdrawn 5 h before administration of Glc and remained withdrawn throughout the study. Mice had free access to water during the study. A cut was made to the animals' tails, then blood (20 was removed for measurement of basal Glc levels 45 min before

administration of the Glc load. Then, the mice were weighed and dosed orally with test compound or vehicle (20% aqueous hydroxypropyl-y^-cyclodextrin or 25% aqueous Gelucire 44/14) 30 min before the removal of an additional blood sample (20

and treatment with the Glc load (2-5 g kg ¹ p.o.). Blood samples (20 uL) were then taken 25, 50, 80, 120, and 180 min after Glc administration. The 20

blood samples for measurement of Glc levels were taken from the cut tip of the tail into disposable micro-pipettes (Dade Diagnostics Inc., Puerto Rico) and the sample added to 480 iL of haemolysis reagent. Duplicate 20 μΐ, aliquots of the diluted haemolysed blood were then added to 180 iL of Trinders glucose reagent (Sigma enzymatic (Trinder) colorimetric method) in a 96-well assay plate. After mixing, the samples were left at room temperature for 30 min before being read against Glc standards (Sigma glucose/urea nitrogen combined standard set). Compounds of the invention statistically reduced the Glc excursion at doses <100 mg kg^-1. Example 16 (30 mpk po) was evaluated in an oral glucose tolerance test in male DIO

C57BL/6J mice. Reactive blood glucouse AUC (0-120 min) was reduced by 44% (p=0.002) relative to vehicle (20%> aqueous hydroxypropyl-y5-cyclodextrin).

Claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

(I) wherein A is a para-substituted phenyl or a para-substituted 6-membered heteroaryl ring containing one to three nitrogen atoms;

R1 is hydrogen, halo, cyano, Ci _4alkyl, Ci .4 haloalkyl, Ci .4 alkoxy or C2- galkoxyalkyl;

2 is:

_s phenyl optionally substituted by one or more halo, methyl, halomethyl or methoxy groups, or pyridyl, N-pyridonyl or N-pyrazolyl, optionally substituted by one or more halo, C\ .2 alkyl or halomethyl groups,

R^ is independently halo, methyl or halomethyl;

Z is -C(0)OR⁴, -C(0)R⁴ , -S(0)₂R⁴ , -S(0)₂N(C₁.₃alkyl)R⁴, heteroaryl or

-CH2-heteroaryl, and when p and q are both 0, Z can also be -CH₂-phenyl, which phenyl is optionally substituted by one or two groups independently selected from Ci .4 alkyl,

C\ .4 haloalkyl and halo;

R⁴ is aryl, heteroaryl, C2-6^alkyl, C3_6cycloalkyl, C4_6heterocyclyl, heterocyclylCi . 4alkyl, C2-6^alkoxyalkyl, arylCi _4alkyl, heteroarylCj .4 alkyl or C4_ cycloalkylCi _4alkyl, which cycloalkylCi _4alkyl is optionally substituted by C\ .4 alkyl; wherein when Z is or includes heteroaryl or when R^ is or includes aryl or heteroaryl, said aryl or heteroaryl may optionally be substituted by one or two groups selected from halo, cyano, SF5,

C 1 .4 alkyl, C i _4haloalkyl, C 1 .5 hydroxyalkyl, Ci _4alkoxy, C2-4alkoxyalkyl, heterocyclyl, heterocyclylC 1 .4 alkyl, heteroarylCi _4alkyl, Ci _4alkylamino, Ci _4alkylaminoC 1 .4 alkyl, C3.

6 cycloalkyl and -(C\ .3 alkyl)-(C3_6 cycloalkyl), wherein the cycloalkyl and alkyl groups are each optionally substituted by one or two groups independently selected from Ci .4 alkyl, hydroxy or halo;

X is selected from CR⁵H, O, and NR⁶ in which R⁵ and R⁶ are independently hydrogen or Ci _2alkyl;

Y is γΐ or W-γΙ, where W is a 5 membered heteroaryl ring containing one or more heteroatoms selected from N, O and S, and γΐ is selected from CR⁷H, O and NR⁸, in which R⁷ is hydrogen, Ci _2alkyl,C2-6^alkoxyalkyl or heterocyclyl; wherein said C i _2alkyl can be optionally substituted by cyano, hydroxy or halo and R⁸ is C\ _4alkyl or C\ _4cycloalkyl, provided that when Y is W-Y¹, X is O and Y¹ is CR⁷H, when Y¹ is O or NR⁸, X is CR⁵H and when X is O or NR⁶, Y¹ is CR⁷H;

each of R^ and R^ is independently H, halo, C\ _2alky, C i _2haloalkyl,

C\ _3alkoxy or hydroxy; or R9 and RIO are joined to form an azabicyclo[3.3.1]nonane, a 3-oxa-

7-azabicyclo[3.3.1]nonane or an azabicyclo[3.2.1]octane;

R11 is H, halo, C\ _2alkyl, C\ _2haloalkyl or C\ _3alkoxy;

m is 0, 1 or 2;

n is 0 or 1 ;

p and q are each 0, 1 or 2, provided that 0 < p+q < 2; and

r is 1 or 2.

2. A compound as claimed in claim 1, wherein the compound has the stereochemistry defined below (compounds of formula (la)):

(la).

3. A compound as claimed in claim 1 or claim 2, wherein p and q are independently 0, 1 or 2 provided that p+q does not exceed 2.

4. A compound as claimed in claim 3, wherein p and q are the same as one another.

5. A compound as claimed in claim 3, wherein p and q are both 1.

6. A compound as claimed in any preceding claim, wherein Y is γΐ .

7. A compound as claimed in claim 6, wherein γΐ is O and X is CR^H.

8. A compound as claimed in any of claims 1-6, wherein Y is γΐ, X is O and γΐ is CR7H.

9. A compound as claimed in claim 8, which has the formula (lb):

(lb).

10. A compound as claimed in any of claims 1-5, wherein Y is W-Y^ , and γΐ is CR^H bonded directly to X.

1 1. A compound as claimed in claim 10, wherein X is O.

12. A compound as claimed in claim 10 or 1 1 , wherein W is oxadiazolyl.

13. A compound as claimed in claim 12, which has the formula (Ic):

14. A compound as claimed in any preceding claim, wherein A is selected from pyridine, pyrimidine, pyrazine and pyridazine.

15. A compound as claimed in claim 14, wherein A is 2- or 3-pyridyl or 2- or 5-pyrimidinyl, where the 2-, 3- or 5- refers to the point of attachment of the pyrrolidine or piperidine ring.

16. A compound as claimed in any of claims 9 to 13, wherein A is selected from:

17. A compound as claimed in any preceding claim, wherein Z is -C(0)OR4., -C(0)R4, -S(0)₂R⁴ or -S(0)₂N(Ci_3alkyl)R⁴.

18. A compound as claimed in claim 17, wherein R^ is selected from C2-6^alkyl,

C4_5alkoxyalkyl, C3_6cycloalkyl and C4_ cycloalkylC j .4 alkyl, wherein said cycloalkylalkyl is optionally substituted by C\ _4alkyl.

19. A compound as claimed in claim 18, wherein R4 is propyl or isopropyl.

20. A compound as claimed in any of claims 1 -16, wherein Z is a heteroaryl or

-CH2-heteroaryl group that is unsubstituted or substituted by one or two groups selected from

SF5, C 1 .4 alkyl, C i _4haloalkyl, C 1 .5 hydroxyalkyl, C2-4alkoxyalkyl, C3_6cycloalkyl,

-(C i _3alkyl)-(C3_6cycloalkyl), heterocyclyl, heterocyclylC 1 .4 alkyl, heteroarylCi _4alkyl,

C\ _4alkylamino, C \ _4alkylaminoC j .4 alkyl, cyano and halogen; wherein the cycloalkyl and alkyl groups are each optionally substituted by one or two groups independently selected from C\ .4 alkyl, hydroxy or halo.

21. A compound as claimed in claim 20, wherein Z is a heteroaryl group selected from oxadiazole, pyrimidine, pyridazine, thiazole, tetrazole, benzothiazole and thiadiazole.

22. A compound as claimed in claim 20 or claim 21 , wherein Z is l ,2,4-oxadiazol-3-yl, l ,2,4-oxadiazol-5-yl or pyrimidin-2-yl.

23. A compound as claimed in claim 22, wherein Z is l ,2,4-oxadiazol-3-yl or

l ,2,4-oxadiazol-5-yl that is substituted by Ci _4alkyl, Ci _4 haloalkyl, C 1 .5 hydroxyalkyl,

Cl-3 hydroxyalkyl, C2-4 alkoxyalkyl or heterocyclyl.

24. A compound as claimed in claim 22, wherein Z is pyrimidin-2-yl that is unsubstituted or substituted with one or more halo groups.

25. A compound as claimed in any of claims 1 -16, wherein Z is -CH2-phenyl, wherein the phenyl is unsubstituted or substituted by one or two groups independently selected

from C \ .4 alkyl, Ci _4haloalkyl and halo.

A compound as claimed in any of claims 1 -25, wherein R^is H or C\ _2alkyl.

27. A compound as claimed in any of claims 1 -25, wherein R^is H.

28. A compound as claimed in any preceding claim, wherein R^ is unsubstituted or substituted phenyl, pyridyl, N-pyrazolyl or N-pyridonyl.

29. A compound as claimed in claim 28, wherein R^ is phenyl substituted by one, two or three halo groups, or when W is a 5 membered heteroaryl ring, R^ may be unsubstituted phenyl or phenyl substituted by one or more halo, methyl or halomethyl groups.

30. A compound as claimed in claim 28, wherein R^ is pyridyl, N-pyrazolyl or N-pyridonyl substituted by one, two or three halo, methyl or methoxy groups.

31. A compound as claimed in any preceding claim, wherein R^ is H or C\ _2alkyl.

32. A compound as claimed in any of claims 17-19, wherein R^ is C\ _2alkyl and R^ is phenyl that is unsubstituted or substituted by one or more halo, methyl or halomethyl groups.

33. A compound as claimed in claim 25, wherein R^ is phenyl that is unsubstituted or substituted by one or more halo, methyl or halomethyl groups.

34. A compound as claimed in any preceding claim, wherein R^ hydrogen or methyl.

35. A compound as claimed in any preceding claim, wherein R^ is hydrogen.

36. A compound as claimed in any preceding claim, wherein R$ is methyl.

37. A compound as claimed in any preceding claim, wherein R11 is H, halo or alkoxy.

38. A compound as claimed in any preceding claim, wherein R9 and RIO are the same as one another.

39. A compound as claimed in claim 38, wherein R^ and R^ are both H.

40. A compound as claimed in any preceding claim, wherein p (or q) is 2 and the two R^ (or RlO) groups are the same as one another.

41. A compound as claimed in claim 40, wherein one of R^ (or RlO) is other than H and the other one is H.

42. A compound according to any of Examples 1-287 or a pharmaceutically acceptable salt thereof.

43. A compound of formula (Id) or a pharmaceutically acceptable salt thereof:

wherein A, R1 to R11, X, Y, m, n, p, q and r are as defined in claim 1;

Z is -C(0)R¹²; and

R¹² is -NHC(0)R¹³ or -NHC(NH)R¹³, in which R¹³ is selected from C 1.4 alkyl, Ci _4haloalkyl, C 1 .5 hydroxyalkyl, Ci _4alkoxy, C2_4alkoxyalkyl, heterocyclyl,

heterocyclylC 1 .4 alkyl, heteroarylCi _4alkyl, C3_6cycloalkyl and

-(Ci .3 alkyl)-(C3_ cycloalkyl), wherein the cycloalkyl and alkyl groups are each optionally substituted by one or two groups independently selected from Ci .4 alkyl, hydroxy or halo.

44. A compound as claimed in claim 43, wherein R^³ is C\ .4 alkyl.

45. A compound as claimed in claim 43 or claim 44, wherein γΐ is CR^H, where R^ is C\ .2 alkyl.

46. A compound as claimed in any of claims 1-45, or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body by therapy.

47. A compound as claimed in any of claims 1-45, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of diabetes.

48. A compound as claimed in any of claims 1-45, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension.

49. A pharmaceutical formulation or composition comprising a compound as claimed in any of claims 1-45 and a pharmaceutically acceptable carrier therefor.

50. A method of treating or preventing diabetes, e.g. type II diabetes, comprising

administering to a human or non-human animal in need thereof an effective amount of a compound as claimed in any of claims 1-45 or a pharmaceutically acceptable salt thereof, or a composition or formulation as claimed in claim 49.

51. A method for the treatment of obesity, metabolic syndrome (syndrome X), impaired glucose tolerance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or hypertension comprising a step of administering to a human or non-human animal in need thereof an effective amount of a compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, or a composition or formulation as claimed in claim 49.