WO2012066077A1 - 1,4 di substituted pyrrolidine - 3 - yl -amine derivatives and their use for the treatment of metabolic disorders - Google Patents

Abstract

Therapeutic compounds are disclosed having the general formula (1) that are useful for the treatment of metabolic disorders, including type II diabetes.The compounds have activity as agonists of GPR1 19. Compounds having the stereochemistry of formula (la) may also demonstrate DPP-IV inhibitory activity.

Description

1 ,4 Dl SUBSTITUTED PYRROLIDINE - 3 - YL -AMINE DERIVATIVES AND THEIR USE FOR THE TREATMENT OF METABOLIC DISORDERS

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)²), 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 GPR1 16) is a GPCR identified as SNORF25 in WOO /50562 which discloses both the human and rat receptors, US 6,468,756 also discloses the mouse receptor (accession numbers: ΑΛΝ95194 (human), AAN95195 (rat) and A N95196 (mouse)).

In humans, GPRi 19 is expressed in the pancreas, small intestine, colon and adipose tissue. The expression profile of the human GPR1 19 receptor indicates its potential utility as a target for the treatment of diabetes.

GPR 1 19 agonists have been shown to stimulate the release of GLP-1 from the GI tract. In doing so, GPR1 19 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-l 's ability to reduce food intake.

International Patent Applications WO 2005/061489, WO 2006/070208, WO 2006/067532, WO 2006/06 531 , WO 2007/003960, WO 2007/003961 , WO 2007/003962, WO 2007/003964, WO 2007/1 16229, 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 2010/001 166, WO 2010/004343, WO 2010/004344, WO 2010/004345, WO 2010/004346, WO 2010/004347 and WO 2010/004348 disclose GPR1 19 receptor agonists.

Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous, yet highly specific, serine protease that cleaves N-terminal dipeptides from polypeptides with L-prolinc or 1.-alanine at the penultimate position. Studies with DPP- IV inhibitors show the principle role of DPP-Γν^* 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 GPR1 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 compatibility in the physicochemical and pharmacokinetic and pharmacodynamic properties of the two active ingredients. WO 2009/034388, WO 2010/103333, WO 2010/103334 and WO 2010/103333 disclose dual GPR119 agonists and DPP-IV inhibitors. The compounds of the invention preferably have dual activity as agonists of GPRl 19 and inhibitors of DPP-IV

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof:

(I) wherein A is a para-linked phenyl, pyridinyl, pyrimidinyl, pyrazinyl or triazinyl;

R* is hydrogen, halo, cyano, Cj ^alkyl, C ^haloalkyl, C j ^alkoxy or C^.galkoxyalkyl;

R is selected from the group consisting of:

(a) phenyl optionally substituted by one or more halo, methyl or halomethyl groups, (b) pyridyl optionally substituted by one or more halo, methyl or halomethy! groups and

(c) N-pyridonyl optionally substituted by one or more halo, methyl or halomethyl groups

R3 is methyl, t^.gcycloalkyl, 4 to 6 membered saturated heterocyclyl (comprising 1 or 2 ring heteroatoms selected from O and S) or C2_4alkyl wherein the C3_gcycloalkyl and C2-4alkyl are optionally substituted by fluoro, cyano, h dro or C_j ^alkyloxy

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

Z is selected from the group consisting of:

(a) C(0)OR⁴,

(b) C(0)R4

(c) S(0)₂R4

(d) a 5- or 6-membered Ν -containing heteroaryl ring optionally

containing 1 to 3 additional heteroatoms selected from Ν, O and S, or a S to 10 membered fused bicyclic system optionally containing 1 to 3 heteroatoms selected from Ν, O and S, wherein the heteroaryl ring or fused bicyclic system is optionally substituted by one or two groups independently selected from halo, cyano, C 1.4 alkyl, C^haloalkyl, C^alkoxy, C.^^alkoxyalkyl, heterocyclyl (a

4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from Ν , O and S), heterocyclyl C \ ^alkyl (wherein the heterocyclyl is a 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from Ν, O and S) and C3_-0cycloaIkyl optionally substituted by Cj .4 alkyl, C \ .4 alkoxy or halo;

and (e) -CH?-phenyl, wherein the phenyl is optionally substituted by one or two groups independently selected from C _j.4 alkyl, C_|_4 haloalkyl and halo;

and when Z is optionally substituted -CH phenyl then p and q are both 0 or 1;

R4 is selected from the group consisting of:

a) Ci_galkyl,

b) phenyl,

c) C2-₀alkoxyalkyl,

d) C^.gcycloalkyl optionally substituted by C^alkyl

e) C3 _f,cycloalkylC _j _4alkyl optionally substituted by C _j _4alkyl, and f) 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms

selected from Ν. O and S, and

g) 5 or 6 membered heteroaryl ring containing 1 to 4 heteroatoms selected from Ν, O and S optionally substituted by one or two groups selected from halo, cyano, Cj _4alkyl, C^haloalkyl, C1.4 lk.oxy, C2.4alkoxyalk.yl, 4 to 6 membered saturated heterocycle comprising 1 or 2 ring hcteroatoms selected from N, O and S and C3_ cycloalkyl wherein the cycloalkyl is optionally substituted by C _] _

4alkyl or halo:

X is selected from C(O) or S(0)₂ with the proviso that when X is S(0)₂ then is methyl, p and q are both 1 and Z is a 5 to 6 membered heteroaryl ring;

each of and is independently hydrogen, halo, Chalky!, Cj^haloalkyl or

Cj .jalkoxy; alternatively ^ and R6 can be joined to form an azabicyclo[33.1 Jnonane, a 3-oxa-7- azabicyclo[3.3.1 jnonane or an azabicyclo[3.2.1 ] octane;

R^ i hydrogen, halo, Cj^alkyl, Cj ^haloalkyl or C^alkoxy;

s is 0, 2 or 3

and when and R^ are both hydrogen then s is 0, 2 or 3,

and when at least one of R^ and is halo, Cj ^alkyl, C _j ^haloalkyl or C^alkoxy, then s is 0

and pharmaceutically acceptable salts thereof.

In particular the invention provides compounds of formula I having the stereochemistry defined below; such compounds may demonstrate DPP-TV inhibitory activity:

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-membcred 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 I .

A is suitably pyridine, pyrimidine or pyrazine typically pyridine or pyrimidinc, e.g., 2- or 3- pyridyl or 2- or 5-pyrirnidinyi, where the 2-, 3- or 5- refers to the point of attachment of the pyrrolidine ring (X being attached in the para position and R¹ being attached at any suitable position).

R1 is suitably hydrogen, halogen or cyano. R^ is preferably hydrogen.

The ring of R^ may optionally be substituted by 1, 2 or 3 substituents. In certain embodiments R^ is optionally substituted by 1 or 2 substituents and in further embodiments it is substituted by 2 or 3 substituents. R^ is preferably optionally substituted by 1, 2, or 3 substituents independently selected from halo and methyl. R^ is preferably optionally substituted by 1 or 2 substituents independently selected from halo and methyl. is suitably phenyl substituted by 1 , 2 or 3 groups selected from halo and methyl groups, R- is suitably phenyl substituted by 2 or 3 halo groups. Halo is suitably fluoro. may be an optionally substituted phenyl or pyridyl, e.g. an optionally substituted phenyl or 2-pyridyl. Examples of R^ include phenyl 2-pyridinyl, 4-fluoro-2- pyridinyl, 5-fluoro-2-pyridinyl, 4-methyl-2-pyridinyl 5-methyl-2-pyridinyl, 2- fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,3-di fluorophenyl, 2,4-difluorophenyl, 2, 5 -di fluorophenyl 2,6- di luorophenyl 2,3 ,4-tri fluorophenyl 2, 3 , 5 -t ri fl uoropheny 1 , 2,3,6-trifluorophenyl, 2,4,5- tri fluorophenyl, 2,4,6-tri fluorophenyl, 2-fluoro-5-methylphenyl and 2 ,4-d ifl uoro -5 -methylpheny 1.

R^ may suitably be methyl, C3_(-,cycloaIkyl or alkyl wherein the C2.4 alkyl is optionally substituted by fluoro, cyano, hydroxy or Cj^alkyloxy. Suitable examples of include methyl, ethyl, n-propyl, i-propyl, cyclopropyl, CH₂CH₂OCH₃ and CH₂CF₃.

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. In certain embodiments p is 1 and q is 0. In other embodiments p is 0 and q is 1 .

In certain embodiments Z is -C(0)OR⁴. In further embodiments Z is C(0)R⁴. In still further embodiments it is S(0)2R .

R⁴ may suitably be alkyl, C .galkoxyalkyl, C3_gcyeloalkyl or€3.5 cy d oalky lalky 1 , wherein said C3_gcycloalkyl or C^.gcycloalkylC \ ^alkyl is optionally substituted by C_j .4 alkyl.

Examples of R⁴ include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl or t-butyl, cyclopropyl and 1 -methylcyclopropyl. In certain embodiments R⁴ is propyl, especially isopropyl.

Z may be a heteroaryl group optionally substituted by one or two groups selected from halo, Cj_4 alkyl, Cj ^haloalkyl, C j ^alkoxy, C2_4alkoxyalkyl, 4 to 6 membercd saturated heterocyclyl comprising 1 or 2 ring heteroatoms selected from N, O and S, C^.gheterocyclyl C_j ^alkyl (wherein the heterocyclyl is a 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from N, O and S) and C3_gcycloalkyl wherein the cycloa!kyl is optionally substituted by C\ .

4 alkyl or halo. Preferred C_j ^haloalkyls are perfluoroalkyls, e.g. CF₃, CF2Me and CHF_?

When Z is heteroaryl suitable heteroaryl groups include oxadiazole, pyrimidinc, pyridazine, thiazole, tetrazole, benzothiazole and thiadiazole, e.g., oxadiazole and pyrimidine. In some embodiments Z may comprise l,2,4-oxadiazoi-3-yi, 1 ,2,4-oxadiazol-5-yl, pyrimidin-2-yi or a 2H- tetrazol-5-yl, which may be substituted by any of the aforementioned substituents. When Z is a substituted heteroaryl suitable substituents include ethyl, i-propyl, t-butyl, cyclopropyl, chloro, 1-methylcyclopropyl, CF₃, CH₂F, CF₂H, CH(OMe)Me, C(Me)₂OH, C(Me)₂F, CF₂Me, CH₂OMe and 2-tetrahydrofuranyl.

In a further alternative, when p and q are both 0 or 1 , Z may be -CFFj-phenyl, wherein the phenyl is optionally substituted by one or two groups independently selected from Ci .4 alkyl, Cj_4 haloalkyl and halo. Particular embodiments include those wherein Z is -€¾ -phenyl optionally substituted by one or two halo or methyl groups, e.g. 4-fluorophcnyl

R7 is preferably hydrogen.

X is suitably C(O), have the formula:

The molecular weight of the compounds of the invention is suitably less than about 800, typically less than about 600.

The invention also includes isotopically labeled compounds, which are similar to those recited in formulae (I), (la) and (lb) 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 ¾, HC, ¹⁴C and ^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 14Q are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ¾ and carbon- 14, i.e., ^C, isotopes are particularly preferred for their ease of preparation and detectability. and % 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), (la) and (lb) 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), (la) and (lb) 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. When used herein the term "cycloalkyl" refers to a 3 to 6 C saturated carbocycle moiety e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. When used herein the term 'heterocyclyl' refers to a 4 to 6 membered saturated heterocyele comprising 1 or 2 ring hetcroatoms selected from N, O and S. Examples of hetcroeyeles include tetrahydrofuran, pyrrolidine, tetrahydropyran, piperidine, oxetane and azetidine. When used herein the term "heteroaryl" refers to a 5- or 6-membered hcteroaryl ring optionally containing one or more, e.g. 1. 2 or 3 heteroatoms selected from N, O and S, or a 8 to 10 membered fused bicyclic system optionally containing one or more, e.g. 1 , 2 or 3 heteroatoms selected from N, O and S. Examples of heteroaryl rings include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 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 exist s, 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, cthanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholinc, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimcthylamine, 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, iscthionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-tolucnesulfonic, trifluoroacetic acid and the like.

Since the compounds of the invention are intended for pharmaceutical use they arc 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, R2 R³, R⁴,

R⁵, R , R , A, X, Z, p, q, r and s are as defined for formula (I). PG is a protecting group, LG is a leaving group, Hal is halogen, Het is heteroaryl.

Compounds of formula (I) can be prepared as outlined in Scheme 1. Removal of the protecting group PG from the amine functionality in compounds of formula (II) can be achieved using standard conditions well known to those skilled in the art.

Compounds of formula (II) where X is C(O) can be prepared as outlined in Scheme 2. Esters of formula (V) can be prepared by SN_Ar displacement of suitable haloaromatic compounds of formula (III) with amines of formula (IV) under standard conditions, for example, DBU and DMSO at 80 - 100°C. Acids of formula (VI) can be prepared from esters of formula (V) under standard conditions, for example, LiOH, water and methanol at room temperature. Amides of formula (If) can be prepared from acids of formula (VI) with amines of formula (VII) under standard amide coupling conditions, for example, HOBT and EDCI, in a suitable solvent, such as DCM.

Scheme 2

VI VII II

Compounds of formula (II) where X is S(0)₂ can be prepared as outlined in Scheme 3. Sulfonamides of formula (IX) can be prepared by reaction of amine of formula (VII) with sulfonyl chloride of formula (VIII) under standard conditions, for example, triethylamine in a suitable solvent, such as DCM. Compounds of formula (II) can be prepared by SN_Ar displacement of suitable haloaromatic compounds of formula (IX) with amines of formula (IV) under standard conditions, for example, DBU and DMSO at 80 - 100°C.

Scheme 3

Compounds of formula (VII) where Z is C(0)OR⁴ can be prepared as outlined in Scheme 4, Carbamates of formula (XII) can be prepared from amines of formula (X) and chloroformates of formula (XI) under standard conditions, for example, triethylamine in a suitable solvent, such as DCM. Removal of the protecting group PG from the amine functionality in compounds of formula (XII) can be achieved using standard conditions well known to those skilled in the art.

S heme 4

Compounds of formula (VII) where Z is C(0)R⁴ can be prepared as outlined in Scheme 5. Amides of formula (XIV) can be prepared from amines of formula (X) and acid chlorides of formula (XIII) under standard conditions, for example, triethylamine in a suitable solvent, such as DCM. Removal of the protecting group PG from the amine functionality in compounds of formula (XIV) can be achieved using standard conditions well known to those skilled in the art.

Compounds of formula (VII) where 7. is S(0)₂R⁴ can be prepared as outlined in Scheme 6. Sulfonamides of formula (XVI) can be prepared from amines of formula (X) and sulfonyl chlorides of formula (XV) under standard conditions, for example, triethylamine in a suitable solvent, such as

DCM. Removal of the protecting group PG from the amine functionality in compounds of formula (XVI) can be achieved using standard conditions well known to those skilled in the art.

Compounds of formula (VII) where Z is heteroaryl can be prepared as outlined in Scheme 7. Compounds o formula (XVIII) can be prepared by SN_Ar displacement of suitable haloaromatic compounds of formula (XVII) with amines of formula (X) under standard conditions, for example, DBU and DMSO at 80 - 100°C. Alternatively, compounds of formula (XVIII) can be prepared by reaction of suitable haloaromatic compounds of formula (XVII) with amines of formula (X) under Buchwald-Hartwig conditions, such as, Pd₂(dba)₃ and BIN/VP in a suitable solvent, such as toluene at 1 10°C. Removal of the protecting group PG from the amine functionality in compounds of formula (XVIII) can be achieved using standard conditions well known to those skilled in the art.

Compounds of formula (IV) where R² is N-pyridonyl can be prepared as outlined in Scheme 8. Compounds of formula (XX) can be prepared from alcohols of formula (XIX) under standard conditions, for example, methanesulfonyl chloride and triethylamine in a suitable solvent, such as, THF at 0°C. Diazabicyclo compounds of formula (XXI) can be prepared from compounds of formula (XX) by treatment with sodium hydride in a suitable solvent, such as, THF at 0°C. Compounds of formula (XXII) can be prepared from compounds of formula (XXI), pyrid-2-one and potassium tert- butoxide in a suitable solvent, such as, ΝΜΡ in a microwave reactor at 100°C. Removal of the protecting group PG' from the amine functionality in compounds of formula (XXII) can be achieved using standard conditions well known to those skilled in the art.

Examples and syntheses of building blocks of formula (IV) have been described elsewhere: Benbow et.al, WO2007148185; Backes et.ai, Bioorg. Med. Chem. Lett., 2007, 17 2005-2012; Pei et.al, J. Med. Chem., 2007, 50 (8), 1983-1987; Cox et.ai, Bioorg. Med. Chem. Lett., 2007, 17 4579- 4583; Wright et.al., Bioorg. Med. Chem. Lett. , 2007, 17 5638-5642.

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 (1). Compound libraries may be prepared by a combinatorial "split and mix" approach or by multiple parallel synthesis using either solution or solid phase chemistry, using procedures known to those skilled in the art.

During the synthesis of the compounds of formula (I), labile functional groups in the intermediate compounds, e.g. hydroxy, carboxy and amino groups, may be protected. The protecting groups may be removed at any stage in the synthesis of the compounds of formula (1) or may be present on the final compound of formula (I). A comprehensive discussion of the ways in which various labile functional groups may be protected and methods for cleaving the resulting protected derivatives is given in, for example, Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wuts, (1991) Wiley-Interscience, New York, 2^nd edition.

The processes for the production of the compounds of formula (I) and intermediates thereto as described above are also included as further aspects of the present invention.

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), (VI), (VII), (IX), (XVI) and (XVIII) 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 GPR1 19 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 nontoxic 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 GPR1 19 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 5g 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 Img to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 2()0mg, 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 ca 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 ().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 GPR1 19 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-TV^" 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 dyslipidacmia). 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 o 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- /γ agonists, RXR agonists, fatty acid oxidation inhibitors, a-glucosidase inhibitors, β-agonists, phosphodiesterase inhibitors, lipid lowerin 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, somo statin analogs, glucokinase activators, glucagon antagonists, insulin signalling agonists, FTP IB inhibitors, gluconeogenesis inhibitors, antilypolitic agents, GSK inhibitors, galanin receptor agonists, anorectic agents, CCK receptor agonists, leptin, serotonergic/dopaminergic antiobesity drugs, reuptake inhibitors e.g. sibutraminc, CRT antagonists, CRF binding proteins, thyromimctic 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:

LCMS-method 1 ; Atlantis 3μ C|_S column (3.0 x 20.0mm, flow rate - 0.85mL/min) eluting with a HjO-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^.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 i either the positive (ES⁺) or negative (ES ) ion modes.

LCMS-method 2: Phenomencx Kinetex CI S 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% I O to 5% MeC 95% H- ₂0; 0.1-1.50 min: Ramp up to 100% MeCN; 1 .5-1.75min: Hold at 100% MeCN; 1.75-1 .Smin: 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 both the positive (ES⁺) or negative (ES^") ion modes.

LCMS-method 3 data were obtained as follows: Xbridge C18 column (3.0 x 150mm, 5μΜ, flow rate l .OmL/min) eluting with an McCN-l OmM NH₄HCO₃ solution over 5 min with UV detection at 215 - 350nm. Gradient information: 0-0.1 min: hold at 5% MeCN 95% NH₄HCO,; 0.1- 3,0 min: 5% MeCN 95%NH₄HC<¾ to 5% NH₄HC(¾ 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 4 data were obtained as follows: Xbridge C_{1 g} 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 5 data were obtained as follows: Xbridge C₁₈ column (2.1 5.0mm, 2.55μΜ, flow rate 0.8mL/min) eluting with an MeCN- 10m VI 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; 4-4.6miri: hold at 98% NH₄HCO3 2% MeCN. 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 I IPLC 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 Qg column (19 x 100mm, 5μΜ, flow rate 20mL/min) cluting with a

H₂0-MeCN solution containing 0.2% NH OH using a 10 minute gradient with UV detection at 220 nm. Unless otherwise stated, the standard method was employed for purification.

Chiral-HPI.C was performed on a Oaicel chiralpak ΙΛ 250 x 20 mm, 5 μΜ column.

Abbreviations and acronyms: AcOH: Acetic acid; Aq: Aqueous; BOP: (Benzotriazol-1- yloxy)tris(dimcthyIamino)phosphonium hexafluorophosphate; DBU: 1 ,8-Diazabicyclo[5.4.0]undec- 7-ene; DCE: 1, 2-Dichloroethane; DCM: Dichloromethane; DEA: Diethylaminc; DIPF.A: Diisopropylethylamine; DMAP: Dimcthylpyridin-4-ylamine; EDO: (3-

Dimcthylaminopropyl)ethylcarbodiimide hydrochloride; Et₂0: Diethyl ether; EtOH: Ethanol; EtOAc: Ethyl acetate; h: hour(s); HC1: Hydrochloric acid; HC0₂H: Formic acid; H₂0: Water; HOBt: 1 - Hydroxybenzotriazole monohydrate; HP EC: High performance liquid chromatography; II I: Isohexane; IPA: Isopropyl alcohol; IMS: Industrial methylated spirits; M: Molar; MeCN: Acetonitrile; MeOH: Methanol; MgS0₄: Magnesium sulfate; min: minute/s; PPA: 1 - Propanephosphonic acid cyclic anhydride; NaHC0₃: Sodium hydrogen carbonate; NaOH: Sodium hydroxide; Na₂S0₄: Sodium sulfate; NE¾: Ammonia; NH₄CI: Ammonium chloride; NH₄HCO₃: Ammonium carbamate; NH₄OH: Ammonium hydroxide; RT: Retention time; r.t.: Room temperature; Sat: saturated; SCX: Strong Cation Exchange resin; Si0₂: Silica gel; THF: Tetrahydrofuran; TEA: Trifluoroacetic acid; TMSC1: Trimcthylsilyl Chloride. The syntheses of the following compounds have been described elsewhere: 2,2-Difluoro-N-hydroxy- acetamidine and 2,2-Difluoro-N-hydroxy-propionamidine: Bertram, L., et al., WO2010004348; 2- Fluoro-N-hydroxy-2-methyl-propionamidinc: Azimioara, M. et al, WO201 1044001 ; (3-Benzyl-3- aza-bicyclo[3.2.1 ]ocl-8-yl)-carbamic acid tert-butyl ester, Aranyi, P. et al., WO2005021536. All other compounds were available from commercial sources.

Preparation 1: 8-Benzyl-8-aza-bicyclo 3.2.1 ] octan-3-one oxime

To a solution of 8-bcnzyl-8-aza-bicyclo[3.2.1]octan-3-one (l O.Og, 46.4mmol) in EtOH (250mL) was added hydroxylamine hydrochloride (3.23g, 46.4mmol) and pyridine (4.13mL, 51.1 mmol) and the mixture was heated to reflux for 18 h. The reaction mixture was cooled to r.t. and a saturated solution of sodium bicarbonate added. The resulting suspension was filtered and the filtrate concentrated in vacuo. The residue was dissolved in DCM and washed with water (x2), then brine. The organics were then dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound. RT = 0.43 min; mlz (ES⁺) - 231 .25 [ + Hf (LCMS Method - 2). Preparation 2: 8-Benzyl-8-aza-bicyclo 3.2.1 ]oct-3-ylamine

To an oven dried, argon purged 3-necked flask containing anhydrous toluene (lOOmL, 900rnmol) was added sodium metal (5.13g, 223mmol) in pieces. The mixture was heated to reflux before the slow addition of a solution of 8-benzyl-8-aza-bicyclo[3.2.1 ]octan-3-one oxime (Preparation 1, 4.67g, 20.3mmol) in pentan-l -ol (30mL) and toluene (40mL) over 15 nun (hydrogen gas evolution). The mixture was heated for a further 2 h before cooling to 80 °C and iso- propanol added (75 ml,). The mixture heated at 80 °C for 1 h before cooling to room temperature. The mixture was diluted with water (200mL) and concentrated HC1 added until pill was obtained. The layers were separated and the organic layer basified with sodium hydroxide pellets until a pH of 12 was obtained. The mixture was extracted with ethyl acetate (x2), the combined organics dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (DCM:7M ammonia in MeOH, 93:7) afforded the title era-compound, mi (ES⁺) = 217.25 [M + H (LCMS Method - 2).

Preparation 3: (8-Bcnzyl-8-aza-bic lo[3.2.1]oct-3-yl)-carbamic acid tert-b\\ y\ ester

To a solution of 8-benzyl-8-aza-bicyclo[3.2.1 ]oct-3-ylamine (Preparation 2, 1.88g, 8.69mmol) in TIIF (75mL) was added di-teri-butyldicarbonate (1 .99g, 9.12mmol) and the mixture allowed to stir at r.t. under argon for 18 h. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water (x2), then brine. The organics were dried (MgS0₄), filtered and the filtrate concentrated in vacuo to afford the title compound. RT = 0.68 min; mlz (ES ) = 317.34 [M i ll]- (LCMS Method - 2).

Preparation 4: 8-Benzyl-8-aza-bic -3-yl)-methyl-carbamic acid fert-butyl ester

To an argon purged, 2-necked flask containing anhydrous THF (80mL) was added lithium aluminum hydride (0.554g, 14.6mmol) and the suspension cooled to 0 °C. A solution of (8-benzyl-8- aza-bicyclo[3.2,l]oct-3-yl)-carbamic acid iert-butyl ester (Preparation 3, 1.54g, 4.87mmol) in THF (20mL) was added dropwise and the mixture allowed to warm to room temperature before heating to reflux for 4 h. The mixture was then cooled to r.t. and water slowly added (O.SmL) followed by aqueous sodium hydroxide solution (2M, 0.75mL) then water (1.5mL). The mixture was filtered through celite and di-7er/-butyldicarbonate (1.06g, 4.87mmol) added to the filtrate. The mixture was allowed to stir at room temperature under argon for 18 h. The mixture was concentrated in vacuo, the residue dissolved in DCM (l OOmL) and washed with 1 M sodium hydroxide solution (30niL) then brine. The organics were dried (MgSC)₄), filtered and concentrated in vacuo. Purification by column chromatography (DCM to DCM:7M ammonia in methanol 95:5) afforded the title compound. RT = 0.72 min; mlz (F.S ) - 331.37 [M + Hf (LCMS Method - 2).

Preparation 5: (8-Aza-bicyclo[3.2.1]oc -3-yl)-methyI-carbamic acid r<?r/-butyl ester

A solution of 8-benzyl-8-aza-bicyclo[3.2.1Joct-3-yl)-methyl-carbamic acid /e/7-butyl ester (Preparation 4, 2.0g, 6.0mmol) in methanol (0.05M) was passed through an H-Cubc apparatus (10% Pd/C Catcart, 50 °C, 8 bar) at a flow rate of ImL per min. The solvent was removed in vacuo to afford the title compound: mlz (ES⁺) = 241.30 [M + R]^~ (LCMS Method-2).

Preparation 6: (l-Benzyl-4-methyl-pi eridin-4-yl)-methyl-carbamic acid fert-butyl ester

The title compound was synthesized from (l -benzyl-4-methyl-piperidin-4-yl)-carbamic acid tert-batyl ester employing a procedure similar to that outlined in Preparation 4: Ή NMR δ_Η (301MHz, CDCI₃): 7.36 - 7.15 (m, 5H), 3.47 (s, 2H), 2.83 (s, 3H), 2.51 - 2.16 (m, 8H), 1.85 - 1.68 (m, 211), 1 .44 (s, 9H), 1 .24 (s, 3H).

Preparation 7: Methyl-(4-methyl-piperidin-4- l)-carbamic acid tert-butyl ester

To a suspension of 10% Pd C (7()0mg) in MeOH (500mL) in an autoclave was added (1- benzyl-4-methyl-piperidin-4-yl)-methyl-carbarnic acid fcrf-butyl ester (Preparation 6, 9.0g, 28.26mmol) and the mixture hydrogenated (40 psi, 75 °C) for 4 h. The mixture was then filtered through celite and the filtrate concentrated in vacuo to afford the title compound: ¾ NMR δ_Η (301MHz, CDCI₃): 2.88 - 2.69 (m, 5H), 2.28 - 2.07 (m, 2H), 1.76 - 1.57 (m, 4H), 1.44 (s, 9H), 1.26 (s, 311). Preparation 8: 3-Fluoro-4-oxo-piperi ester

To a solution of 4-oxo-piperidine- l -carboxylic acid benzyl ester (15g, 64mmol) in anhydrous DMF (80mL) was added anhydrous triethylamine (22mL, 150mmol) and the reaction heated to 80 °C for 18 h. TMSC1 (9.8mL, 77ramol) was added followed by triethylamine (22mL) and the reaction heated to 80 °C for 18 h. The reaction was cooled to room temperature, diluted with hexane and washed with water then brine solution. The organics were dried (sodium sulfate), filtered and concentrated in vacuo. To a solution of the residue in MeCN (300 rnL) at 0 °C under argon was added 1 -chloromethyl-4-fluoro-l ,4-diazaoniabicyclo[2.2.2]octane bis(tetrafiuoroborate) (25g, 71 mmol) portion wise and the mixture allowed to warm to room temperature and stirred for 18 h. The mixture was concentrated in vacuo and the residue partitioned between water and ethyl acetate. The organics were then washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by flash chromatography (hexane: HtOAc 7:3 - 1 : 1 ) afforded the title compound: Ή MR 8„ (400MHz, CDCU): 7.41 -7.39 (m, 5H), 5.35 (s, 2H), 4.91 -4.80 (m, 1H), 4.60-4.49 (m, 1 H), 4.29-4.23 (m, I H), 3.41 -3.36 (m, 2H), 2.69-2.55 (m, 2H).

Preparation 9: ci.v-3-F!uoro-4-methylamino-piperidine-l-carboxylic acid benzyl ester

To a solution of 3-fluoro-4-oxo-piperidine-l -carboxylic acid benzyl ester (Preparation 8, 4.00g, 15.9rnmol) in anhydrous 1 ,2-dichloroethane (40mL) was added a solution of methylamine in MeOH (2M, 24mL, 48mmol) and the mixture stirred for 2 h at r.t. before the addition of sodium triacetoxyborohydride (5. l g, 24mmol). The reaction was stirred at r.t. for 1 8 h before the addition of saturated potassium carbonate solution and the organics extracted with DCM. The organics were then dried (sodium sulfate), filtered and concentrated in vacuo. Purification by flash chromatography (1 :2:97 7 ammonia in MeOH:MeOH:DCM) afforded the title compound: RT = 0.56 min, m/z (ES⁺) = 267.3 [M + Hf (LCMS Method - 2). Preparation 10: m-4-(it'ri-Butox carbon l-methyl-amino)-3-fluoro-piperidine-l-carbox lic acid benzyl ester

To a solution of s-3-fluoro-4-methylamino-piperidine-l -carboxylic acid benzyl ester (Preparation 9, 542mg, 2,04mmol) in DCM (10 ml.) was added triethylamine (0.85 I mL, 6.10mmol) followed by di-teri-butyldicarbonate (444mg, 2.04mmol) and the mixture stirred at r.t. for 18 h. The mixture was diluted with water and the organics dried (sodium sulfate), filtered and concentrated in vacuo. Purification by flash chromatography (hexane - 7:3 hexanerethyl acetate) afforded the title compound. RT = 1 .28 min, m/z (ES⁺) = 389.3 [M +Na]⁺ (LCMS Method - 2).

Preparation 11: ds-3-Fluoro-piperidin-4- l)-methyl-carbamic acid tert-butyY ester

To a solution of cw-4-(½rt-butoxycarbonyl-methyl-amino)-3-fluoro-piperidine-l -carboxylic acid benzyl ester (Preparation 10, 634mg, 1 .73mmol) in EtOH (20 mL) and 1 ,4-cyclohexadiene (4.05mL, 43.2mmol) was added 10% Pd/C (150mg, 4.2mmol) as a slurry in EtOH under argon. The reaction was stirred at r.t. for 18 h then filtered through celite and concentrated in vacuo. The crude residue was loaded onto a SCX cartridge, washed with methanol, eluted with 7N ammonia in MeOH and concentrated in vacuo to afford the title compound: Ή N.MR δ_Η (400MHz, CDC1₃): 4.79-4.66 (m, 1H), 4.27-4.18 (m, 1H), 3.31 -3.20 (m, 2H), 2.92 (s, 3H), 2.78-2.71 (m, 2H), 2.09-1.85 (dq, J = 14, 6 Hz, 1H), 1.57-1.50 (m, 10H).

Preparation 12: afrans-3-Fluoro-4-methylamino-piperidine-l-carboxyIic acid benzyl ester

To a solution of 3-fluoro-4-oxo-pipcridine-l -carboxylic acid benzyl ester (Preparation 8, l .OOg, 3.98mmol) in anhydrous MeOH (l OmL) was added AcOH (0.5mL, 9mmol) followed by a solution of methylamine in MeOH (2 M, 6mL). The mixture was stirred at r.t. for 1 h before the addition of sodium cyanoborohydride (0.38g, 6.0mmol) portion wise over 5 min. After 3 h the reaction was quenched with a saturated solution of sodium bicarbonate and the organics extracted with ethyl acetate. The organics were then dried (sodium sulfate), filtered and concentrated in vacuo.

Purification by flash chromatography (97:3 DCMrMeOH then 1 :5:94 7N ammonia in MeOH:MeOH:DCM) afforded the title compound. RT = 0.56 min, m/z (ES⁺) = 267.3 [M +Naf (Method -2).

Preparation 13 : fra«s-4-(teri-Butoxycarbonyl-methyI-amino)-3-fluoro-piperidine-l-carboxylic acid benzyl ester

The title compound was synthesized from ira«.< -3-fluoro-4-methylamino-piperidine-l - carboxylic acid benzyl ester (Preparation 12) employing a procedure similar to that outlined in Preparation 10: ^!H NMR ¾ (400MHz, CDC1₃): 7.48 - 7.32 (m, 511), 5.17 (s, 2H), 4.67 - 4.36 (m,

2H), 4.36 - 4.17 (m, 2H), 2.91 - 2.77 (m, 511), 1.85 - 1.69 (m, 2H), 1.50 (s, 9H).

Preparation 14: (ira/is-3-ITuoro-piperidin-4-yi)-meth l-carbaniic acid fert-butyl ester

The title compound was synthesized from ira«5-4-(/er/-butoxycarbonyl-methyl-amino)-3- fluoro-piperidine- 1 -carboxylic acid benzyl ester (Preparation 13) employing a procedure similar to that outlined in Preparation 11 : Ή NMR δ_Η (400MHz, CDC1_.,): 4.64 - 4.39 (m, 1H), 4.31 - 3.89 (m,

1H), 3.52 - 3,39 (m, 1H), 3.12 - 3.01 (m, 1H), 2.86 (br. s., 3H), 2.74 - 2.56 (m, 2H), 1 .83 - 1.62 (m, 2H), 1.50 (s, 9H).

Preparation 15: 4-Cyclopropylamin -piperidine-l-carboxylic acid benzyl ester

To a solution of 4-oxo-piperidine-l -carboxylic acid benzyl ester (l Og, 43.1 mmol) in DCM (lOOmL) was added acetic acid (3.7mL, 64.6mmoI) and cyclopropylamine (3.7g, 64.6mmol). The mixture was cooled to 10 °C, sodium triacetoxyborohydride (13.7g, 64.6mmol) added and the mixture was stirred at room temperature for 1 8 h. The reaction mixture was quenched with water and washed with NaHCOj. The aqueous layer was extracted with DCM (3x), the organics dried (MgSC^), filtered and concentrated in vacuo. Purification by column chromatography (DCM:7M ammonia in MeOH, 95 :5) afforded the title compound: RT = 0.78 min; miz (ES~) = 275.5 [M + II] ' (LCMS Method - 4).

Preparation 16: 4-(2-Methoxy- boxylic acid benzyl ester

The title compound was synthesized from 4-oxo-piperidine- 1 -carboxylic acid benzyl ester and 2-methoxy-ethylamine employing a procedure similar to that outlined in Preparation 15: Ή NMR δ„ (301 MHz, CDCh): 7.40 - 7.27 (m, 5H), 5.12 (s, 2H), 4.24 - 4.01 (m, 2H), 3.49 (t, J=5.0 Hz, 2H), 3.35 (s, 3H), 2.74 - 2.98 (m, 4H), 2.71 - 2.55 (m, 1H), 1.96 - 1.76 (m, 2H), 1.39 - 1.19 (m, 2H). Preparation 17: 4-(½r/-Butoxycarbonyl-cyclopropyl-amino)-piperidinc-l-carboxylic acid benzyl ester

To a solution of 4-cyclopropylamino-piperidine-l -carboxylic acid benzyl ester (Preparation 15, 1 1 .79g, 43 , 13mmol) in THF (1 18mL) was added aqueous sodium carbonate solution (2N, 151 mL) followed by di-teri-butyldicarbonate ( 1 1.3g, 5 1.75mmol) and the mixture stirred at r.t. for 18 h. The mixture was diluted with DCM, washed with water and the organics dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (heptane: EtOAc, 50:50) afforded the title compound: Ί ΐ NMR δ_Η (301 MHz, CDC1₃): 7.43 - 7.28 (m, 5H), 5. 12 (s, 211), 4.39 -4.14 (m, 2H), 3.88 -3.70 (m, I I I), 2.89 -2.66 (m, 2H), 2.38 -2.25 (m, 1 H), 2.03 - 1 .1 8 (m, 2H), 1 .79 -1 .63 (m, 211), 1.45 (s, 9H), 0.79-0.69 (m, 2H), 0.67-0.58 (m, 2H). Preparation 18: 4-[½r -Butoxycarbonyl-(2-methoxy-ethyl)-amino|-piperidine-l-carboxylic acid benzyl ester

The title compound was synthesized from 4-(2-methoxy-ethylamino)-piperidine- 1 -carboxylic acid benzyl ester (Preparation 16) employing a procedure similar to that outlined in Preparation

17: Ή NMR δ_Η (301MHz, CDC1₃): 7.41 - 7.28 (m, 5H), 5.12 (s, 2H), 4.39 - 4.14 (m, 2H), 3.47 - 3.36 (m, 211), 3.32 (s, 311), 3.29 - 3.14 (m, 2H), 2.91 - 2.69 (m, 311), 1.80 - 1.59 (m, 411), 1.46 (s, 9H).

Preparation 19: Cyclopropyl-piperidin-4- l-carbamic acid tert-butyl ester

To a solution of 5% Pd/C (0.50g) in IMS ( l OOmL) was added 4-(½/7-butoxycarbonyl- cyclopropyl-amino)-piperidinc-l -carboxylic acid benzyl ester (Preparation 17, 14.92g, 39.9mmol) and the mixture hydrogenated at 40 bar for 1 h at room temperature. The mixture was then filtered through celite and the filtrate concentrated in vacuo to afford the title compound: Ή NMR δ_Η (301MHz , CDClj): 3.81 -3.66 (m, 1H), 3.19 - 3,07 (m, 2H), 2.71 - 2.56 (m, 2H), 2.38 - 2.27 (m, 1 H), 2.08 -1 .98 (m, IH), 1 ,98 - 1.81 (m, 2H), 1.79 - 1.67 (m, 2H), 1.46 (s, 9H), 0.80 - 0.70 (m, 211), 0.70 - 0.61 (m, 2H).

Preparation 20: (2-Methoxy-ethyl)-piperidin-4- l-carbamic acid tert-butyl ester

The title compound was synthesized from 4-[teri-butoxycarbonyl-(2-methoxy-ethyl)-amino]- piperidine-1 -carboxylic acid benzyl ester employing a procedure similar to that outlined in Preparation 18: RT = 0.63 min; mlz (ES⁺) = 259.49 [M l H]⁺ (LCMS Method - 4). Preparation 21: (l-Cyano-piperidin-4- l)-methyl-carbamic acid tert-butyl ester

To a solution of methyl-pipcridin-4-yl-earbamic acid tert-butyl ester (2,G8g, 9,68mmol) in DCM (25mL) was added a slurry of NaHC0₃ (2.44g, 29.1mmol) in water (6mL). The resulting reaction mixture was cooled to 0 °C and a solution of cyanogen bromide (1.23g, 1 1.6mmol) in DCM (3mL) was added dropwise over 1 min, before warming to r.t. and stirring for 2.5 h. The reaction mixture was diluted with water, the layers separated and the aqueous layer extracted with DCM. The combined organic extracts were washed with brine, dried (MgSC^), filtered and concentrated in vacuo to afford the title compound: RT = 3.12 min; m/z (ES⁺) = 240.17 [M + H]^~.

Preparation 22: (8-Cyano-8-aza-bic 1]oct-3-yl)-methyl-carbamic acid tert-butyl ester

The title compound was synthesized from (8-aza-bicyclo[3.2.1]oct-3-yl)-methyl-carbamic acid tert-butyl ester (Preparation 5) employing a procedure similar to that outlined in Preparation 21 : RT = 1.05 min; m/z (ES⁺) = 266.3 [M + H]⁺ (LCMS Method - 2).

Preparation 23: (l-Cyano-4-methyl-pi eridin-4-yl)-methyl-carbaniic acid tert-butyl ester

The title compound was synthesized from methyl-(4-methyl-piperidin-4-yl)-carbamic acid tert-butyl ester (Preparation 7) employing a procedure similar to that outlined in Preparation 21:

Ή MR δ_Η (301MHz, CDC¾): 3.29 - 3.11 (m, 4H), 2.80 (s, 3H), 2.56 - 2.42 (m, 2H), 1.78 - 1.62 (m, 2H), 1.44 (s, 9H), 1.25 (s, 3H).

Preparation 24: (m-l-Cyano-3-fluoro- iperidin-4-yl)-methyl-carbamic acid tert-butyl ester

The title compound was synthesized from (cij-3-fluoro-piperidin-4-yl)-methyI-carbamic acid tert-butyl ester (Preparation 11) employing a procedure similar to that outlined in Preparation 21 : RT - 0.97 min; miz (ES') = 280.29 [M+ II] ^' (LCMS Method - 2). Preparation 25: (l-Cyano-piperidin-4- l)-ethyI-carbamic acid tert-butyl ester

The title compound was synthesized from ethyl-piperidin-4-yl-carbamic acid tert-butyl ester employing a procedure similar to that outlined in Preparation 21: RT = 3.43 min; miz (ES^') = 254.16 [ + Hf.

Preparation 26: (l-Cyano-piperidid-4- l)-cyclopropyl-carbamic acid tert-butyl ester

The title compound was synthesized from cyclopropyl-pipcridin-4-yl-carbamic acid tert- butyl ester (Preparation 19) employing a procedure similar to that outlined in Preparation 21 : RT = 1.07 min; miz (ES⁺) = 288.32 [M + I If (LCMS Method - 2).

Preparation 27: (l-Cyano-piperidin-4- l)-isopropyl-carbamic acid tert-butyl ester

The title compound was synthesized from isopropyl-piperidin-4-yl-earbamic acid tert-butyl ester employing a procedure similar to that outlined in Preparation 21: Ή NMR δ_Η (301 MHz, CDClj): 3.56 - 3.38 (m, 3H), 3,17 - 2.96 (m, 3H), 2.26 - 1.92 (m, 2H), 1.69 - 1.57 (m, 2H), 1.48 (s, 9H), 1.20 (d, J=6.4 Hz, 611). Preparation 28: (l-Cyano-piperidin-4- l)-propyl-carbaniic acid tert-butyl ester

The title compound was synthesized from piperidin-4-yl-propyl-carbamic acid tert-butyl ester employing a procedure similar to that outlined in Preparation 21 : Ίΐ NMR δ_Η (301MHz, CDC1,): 4.14 - 3.88 (m, 1H), 3.56 - 3.37 (m, 2H), 3.17 - 2.89 (m, 411), 1.99 - 1.63 (m, 4H), 1.60 - 1.48 (m, 21 Γ), 1.45 (s, 9H), 0.93 - 0.83 (m, 3H).

Preparation 29: (l-Cyano-piperidin- -yl)-(2-methoxy-ethyl)-carbamic acid tert-butyl ester

The title compound was synthesized from (2-methoxy-ethyl)-piperidin-4-yl-carbamic acid tert-butyl ester (Preparation 20) employing a procedure similar to that outlined in Preparation 21 :

Ή NMR δ_Η (301MHz, CDC1₃): 3.56 - 3.38 (m, 5H), 3.33 (s, 3H), 3.31 - 3.20 (m, 2H), 3.15 - 2.98 (m, 2H), 2.03 - 3.15 (m, 2H), 1.77 - 1.64 (m, 211), 1.46 (s, 9H).

Preparation 30: 4-(2,2,2-Trifluo ro-ethylamino -piperidine- l-carbonitrile

The title compound was synthesized from piperidin-4-yl-(2,2,2-trifluoro-ethyl)-aminc employing a procedure similar to that outlined in Preparation 21 : ^lH NMR δ_Η (301 MHz, CDC1₃): 3,46 (dt, 7=13.2, 4,0 Hz, 2H), 3.29 - 3.12 (in, 2H), 3.1 1 - 2.94 (m, 211), 2.84 - 2.68 (m, 1 H), 1.91 (dd, J=13.1 , 3.4 Hz, 2H), 1.57 - 1 ,39 (m, 2H), 1.34 - 1.08 (m, 1H).

Preparation 31: (3-Benzyl-3-aza-bic clo[3.2.1]oct-8-yi)-methyl-carbamic acid tert-butyl ester

The title compound was synthesized from (3-benzyl-3-aza-bicyclo[3.2.1]oct-8-yl)-carbamic acid tert-butyl ester employing a procedure similar to that outlined in Preparation 4. The crude mixture was then taken on without further purification to Preparation 32. Preparation 32: (3-Cyano-3-aza-bic clo[3.2.1|oct-8-yl)-niethyI-carbamic acid ferf-butyl ester

To a suspension of 10% Pd/C (2,5g) in MeOH (500mL) in an autoclave was added (3- benzyl-3-aza-bicyclo[3.2.1 ]oct-8-yl)-mcthyl-carbamic acid /erf-butyl ester (Preparation 31, 32, 8g, O.lmol) and the mixture hydrogenated (40 psi, 80°C) for 5 h. The mixture was then filtered through celite and the filtrate concentrated in vacuo. To a solution of a portion of the residue (700mg, 2.9mmol) in DCM (7mL) was added a slurry of NaHC0₃ (730mg) in water (4mL), The resulting reaction mixture was cooled to 0 °C and a solution of cyanogen bromide (310mg, 2.9mmol) in DCM (3mL) was added dropwise over 1 min, before warming to r.t. and stirring for 18 h. The reaction mixture was diluted with water, the layers separated and the aqueous layer extracted with DCM. The combined organic extracts were washed with brine, dried (MgS0 ), filtered and concentrated in vacuo. The stereoisomers were separated by column chromatography (90: 10 to 80: 10 heptane: EtO Ac, then 60:40 heptane :EtO Ac) to afford the title compound: Ή NMR δ„ (301 MHz, CDC ): 3.77 - 3.66 (m, 1H), 3.43 - 3.32 (m, 211), 3.28 - 3.16 (m, 2H), 2.81 (s, 311), 2.49 - 2.34 (m, 2H), 1.95 - 1.78 (m, 411), 1.46 (s, 9H).

Preparation 33: (5 A^r-Hydroxy-2-mctho ine

To a solution of (S)-2-methoxypropionitrile ( 10mg, 10.69mmol) in IMS (lOmL) was added hydroxylaminc (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 rccrystallised from heptane: HtO Ac (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: RT = 0.33 min; m/z (ES⁺) = 1 19.0 [M ~ H]^' (LCMS Method - 2).

Preparation 34: (5)-A'-Hydroxytetrahydrofuran-2-carboxamidine

To a solution of (_lS)-tetrahydrofuran-2-carbonitrile (l OOOmg, 10.3mmol) in IMS (7mL) was added hydroxylamine (50% in water, 750μΤ, 1 1.3mmol) and the reaction was heated to 70 °C for 18 h. On cooling, the solvent was removed in vacuo, azeotroping with toluene. The residue was purified by column chromatography (EtOAc) to afford the title compound. ¾ NMR δ_Η (300MHz, CDC1₃): 4.85 (bs, 2H), 4.44 - 4.32 (m, 111), 4.00 - 3.74 (m, 2H), 2.20 - 1.80 (m, 4H).

Preparation 35 : [ l-(3-Isopropyl- [ 1 ,2,4] oxadiazol-S-yl)-piperidin-4-yl] -methyl-amine

To a solution of ( 1 -cyano-piperidin-4-yl)-methyl-carbamic acid iert-butyl ester (Preparation 21, l .OOg, 4.18mmol) and N-hydroxy-isobutyramidine (512mg, S.O l mmol) in EtOH (20mL) was added a solution of zinc dichloride (683mg, 5.01mmol) in EtOH (7mL) and the resulting reaction mixture was stirred at r.t. for 2 h. Aqueous HC1 solution (1 1.7 M, 1 .07mL, 12.5mmol) was added and the reaction mixture stirred at 50 °C for 16 h and at r.t. for 120 h. The solvent was removed in vacuo and the residue triturated with MeCN. The solid was removed by filtration and the filtrate concentrated in vacuo, dissolved in water and washed with EtOAc. The aqueous was basified to pH12 with 2M aqueous NaOH solution, extracted with tOAc and the resulting emulsion was filtered through celite. The layers of the filtrate were separated and the aqueous was extracted with EtOAc (3 x). The combined organic extracts were washed with brine, dried (MgSO.,), filtered and concentrated in vacuo to afford the title compound: RT = 1.68 min; mlz (ES ) - 225.13 [M+

Preparation 36; 8-(3-IsopropyI-[1 ,2,4] oxadiazol-5-yl)-8-aza-bicyclo [3.2.1] oct-3-yl] -methyl- amine

The title compound was synthesized from (8-cyano-8-aza-bicyclo[3.2.1]oct-3-yl)-meihyl- carbamic acid tert-butyl ester (Preparation 22) and N-hydroxy-isobutyramidine employing a procedure similar to that outlined in Preparation 35: RT = 0.55 min; mlz (ES^*) = 251.28 [M + H]^' (LCMS Method - 2).

Preparation 37 : [3-(3-Isopropyl- [ 1 ,2,4] oxadiazol-5-yI)-3-aza-bicyclo [3.2.1] oct-8-yl] -methyl- amine

The title compound was synthesized from (3-cyano-3-aza-bicyclo[3.2.1 ]oct-8-yl)-methyl- carbamic acid ίετί-butyl ester (Preparation 32) and N-hydroxy-isobutyramidine employing a procedure similar to that outlined in Preparation 35: RT = 0.64 min; m/z (ES⁺) = 251.5 [M + H]⁺ (LCMS Method - 3).

Preparation 38: | l-(3-Isopropyl-[l, eridin-4-yll -methyl-amine

The title compound was synthesized from ( 1 -cyano-4-methyl-piperidin-4-yl)-methyl- carbamic acid tert-butyl ester (Preparation 23) employing a procedure similar to that outlined in Preparation 35: RT = 0.62 min; m/z (ES⁺) = 239.4 [M+ H]⁺ (LCMS Method - 4).

Preparation 39: ds-{l-[3-(l,l-Difluoro-ethyl)-[l,2,4]oxadiazol-5-yl]-3-fluoro-piperidin-4-yl}-

The title compound was synthesized from cis- 1 -cyano-3-fluoro-pipcridin-4-yl)-methyl- carbamic acid /ert-butyl ester (Preparation 24) employing a procedure similar to that outlined in Preparation 35: RT = 0.42 min; m/z (ES⁺) = 265.3 [M+ H] ^' (LCMS Method - 2).

Preparation 40 : imns-{l-[3-( 1 , 1 -Difluoro-ethyl)- [ 1 ,2,4] oxadiazol-5-yl]-3-fluoro-piperidin-4-yl}- methyl-amine

To a cooled solution of /ra«.v-3-fluoro-piperidin-4-yl)-methyl-carbamic acid ieri-butyl ester (Preparation 14, 95 mg, 0.41mmol) in DCM (5mL) was added a solution of sodium bicarbonate (93.7mg, 1.12mmol) in water (lmL) and a solution of cyanogen bromide (43mg, 0.41 mmol) in DCM (2mL) dropwise over 5 min. The mixture was stirred at 0 °C for 1 h then at r.t. for 10 min. The organics were separated using a phase separator and concentrated in vacuo. The residue was then dissolved in EtOH and the title compound synthesized employing a procedure similar to that outlined in Preparation 35: RT = 0.46 min; m/z (ES⁺) = 265.2 [M+ H]⁺ (LCMS Method - 2). Preparation 41 : |l-(3-Ethyl-[l,2,4]o n-4-yl]-niethyl-amine

The title compound was synthesized from ( 1 -cyano-piperidin-4-yl)-methyl-carbamic acid tert-butyl ester (Preparation 21) and N-hydroxy-propionamidine employing a procedure similar to that outlined in Preparation 35: RT = 0.43 min; mlz (ES⁺) = 211.24 [M+ H]⁺ (LCMS Method - 2).

The following compounds were prepared by reacting ( 1 -cyano-piperidin-4-yl)-methyl-carbamic acid tert-butyl ester (Preparation 21) with the appropriate amidoxime intermediate employing a procedure similar to that outlined in Preparation 35:

Prep. Structure Name Spectral Data

{ l -[3-((5)- l -Methoxy-ethyl)-

RT = 1.82 min; mlz (ES⁺) = 241.2 [M

48 [1 ,2,4] oxadiazol-5 -yl] - + H]⁺ (LCMS Method - 3). piperidin-4-yl} -methyl-amine

Methyl- { 1 -[(S)-3-(lctrahydro-

RT = 1.86 min; mlz (ES⁺) = 253.2 [M

49 furan-2-yl)-[l ,2,4]oxadiazol-5- + H]⁺ (LCMS Method - 3).

yl]-pipcridin-4-yl} -amine

The following compounds were prepared by reacting ( 1 -cyano-piperidin-4-yl)-cthyl-carbamic acid iert-butyl ester (Preparation 25) with the appropriate amidoxime intermediate employing a procedure similar to that outlined in Preparation 35;

Prep. Structure Name Spectral Data

[ 1 -(3-Difluoromethyl-

RT = 1.98 min; mlz (ES⁺) = 247.2 [M

50 [1 ,2,4]oxadiazol-5~yl)- + H] ^' (LCMS Method - 3).

F piperidin-4-yl] -ethyl-amine

{l-[3-(l ,l-Difluoro-ethyl)-

RT = 2.18 min; miz (ES⁺) - 261.2 [M

51 [ 1 ,2,4] oxadiazol-5 -yl] - + H] ' (LCMS Method - 3). piperidin-4-yl} -ethyl-amine

Ethyl-[l-(3-isopropyl-

RT = 2.27 min; mlz (ES⁺) = 239.3 [M

52 [1 ,2,4Joxadiazol-5-yl)- + H]⁺ (LCMS Method - 3). pipcridin-4-yl] -amine

[ 1 -(3 -Cyclopropyl-

RT = 2.18 min; mlz (ES ) - 237.2 [M

53 [l ,2,4]oxadiazol-5-yl)- + H]⁺ (LCMS Method - 3). piperidin-4-yl]-ethyl-amine

[l -(3-½«-Butyl-

RT = 1.65 min; mlz (ES ) - 253.3 [M

54 [1 ,2,4]oxadiazol-5-yl)- + H]⁺ (LCMS Method - 5). piperidin-4-yl]-ethyl -amine

Ethyl- { 1 -[3 -((5)- -methoxy-

RT = 1.16 min; mlz (ES ^' ) = 255.19

55 0./-N ethyl)- [1 ,2,4] oxadiazol-5 -yl] - [M+ H]⁺ (LCMS Method - 5). piperidin-4-yl} -amine

Ethyl- { 1 -[(5)-3 -(tetrahydro-

RT - 2.04 min; mlz (ES ) = 267.2 [M

56 Furan-2-yl)-[l ,2,4]oxadiazol-5- + I If (LCMS Method - 3).

yl]-piperidin-4-yl } -amine The following compounds were prepared by reacting the appropriate cyano-piperidinyl intermediate with the appropriate amidoxime intermediate employing a procedure similar to that outlined in Preparation 35:

Preparation 64: 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 1 10 °C for 17 h, prior to removal of the solvent in vacuo. The residue was dissolved in EtOAc (80mL), washed with saturated aqueous NaHCOj solution (2x) and concentrated in vacuo to afford the title compound: Ή NMR δ_Η (400 MHz, CDCh): 4.58 (q, J=7.29 Hz, 2 H), 1.50 (t, J=7.22 Hz, 3 H). Preparation 65: 5-[4-(feri-ButoxycarbonyJ-cycIopropyI-amino)-piperidin-l-yl]- [l,2,4)oxadiazole-3-carboxylic acid eth l ester

To a solution of cyclopropyl-piperidin-4-yI-carbamic acid teri-butyl ester (Preparation 19: l .Og, 4.2mmol) in DMF (S.OmL) under an argon atmosphere was added trichloromethyl- [l,2,4]oxadiazole-3-carboxylic acid ethyl ester (Preparation 64, 0.7g, mmol) and the reaction mixture heated to 50 °C for 2.5 h. The reaction was diluted with EtOAc before washing with water (2x) and finally brine. The EtOAc layer was dried over magnesium sulfate before filtering and concentrating in vacuo. Purification by column chromatography (2: 1 - 3:2 heptane:EtOAc) afforded the title compound: RT = 1.23 min; mlz (ES⁺) = 381.36 [M+ H]⁺ (LCMS Method - 2).

Preparation 66: Cyclopropyl-{l-[3-(l-hydroxy-l-methyl-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-

4-yI}-carbamic acid teri-butyl ester

To a solution of 5-[4-(ier/-butoxycarbonyl-cyclopropyl-amino)-piperidin-l -yl]-

[l,2,4]oxadiazoie-3-carboxylic acid ethyl ester (Preparation 65, 380mg, l .Ommol) in anhydrous THF (8mL) at -20°C was added a solution of methylmagncsium bromide in diethyl ether (3M, 1.6mL, 5.0mmol). The reaction was allowed to stir at -20 °C for 1.5 h before the addition of a saturated aqueous solution of ammonium chloride. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organics were washed with water and brine then dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: RT = 1.04 min; tnlz (ES⁺) - 367.37 [M+ Hf (LCMS Method - 2).

Preparation 67 : 2-f 5-(4-C cloprop 1,2,4] oxadiazoI-3-yl] -prop an-2-ol

To a solution of cyclopropy]-{ ] -[3-( l -hydro.xy-1 -methyl -ethy])-[] ,2,4]oxadiazo]-5-y]]- piperidin-4-yl}-carbamic acid tert-butyl ester (Preparation 66, 20 mg, 0.05mmol) in DCM (400 μΕ) at 0 °C was added TFA (lOOpL, lmmol). The reaction mixture was allowed to stir for 1 h before concentrating in vacuo. The residue was dissolved in MeOH and loaded onto a SCX cartridge. The product was eluted with a 7M ammonia in MeOH solution and concentrated in vacuo to afford the title compound: RT = 0.44 min; mlz (ES⁺) - 267.30 [M+ II] (LCMS Method - 2). Preparation 68: l-(2-Fluo thanol

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) dropwisc over 10 min and the resulting reaction mixture was stirred at r.t. for 50 min. The reaction mixture was poured into saturated aqueous NII₄C1 solution and extracted with DCM (3 x). The combined organics were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: Ή NMR δ„ (300MHz, CDC1₃): 7.34-7.30 (m, 1H), 7.15-7.10 (m, 1 H), 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 69: l-Fluoro-4-methyl-2-((£)-2-nitro-vinyl)-benzene

To a solution of l -(2-fluoro-5-methyl-phenyl)-2-nitro-ethanol (Preparation 68, 7.18g, 36. lmmol) in acetic anhydride (6.8mL, 22.2mmol) was added DMA? (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 NaHCO . solution and stirred vigorously for 1 h. The solid was collected by filtration, washing with saturated aqueous Nal ICO_.¾ solution, then H₂0 to afford the title compound: Ή NMR 6_H (300MHz, CDC1₃): 8.04-7.99 (d, J= 13.76 Hz, I H), 7.74-7.69 (d, J=1 3.76 Hz, 111), 7.30-

7.26 (m, 2H), 7.1 -7.0 (m, 1H), 2.36 (s, 3H).

Preparation 70: (ira«s)-l-Benzyl-3-(2~fluoro-5-meth l- henyl)-4-nitro-pyrrolidine

To a solution of l-fluoro-4-methyl-2-((£)-2-nitro-vinyl)-benzene (Preparation 68, 6.38g, 35.3mmol) in DCM (70mL) at 10 °C was added TFA (0.27mL, 3.52mmol), followed by dropwise addition of N-(methoxymcthyl)-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: Ή NMR δ_Η (300MHz, CDClj): 7.35-7.26 (m, 5H), 7.1 -7.0 (m, 2H), 7.0-6.9 (m, I I I), 5.04-5.02 (m, 1 H), 4.17- 4.15 (m, IH), 3.77-3.65 (m, 2H), 3.5-3.46 (m, 1 H), 3.3-3.26 (m, 1 H), 3.1 -3.0 (m, I H), 2.65-2.60 (m, 1. XX_jij 2_*30 311) »

Preparation 71 : (ira«s)-Benzyl-4-(2-fluoro-5-meth l-phenyl)-pyrrolidin-3-ylamine

To a solution of (/rans)-l -benzyl-3-(2-fluoro-5-methyl-phenyl)-4-nitro-pyrrolidine

(Preparation 70, 1 1. g, 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 (900 ml.) . 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 chromatography (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; mix (ES^÷) = 285.1 [M + Hf (LCMS Method - 3). Preparation 72: [(/fa«.v)-l-Benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid fert-butyl ester

To a solution of (/ra«i-)-ben.7yl-4-(2-fluoro-5-melhyl-phenyl)-pyrrolidin-3-ylamine (Preparation 71, 5.6g, 19.7mrnol) in THF (80mL) at 0 °C was added triethylamine (5.65mL, 40mmol) and di-tert-butyldieatbonate (5.15g, 23.6mn.ol) 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 EtO Ac (3 x) and the combined organic extracts washed with brine, dried (MgS0₄), 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 EH, to afford the title compound: RT = 3.36 min; mlz (ES ) - 385.1 [M + H]^' (LCMS Method - 3).

Preparation 73: l(3/?,45 l-Benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl|-carbamic acid iert-butyl ester

The title compound was afforded via chiral HPLC separation of [(rram)-l -bcnzyl-4-(2-fluoro- -methyl-phenyl)-pyrrol idin-3 -y 1] -carbamic acid iert-butyl ester (Preparation 72): IH:IPA:DF.A 96:4:0.1 , 15ml/min, 270nm, RT = 8.2 min. Preparation 74: [(3 ?,4.9)-4-(2-Fluoro-5-methyl-phenyl)-pyrrolidin-3-yIj-carbamic acid tert- butyl ester

A solution of [(3R,4S)-l -benzyl-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 73, 2.4g, 6.2mmol) in MeOH (124mL) was passed through an H-Cube apparatus (10% Pd/C Catcart 70, 100 bar, 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 + II] ^' .

Preparation 75: l-(2,4-Difluoro-5-meth -phen l)-2-nitro-ethanol

To a solution of 2,4-difluoro-5-methyl-benzaldelryde ( 15.0g, 96.1 mmol) and nitromethanc

(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 NH CI solution ( 105mL) were added and extracted with DCM (3 x 250mL). The combined organic extracts were washed with brine, dried ( a2SO, , filtered and concentrated in vacuo. Purification by column chromatography (IH:EtOAc, 9: 1 to 7:1 to 4: 1 to 3: 1) afforded the title compound: Ή NMR δ_Η (300MHz, CDCI₃): 7.38-7.34 (m, I II), 6.82-6.76 (m, I I I), 5,69-5.66 (m, IH), 4.61 -4.53 (m, 2H), 2.95 (s, IH), 2.28 (s, 3H).

Preparation 76: l,5-Difluoro-2-methyl- -((£)-2-nitro-vinyl)-benzene

The title compound was synthesized from l -(2,4-difluoro-5-methyl-phenyl)-2-nitro-ethanol (Preparation 75, 14.5g, 66.9mmol) employing a procedure similar to that outlined in Preparation

69: Ή NMR δ_Η (400MHz, CDC¾): 7.99-7.96 (d, J= 13.73 Hz, IH), 7.68-7.65 (d, J=13.73 Hz, IH), 7.34-7.3 (m, I H), 6.91-6.89 (m, IH), 2.27 (s, 3H).

Preparation 77: (rra«s)-l-Benzyl-3-(2,4-difluoro-5-methyI-phcnyl)-4-nitro-pyrroHdine

The title compound was synthesized from l ,5-difluoro-2-methyl-4-((£,^")-2-nitro-vinyl)- benzene (Preparation 76, 12. Og, 60.3mmol) employing a procedure similar to that outlined in Preparation 70: RT - 1.00 min; mlz (ES ) = 333.2 [M+ R]^~ (LCMS Method - 4). Preparation 78: (ira/i.v)-l-Benzyl-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3-ylarnine

The title compound was synthesized from (trans)- l-benzyl-3-(2,4-difluoro-5-methyl- phenyl)-4-nitiO-pyrrolidinc (Preparation 77, 21. Og, 63.3mmol) employing a procedure similar to that outlined in Preparation 71 : RT = 0.93 mm; mlz (ES⁺) = 303.2 [M + H]⁺ (LCMS Method - 4).

Preparation 79: [(rra«s)-l-Benzyl-4-(2,4-difluoro-S-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid iert-butyl ester

The title compound was synthesised from (irans)-l-benzyl-4-(2,4-difluoro-5-methyl- phenyl)-pyrrolidin-3-ylamine (Preparation 78, 9,5g, 31.5mmol) employing a procedure similar to that outlined in Preparation 72: RT = 3.25 min; mlz (ES⁺) = 403.3 [M+ H] ^' (LCMS Method - 5).

Preparation 80: [(3 i,45)-l-Benzyl-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbaraic acid tert-butyl 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 terf-butyl ester (Preparation 79): IH:IPA:DEA 96:4:0.1, 15ml/min, 270nm, RT = 9.0 min. Preparation 81: [(3 ?,45 -4-(2,4-Difluoro-5-meth l-phenyl)-p rrolidin-3-ylj-carbamic acid tert- butyl ester

A solution of [(3Λ,45)-1 -benz>'l-4-(2,4-difluoro-5-mclhy]-phenyl)-pyrro)idin-3-ylJ-carbamic acid iert-butyl ester (Preparation 80, 1.97g, 4.9mmol) in MeOH (100 mL) was passed through an H- Cube apparatus (10% Pd/C Catcart 70, 80 bar, 50 °C) at a flow rate of 1 mL per min. The solvent was removed in vacuo to afford the title compound: RT = 0.68 min; mlz (ES^÷) = 313.32 [M + H] ' (LCMS Method - 2).

Preparation 82: l-(2-Fluoro-phenyl)-

The title compound was synthesized from 2-fluoro-benzaldehyde (41 g, 330mmol) employing a procedure similar to that outlined in Preparation 68: Ή NMR 5_H (300MHz, CDC1₃): 7.60-7.50 (m, IH), 7.40-7.29 (m, IH), 7.23-7.13 (IH, m), 7.12-7.01 (m, IH), 5.8-5.68 (m, IH), 4.69-4.52 (m, 2H), 3.15-3.0 (m, IH).

Preparation 83: l-Fluoro-2-((£)-2-nitro

The title compound was synthesized from l -(2-iluoro-phcnyl)-2-nitro-ethanol (Preparation 82, 59g, 319mmol) employing a procedure similar to that outlined in Preparation 69: Ή NMR δ₍₁ (400MHz, CDCl,): 8.05 (d, J= 13.79 Hz, IH), 7.72 (d, .7-13.79 Hz, I H), 7.55-7.42 (m, 2H), 7.28- 7.12 (m, 2H). Preparation 84 : (tram)- 1 -Benzyl-3-(2-fluoro- henyl)-4-nitro-pyrroIidine

The title compound was synthesized from l -fluoro-2-((£ -2-nitro-vinyl)-benzene (Preparation 83, 26.5g, 159mmol) employing a procedure similar to that outlined in Preparation

70: RT - 0.90 min; mlz (ES⁺) = 301.2 [M+ H]⁺ (LCMS Method - 4).

Preparation 85: (iw«$)-l-Benzyl-4-(2-fluoro- henyl)-pyrroIidin-3-yIamine

The title compound was synthesized from (/r«m')-l -bcnzyl-3-(2-tluoro-phenyl)-4-nitro- pyrrolidine (Preparation 84, 54.5g, 181mmol) employing a procedure similar to that outlined in Preparation 71: RT = 0.75 min; mlz (ES⁺) = 271.2 [ + H]⁺ (I CMS Method - 4).

Preparation 86: |(/rany)-l-Benzyi-4-(2-fluoro-phenyl)-pyrrolidin-3-yI|-carbamic acid tert-buryl ester

The title compound was synthesised from (/rart.s)-l -benzyl-4-(2-fluoro-phenyl)-pyrrolidin-3- ylamine (Preparation 85, 11.7g, 43.3mmol) employing a procedure similar to tha outlined in Preparation 72: RT = 3.00 min; mlz (ES⁺) = 371.3 [M + H] (LCMS Method - 5).

Preparation 87: f(3 f,45)-l-Benzyl-4-(2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-but l ester

The title compound was afforded via chiral HPLC separation of [(trans)-\ -benzyl -4-(2-fluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid ferr-butyl ester (Preparation 86): IH:IPA:n-butylamine 96:4:0. ] , I Smlhmn, 27()nm, RT = 10.6 rain.

Preparation 88: [(3i?,45)-4-(2-Fluoro-p enyl)-pyrroIidin-3-yl]-carbamic acid terf-butyl ester

The title compound was synthesiscd from [(3R,45)-l-benzyl-4-(2-iluoro-phenyl)-pyrrolidin- 3-yl]-carbamic acid terf-butyl ester (Preparation 87, 880mg, 2.37mmol) employing a procedure similar to that outlined in Preparation 74: RT = 0,63 mm; mlz (ES⁺) = 281.3 [M + H]⁺ (LCMS Method - 2).

Preparation 89: 2-[(3J?,45 -3-ic'i-i-Butoxycarbonylamino-4-(2,5-difluoro-phenyI)-pyrroIidin-I- yl]-pyrimidine-5-carboxylic acid meth l ester

To a solution of 2-chloro-pyrimidine-5-carboxylic acid methyl ester (2.1g, 12mmol) and [(3i?,4.S)-4-(2,5-di£luorophenyl)pyrrolidin-3-yl]carbamic acid iert-butyl ester (Preparation 206, 4.0g, ! 3mraol) in DCE (lOOmL) was added triethylamine (3.3mL, 23rnmol) and the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was diluted with DCM (200mL), washed with water (200mL) and brine (4()0mL), dried (MgS0₄), filtered and concentrated in vacuo. The remainder was triturated with McOH and the solid collected by filtration to afford the title compound: RT = 3.95 min; mlz (ES⁺) = 435.18 [M+ H]⁺. Preparation 90: 2-[(3/?,4,S -3-ii;«-Butoxycarbonylamino-4-(2,5-(lifluoro-phenyI)-pyrrolidiii-l- yl]-pyrimidine-5-carboxylic acid

To a solution of 2-[(3i?,4S -3-ieri-butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin- l -yl]-pyrimidine-5-carboxylic acid methyl ester (Preparation 89, 3.89g, 8.95mmol) in THF (lOOmL) was added aqueous NaOH solution (IM, 50mL, 50mmol) and the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was acidified to pH 6 using 2M aqueous HQ solution and extracted with EtOAc (3 x 2()0niL). The combined organic extracts were dried (MgS0₄), filtered and concentrated in vacuo. The remainder was triturated with Et₂0 and the solid collected by filtration to afford the title compound: RT = 3.50 min; m/z (ES⁺) = 421.19 [M+ H] ^' .

Preparation 91: 2-[(3 ?,45 -3-rm-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l- yl]-pyrimidine-5-carboxylic acid methyl ester

The title compound was synthesized from 2-chloro-pyrimidine-5-carboxylic acid methyl ester (350mg, 3.85mmol) and [(3i?,4^-4-(2,4,5 rifluorophenyi)pyrrolidin-3-yl]carbamic acid tert- butyl ester (Preparation 212, 784mg, 2.48mmol) employing a procedure similar to that outlined in Preparation 89: RT = 1.29 min; m/z (ES ) = 453.00 [M+ H] ^' (LCMS Method - 2).

Preparation 92: 2-l(3 ?,4i^,)-3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin- yl]-pyrimidine-5-carboxylic acid

The title compound was synthesized from 2-[(3/?,45)-3-tert-butoxycarbonylamino-4-(2,4,5- trifiuoro-phenyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid methyl ester (Preparation 91, 820mg, 1.8mmol) employing a procedure similar to that outlined in Preparation 90: RT = 1.1 1 min; mlz (ES⁺) = 439,3 \M~ \\\ (I .CMS Method - 2).

Preparation 93 : 5- [(3 ?, S -3-r6' 'i-Butoxyearbonylamino-4-(2,4_r5-trifluoro-phenyl)-pyrrolidin- 1- yl]-pyrazine-2-carboxylic acid

The title compound was synthesized from 2,5-chloro-pyrazine-2-carboxylic acid methyl ester (292mg, 1.69rnmol) and [(3R,45^*)-4-(2,4,5-trifluorophenyl)pyrrolidin-3-yl]carbamic acid /eri-butyl ester (Preparation 212, 1.()7g, 3.38mmol) employing a procedure similar to that outlined in Preparation 89: RT = 1.18 min; mlz (ES') = 453.38 [M + H] ^" (LCMS Method - 2).

Preparation 94: 5-[(3i?,45)-3-^rt-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l- yl|-pyrazine-2-carboxylic acid

The title compound was synthesized from 5-[(3R,45)-3-fert-butoxycarbonylamino-4-(2,4,5- trifluoro-pheny -pyrrolidin- 1 -yl]-pyrazine-2-carboxylic acid methyl ester (Preparation 93, 400mg, 0.884mmol) employing a procedure similar to that outlined in Preparation 90: RT = 1.05 min; mlz

(ES⁺) = 439.33 [M+ H]⁺ (LCMS Method - 2). Preparation 95: 2-|(3/?,4i^,)-3-<^,i?rt-Butoxycarbonylamino-4-(2,4-difluoro-5-methyI-phenyI)- pyrrolidin-l-ylJ-pyrimidinc-5-carboxylic acid methyl ester

The title compound was synthesized from 2-chloro-pyrimidinc-5-carboxylic acid methyl ester (295mg, 1 .71 mmol) and [{3R,4S)-4-(2,4-difluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid ieri-butyl ester (Preparation 81 , 640mg, 2.05mmol) employing a procedure similar to that outlined in Preparation 89: RT = 1.33 min; mlz (ES⁺) - 449.38 [ + H] ^" (I .CMS Method - 2).

Preparation 96: 2-[(3 ?,45 -3-ii'ri-Butoxycarbonylamino-4-(2,4-difluoro-5-methyl-phenyl)- pyrrolidin-l-ylj-pyrimidine-5-carboxylic acid

To a solution of 2-[(3R,4.S)-3-fe^butoxycarbonylamino-4-(2,4-difluoro-5-methyl-phenyl)- pyrrolidin-l -yi]-pyrimidine-5-carboxylic acid methyl ester (Preparation 95, 767mg, 1.71mmol) in THF (5.5mL), MeOH (2.8mL) and water (2.5mL) was added lithium hydroxide monohydrate (86.1 mg, 2.05mmol) and the resulting reaction mixture was heated at 30 °C for 5.5 h. The solvent was removed in vacuo, water was added and the mixture acidified to pH 1 with aqueous HCl solution (1 M) prior to extraction with EtOAc. The organic extract was dried (MgS0₄), filtered and concentrated in vacuo to afford the title compound: RT = 1.14 min; m!z (ES⁺) - 435.39 [M + H]⁺ (LCMS Method - 2).

Preparation 97: 2-[(3/?,4-S 3-rcrt-Butoxycarbonylaniino-4-(2-fluoro-5-methyl-phenyI)- pyrrolidin-l-yl]-pyrimidine-5-earbox lic acid methyl ester

The title compound was synthesized from 2-chloro-pyrimidine-5 -carboxyl ic acid methyl ester (375mg, 2.17mmol) and [(3R,4.S)-4-(2-fluoro-5-mcthyl-phenyl)-pyrrolidm-3-yl]-carbamic acid terf-butyl ester (Preparation 74, 704mg, 2.39mmol), employing a procedure similar to that outlined in Preparation 89: RT = 1.32 min; mlz (ES⁺) = 431.39 [ + H] ^" (LCMS Method - 2).

Preparation 98: 2-[(3 ?,4.S)-3-/^/-/-Butoxycarbonylamino-4-(2-fluoro-5-niethyJ-phenyl)- pyrrolidin-I-yl]-pyrimidine-5-carbox lic acid

The title compound was synthesized from 2-[(3i?,4S)-3-tert-butoxycarbonylamino-4-(2- fluoro-5-methyl-phenyl)-pyrrolidin-l -ylJ-pyrimidine-5-carboxylic acid methyl ester (Preparation 97, 850mg, 2.0mmol), employing a procedure similar to that outlined in Preparation 90: RT = 1 ,13 min; mlz (ES⁺) = 417.38 [M + H]⁺ (LCMS Method - 2).

Preparation 99: 2-[(3 ?,4S -3-½rt-Butoxycarbonylaniino-4-(2-fluoro-phenyl)-pyrrolidin-l-yl]- pyrimidinc-5-carboxylic acid meth l ester

The title compound was synthesized from 2-chloro-pyrimidine-5-carboxylic acid methyl ester (271 mg, 1.57mmol) and [(3R,4S)-4-(2-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (Preparation 88, 440mg, 1.57mmol), employing a procedure similar to that outlined in Preparation 89: RT = 1.24 min; mlz (ES⁺) = 417.33 [ + Hf (LCMS Method - 2). Preparation 100: 2-[(3 ?,45)-3-^/-i-Butoxycarbonylamino-4-(2-iluoro-phen I)-pyrrolidin-l-yll- pyriniidinc-5-carboxylic acid

The title compound was synthesized from 2-[(3R,4S)-3-tert-butoxycarbonylamino-4-(2- iluoro-phenyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid methyl ester (Preparation 99, 460mg, l .lmmol), employing a procedure similar to that outlined in Preparation 90: RT = 1.06 min; mlz

(ES⁺) - 403.30 [M + H]⁺ (LCMS Method - 2).

Preparation 101: [(3i?,4-¾-l-{5-[(l-BenzyI-piperidin-4-yI)-cycIopropyI-carbamoylJ-pyrimidin-2- yl}-4-(2,4,5-trifluoro-ph ester

To a solution o 2-[(3i?,4S)-3-ter/-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-l-yl]-pyrimidine-5-carboxylic acid (Preparation 92, 400mg, 900μιτιο1) in THF (12mL) was added EDCI (289mg, i .SOmmol), HOBt (2.30mg, 1.50mmol) and DIPF.A (421 μΐ,, 2.42mmol). The resulting reaction mixture was stirred at r.t. for 20 min prior to the addition of (1-benzyl- piperidin-4-yl)-cyclopropyl-amine (32()mg, 1.4mmol) in THF (3mL) and the resulting reaction mixture was stirred at r.t. for 16 h. The solvent was removed in vacuo, then the residue was dissolved in EtOAc, washed with aqueous NaOH solution (2M, 2 x) and brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc) afforded a crude product which was dissolved in DCM and added to an SCX cartridge. The SCX cartridge was washed with MeOlI then elutcd with 7M N¾ in MeOH and the basic fraction was concentrated in vacuo to afford the title compound: RT = 0.93 min: mlz (ES⁺) = 651 .57 [M + H] ' (LCMS Method - 2). Preparation 102: |(3 <!, S -l-[5-(Cyclopropyl-piperidin-4-yl-carbamoyl)-pyrimidin-2-yl]-4- (2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid t erf-butyl ester

A solution of [(3R,45)-l-{5-[(l -benzyl-piperidin-4-yl)-cyclopropyl-caAamoyl]-pyrirnidin-2- yl} -4-(2,4,5-trifluoro-phcnyl)-pyrrolidin-3-yl]-carbamic acid tert-hutyl ester (Preparation 101, 162mg, 249μηιο1) in EtOH (5mL) was reacted on the Il-cube cube (10% Pd/C Catcart 70, 50 bar, 70 °C) at a flow rate of 1 mL/min. The resulting solution was concentrated in vacuo and the remainder was re-dissolved in EtOH (25mL) and reacted on the Il-cube (10% Pd/C Catcart 70, 100 bar, 75 °C) at a flow rate of 1 mL/min. The resulting solution was concentrated in vacuo and the remainder was re-dissolved in EtOH (35mL) and reacted on the H-cube (10% Pd/C Catcart 70, 100 bar, 80 °C) at a flow rate of 0.7 mL/min. The resulting solution was concentrated in vacuo to afford the title compound: RT = 0.81 min; mlz (ES⁺) = 561.57 [M+ I ff (LCMS Method - 2).

Preparation 103: [(3/?,45)-l-{5-[(l-Cyano-piperidin-4-yl)-cyclopropyl-carbamoyll-pyrimidin-2- yl}-4-(2,4,5-trifluoro-phe tyl ester

To a solution of [(3R,4S)-l -[5-(cyclopropyl-piperidin-4-yl-carbamoyl)-pyrimidin-2-yl]-4- (2,4,5-trifluoro-phenyl)-pyrrolidin-3-yi]-carbamic acid tert-butyl ester (Preparation 102, 78.2mg, 139μιηο1) in DCM (500,uL) was added a slurry of NaHC0₃ (35mg. 420_,umol) in water (400 μί), followed by cyanogen bromide (18mg, 170pmol) in DCM (500μί). The resulting reaction mixture was stirred at r.t. for 1.25 h, then diluted with DCM and water. The layers were separated, the aqueous layer extracted with DCM (3 x) and the combined organic extracts were washed with brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAcrlH, 4: 1) afforded the title compound: RT = 1.16 min; mlz (ES^÷) = 586.52 [M + Hf (LCMS Method - 2). Preparation 104: [(3/?,4S)-4-(2,5-Difluoro-phenyl)-l -(5- { [ 1 -(3-isopropyl- [ 1 ,2,4| oxadiazol-5-yl)- piperidin-4-yl]-methyl-carbamoyl}-pyrimidin-2-yl)-pyrrolidin-3-ylj-carbamic ester ferr-butyl ester

To a solution of 2-[(3J?,4S)-3-ter^butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin- l-yl]-pyrimidine-5-carboxylic acid (Preparation 90, 120mg, 280μηιο1) in THF (4mL) was added EDCI (71.1 mg, 371μηιο1), HOBt (56.8mg, 371μηιο1) and DIPEA (99.4μΕ, 571 μιηο1). The resulting reaction mixture was stirred at r.t, for 20 min prior to the addition of [l -(3-isopropyl- [ 1 ,2,4]oxadiazol-5-yl)-piperidin-4-yl]-methyl-amine (Preparation 35, 96.0mg, 428μηιο1), then stirred at r.t. for 16 h. The solvent was removed in vacuo and the remainder dissolved in EtOAc, washed with aqueous NaOH solution (2M, 2 x), aqueous citric acid solution (10%, 2 x) and brine, dried (MgS0₄), filtered and concentrated in vacuo. Purification by column chromatography (EtOAc:IH, 4: 1 to 9: 1) afforded the title compound: RT = 3.87 min; mlz (ES⁺) = 627,33 [M+ H] ^' . Preparation 105: {(3 ?,45)-4-(2,5-Difluoro-phenyl)-l-[5-({l- [3-(l-tluoro-l-methyl-ethyl)-

[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-methyl-carbamoyI)-pyrimidin-2-yl]-pyrrolidin-3-yl}- carbamic acid tert-butyl ester

To a solution of 2-[(3^,46 3-i£'rt-butoxycarbonylamino-4-(2,5-dinuoro-phenyl)-pyrrolidin- 1 -yl]-pyrimidine-5-carboxylic acid (Preparation 90, 70mg, 166μιηο1) in DCM (2mL) was added {1- [3-( 1 -fluoro-1 -methyl-ethyl)-[l ,2,4]oxadiazol-5-yl]-pipcridin-4-y! } -methyl-aminc (Preparation 46, 40mg, 166μιηο1) and DIPEA (87μί, 499μηιο1) followed by PPA (50% w/w in EtOAc, 149μΕ, 250μιηοΙ). The resulting reaction mixture was stirred at r.t. under argon for 3 h. After this time the mixture was diluted with water and filtered through a hydrophobic frit and concentrated in vacuo. Purification by column chromatography (DCM to 2:98 MeOH:DCM) afforded the title compound: RT = 1.23 min; mlz (ES⁺) = 645.45 [ + H]⁺ ((LCMS Method - 2 ). The following compounds were prepared by reacting 2-[(3R,45}-3-ieri4jutoxycarbonylamino-4-(2,5- ditluoro-phenyl)-pyrrolidin- l -yl]-pyrimidinc-5-carboxylic acid (Preparation 90) with the appropriate amine intermediate employing a procedure similar to that outlined in Preparation 104:

The following compounds were prepared by reacting 2-[(3i?,45}-3-ier/-butoxycarboriylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5-carboxylic acid (Preparation 90) with the appropriate amine intermediate employing a procedure similar to that outlined in Preparation 105:

teri-butyl ester

The following compounds were prepared by reacting 2-[(3/?,4S)-3-re i-butoxycarbonylamino-4- (2,4,5-trifluoro-phenyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid (Preparation 92) with the appropriate amine intermediate employing a procedure similar to that outlined in Preparation 104:

Prep, Structure Name LCMS Data

RT = 1.18

[(3R,45)-l -(5-{[l-(3-Ethyl- [ 1 ,2,4]oxadiazol-5-yl)- min; mlz piperidin-4-yl] -methyl- (ES⁺) =

131 carbamoyl} -pyrimidin-2-yl)-4- 631.6 [M +

O^o (2,4,5-trifluoro-phenyl)- H] ^" (LCMS pyrrolidin-3 -yl] -carbamic acid

tert-h tyl ester Method - 2).

RT = 1.29

[(3R,45)-l .(5-{Ethyl-[l-(3- isopropyl-[ 1 ,2,4]oxadiazol-5 - min; mlz yl)-piperidin-4-yl] -carbamoyl} - (ES⁺) =

1 !_' pyrimidin-2-yl)-4-(2,4,5- 659.57 [M + trifluoro-phenyl)-pyrrolidin-3- H]⁺ (LCMS yl] -carbamic acid terf -butyl

ester Method - 2).

RT = 1.25

[(3R,4S)-l -(5-{[l-(3-Isopropyl- [L2,4]oxadiazol-5-yl)- min; mlz piperidin-4-yl]-methyl- (ES⁺) =

133 carbamoyl}-pyriniidin-2-yl)-4- 645.6 [M +

(2,4,5 -trifluoro-phenyl)- II] ^' (LCMS pyrrolidin-3-yl] -carbamic acid

(ert-butyl ester Method - 2).

[(3R,45)- 1 -(5 - { [ 1 -(3 -tert-Butyl- RT - 1.32 min; mlz

--VHT . - ^' C [1 ,2,4]oxadiazol-5-yl)- piperidin-4-yl]-methyl- (ES^÷) =

134 carbamoyl} -pyrimidin-2-yl)-4- 659.6 [M '

(2,4,5-tnfluoro-phcnyl)- H]⁺ (LCMS pyrrolidin-3-yl] -carbamic acid

/e/ -butyl ester Method - 2).

[(3R,4S)-l -(5-{[l -(3- RT - 1 .26

Difluoromethyl- min; mlz

[1 ,2,4]oxadiazol-5-yl)- (ES ) =

135 piperidin-4-yl]-ethyl- carbamoyl} -pyrimidin-2-yl)-4- 667.54 [M +

(2,4,5-trilluoro-phenyl)- H] ^" (LCMS pyrrolidin-3-yl] -carbamic acid Method - 2). tet-butyl ester

iert-butyl ester Method - 1).

The following compounds were prepared by reacting the appropriate acid intermediate with the appropriate amine intermediate employing a procedure similar to that outlined in Preparation 105:

- - - -

tert- uty ester

The following compounds were prepared by reacting 2-[(3R,45)-3-teri-butoxycarbonylamino-4-(2- fluoro-5-methyl-phenyl)-pyrrolidin-l -yl]-pyrimidine-5-earboxylic acid (Preparation 98) with the appropriate amine intermediate employing a procedure similar to that outlined in Preparation 104:

Structure Name LCMS Data

[(3RAS>4-(2-Fluoro-5-methyl- phenyl)-l -(5-{[l -(3-isopropyl- RT = 1.26 min; mlz [1 ,2,4]oxadiazol-5-yl)- (ES⁺) = 623.57 [M +

152 piperidin-4-yl]-methyl- H]⁺ (LCMS Method - carbamoyl} -pyrimidin-2-yI)- 2).

pyrrolidin-3-yl]-carbamic acid

tert-butyl ester

[(3R,45)-l-(5-{Ethyl-[l-(3- isopropyl-[ 1 ,2,4]oxadiazol-5- RT = 4.15 min; mlz yl)-piperidin-4-yl] -carbamoyl} - (ES^') - 637.32 [M +

153 pyrimidin-2-yl)-4-(2-fluoro-5- H]⁺ (LCMS Method - methyl -phenyl)-pyrrolidin-3 - i).

yl]-carbamic acid tert-butyl

ester

teri-butyl ester

eser

fer/-butyl ester

The following compounds were prepared by reacting 2-[(3R,4S)-3-teri-butoxyearbonylamino-4-(2- iluoro-5-methyl-phenyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid (Preparation 98) with the appropriate amine intermediate employing a procedure similar to that outlined in Preparation 105:

5

Prep. Structure LCMS Data

[(3RAS 1 - [5 -(Cyclopropyl- { 1 - [3 -( 1 , 1 -difluoro-cthyl)- RT - 1.35 min; mlz

[ 1 , 2 ,4]oxadiazol -5 -yl] - (ES⁺) = 671.46 [M+

167 piperidin-4-yl} carbamoyl)- H] ^' (LCMS Method - pyrimidin-2 -yl] -4-(2-fluoro-5 - 2).

methyl-phcnyl)-pyrrolidin-3 - yl]-carbamic acid ieri-butyl

ester

The following compounds were prepared by reacting 2-[(3R,45)-3-tert-butoxycarbonylamino-4-(2- fluoro-phenyl)-pyrrolidin-l -yl]-pyrimidinc-5-carboxylic acid (Preparation 100) with the appropriate amine intermediate employing a procedure similar to that outlined in Preparation 105:

5

Prep. Structure Name LCMS Data

L(3R,4S)-l -(5- {Ethyl-[l -(3-

RT = 1.25 min; mlz isopropyl-[ 1 ,2,4] oxadiazol-5 - (ES⁺) = 623.46 [M+

170 yl)-piperidin-4-yl]-carbamoyl} - pyrimidin-2-yl)-4-(2-fluoro- H] ^" (LCMS Method - phenyl)-pyrrolidin-3 -yl] - 2).

carbamic acid terf-butyl ester

[ R S 1 -[5-(Cyclopropyl- { 1 - [3-(l ,l -difluoroethyl)- RT = 1.30 min; mlz [l ,2,4]oxadiazoI-5-yl]- (ES⁺) = 657,44 [ +

171 pipcridin-4-yl} -carbamoyl)- H]⁺ (LCMS Method - pyrimidin-2-yl]-4-(2- 2).

fluorophenyl) -pyrrolidin-3 -yl] - carbamic acid ieri-butyl ester

The following compounds were prepared by reacting 2-[(3R,4S)-3-fert-butoxycarbonylamino-4-(2,4- difluoro-5-methyl-phenyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid (Preparation 96) and the appropriate amine intermediate employing a procedure similar to that outlined in Preparation 104:

ier/- uty ester

t Prep. Structure Name LCMS Data

{(3i?,4S)-4-(2,4-Difluoro-5- methyl-phenyl)-l -[5-(ethyl- { 1 -

RT = 3.98 min; mlz [(6)-3-(tetrahydro-furan-2-yl)- (LS ^' ) - 683.15 [M+

182 [1 ,2,4]oxadiazol-5-yl]- piperidin-4-yl } -carbamoyl)- H] ⁺ (LCMS Method - pyrimidin-2 -yl] -pyrrolidin-3 - I) .

yl} -carbamic acid fcrZ-butyl

ester

(3R,4S^*)-4-(2,4-Diiluoro-5- methyl-phenyl)- 1 -(5 - { ethyl- [ 1 - RT = 4.22 min; mlz (3-isopropyl-f 1 ,2,4]oxadiazol- (ES⁺) = 655.19 [M+

183

υ ™ NH 5-yl)-piperidin-4-yl]-

H] ⁺ (LCMS Method - carbamoyl} -pyrimidin-2-yl)- 0 I) .

- pyrrolidin-3-yl]-carbamic acid

to-Z-butyl ester

Preparation 184: [(3«A^-l-{^l{l-l3-(1 -Difluoro-ethyi)-[l,2,4]oxadiazol-5-yl|-piperidin-4-yl}- (2,2,2-trifluoro-ethyl)-carbamoyl]-pyrimidin-2-yl}-4-(2,5-dinuoro-phenyl pyrroUdin-3-yl]- carbamic acid terf-butyl ester

To a suspension of 2-[(3i?,45)-3-teri-butoxycarbonylamino-4-(2,5-difluoro-phenyl)- pyrrolidin- l -ylj-pyrimidine-5-carboxylic acid (Preparation 90, 150mg, 360μηιο1) i DCM (3mL) was added pyridine (38μΕ, 460μηιο1), DMF (20μΕ, 200μηιο1) followed by the dropwise addition of oxalyl chloride (36 iL, 430μη ο1) under argon. The reaction mixture was stirred at r.t. for 1 h. To this

10 was added a solution of { l -[3-(l , l -difluoro-ethyi)-[l ,2,4]oxadiazol-5-yl]-piperidin-4-yl}-(2,2,2- trifluoro-ethyl)-amine (Preparation 60, 1 20mg, 390μηιο1) and pyridine (38μί) in DCM (2mL) and the mixture stirred at r.t. for 18 h. The reaction mixture was diluted with EtOAc and washed with water (15mL) then a saturated solution of sodium carbonate (15mL). The organic extracts were dried (MgS0₄), filtered and concentrated in vacuo. The residue was purified by preparative HPLC

1 5 (standard method) to afford the title compound: RT = 1.37 min; mlz (ES⁺) = 717.43 [M + H] ' (LCMS

Method - 2). Preparation 185: I(3i?,4,S)-l-[5-({l-[3-(l,l-Difluoro-etliyl)-[l,2,4Joxadiazol-5-yi]-3-fluoro- piperidin-4-yl}-methyI-carbamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]- earbamic acid tett-butyl ester

The title compound was prepared by reacting 2-[(3R,4 3-/er?-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l -yl]-pyrimidinc-5-carboxylic acid (Preparation 90) with c s- { l -[3-( l , 1 - difluoro-ethyl)-[l ,2,4]oxadiazol-5-yl]-3-fluoro-piperidin-4-yl}-methyl-amine (Procedure 39) employing a procedure similar to that outlined in Preparation 105 to afford the title compound as a mixture of diastereoisomers: RT = 1 .30 min; mlz (ES⁺) = 667.44 [M + H] ^' (LCMS Method - 2).

Preparation 186: [(3 ?,45)- 1- [5-( {(35,4/?)- 1 -[3-(l , l-Difluoro-ethyi)- [ 1 ,2,4] oxadiazol-5-yl] -3- fluoro-piperidin-4-yl}-methyl-carbamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-pyrrolidin-3- yl]-carbamic acid tert-but l ester

[(3R,4S)-1 -[5-({ 1 -[3-(l,l -Difluoro-ethyl)-[l ,2,4]oxadiazol-5-yl]-3-fluoro-piperidin-4-yl} - mcthyl-carbamoyl)-pyrimidin-2-ylJ-4-(2,5-difluoro-phcnyl)-pyrrolidin-3-yl]-carbamic acid ieri-butyl ester (Preparation 185) was separated via chiral HPLC: MTBE:MeOH:IH 35:35:30, 15ml/min, 270nm, RT = 12.1 min to afford the title single diastereomer with arbritrarily assigned stereochemistry: RT = 1.30 min; mlz (ES ) = 667.44 [M + ll] ^' (LCMS Method - 2).

Preparation 187: [(3«,4JS 1 - [5-({(3 ?,45)- 1 - [3-(l , 1 -Difluoro-ethyl)- [ 1 ,2,4] oxadiazol-5-yl] -3- fluoro-piperidin-4-yl}-methyl-carbamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-pyrrolidin-3- yl]-carbamic acid tert-butyl ester

[(3R,4S> 1 -[5-({ 1 -[3-(l ,l -Difluoro-ethyl)-[l ,2,4]oxadiazol-5-ylJ-3-fluoro-pipcridin-4-yl} - methyl-carbamoyl)-pyriinidin-2-yl]-4-(2,5-difluoro-phenyl)-pyrrolidin-3- acid feri-butyl ester (Preparation 185) was separated via chiral HPLC: MTBE:MeOH:IH 35:35:30, 15ml/mm, 270nm, RT = 9.7 min to afford the title single diastcreomer with arbritrarily assigned stereochemistry. RT = 1.30 min; mlz (ES ) = 667.44 [M + H]^' (LCMS Method - 2).

Preparation 188: [(3 ?,45)-l-15-({(3 f,4/?)-l-[3-(l,l-Difluoro-ethyl)-[l,2,4]oxadiazol-5-yl]-3- fluoro-piperidin-4-yl}-methyl-carbamoyl)-pyrimidin-2-yI]-4-(2,5-difluoro-phenyl)-pyrrolidin-3- yl]-carbamic acid tert-but l ester

The title compound was prepared by reacting 2-[(3i?,45)-3-teri-butoxycarbonylamino-4-(2,5- difluoro^henyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid (Preparation 90) with trans- {l-[3- (1 ,1 -difluoro-ethyl)-[l ,2,4]oxadiazol-5 -yl] -3 -fluoro-piperidin-4-yl} -mcthyl-amine (Procedure 40) employing a procedure similar to that outlined in Preparation 105 to afford the title compound as a mixture of diastereoisomers. The diastereomers were separated via chiral HPI.C: MTBE:MeOH 80:20, 15ml/min, 270nm, RT = 9.7 min to afford the title single diastereomer with arbitrarily assigned stereochemistry: RT = 1.26 min; mlz (ES⁴) = 667.5 [M - H] (LCMS Method - 2).

Preparation 189: [(3 ?,45 -4-(2,4-Difluoro-5-methyl-phenyl)-l-(5-{[l-(3-isopropyl- [1,2,4] oxadiazol-5-yl)-piperidin-4-yl]-mcthyl-carbamoyl}-pyrimidin-2-yl)-pyrrolidin-3-yll carbamic acid teri-butyl ester

The title compound was synfhesised from 2-[(3^,45)-3-ft^,ri-buloxycarbonylamino-4-(2,4- difluoro-5-methyl-phenyl)-pyrrolidin-l -yl]-pyrimidinc-5-carboxylic acid (Preparation 96) and [1 - (3-isopropyl-[l ,2,4]oxadiazol-5-yl)-piperidin-4-yll-methyl-aminc (Preparation 35) employing a procedure similar to that outlined in Preparation 1 4: RT = 1.28 min; mlz (ES^*) ^~ 641.61 [M + H] ^' (LCMS Method - 2). Preparation 190: (3 ?,45 -l-(5-{EthyI-[l-(3-isopropyl-|l,2,4]oxadiazol-5-yl)-piperidin-4-yl|- carbamoyI}-pyrazin-2-yl)-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl)-carbamic acid tert-butyl ester

The title compound was synthesised from 5-[(3R,45 -3-teri-butoxycarbonylamino-4-(2,4,5- trifluoro-phenyl)-pyn lidin- l -yl]-pyrazine-2-carboxylic acid (Preparation 94) and ethyl-[l -(3- isopropyl-[ 1 ,2,4]oxadiazol-5-yl)-piperidin-4-ylJ-amine (Preparation 52) employing a procedure similar to that outlined in Preparation 104: RT - 4.15 min; mlz (ES⁺) = 659.19 [M + II] ^' (LCMS Method - 1).

Preparation 191 : 4-({2-[(3 ?,4-S^T)-3-ter -Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)- pyrrolidin-l-yl]-pyrimidine-5-carb nyl}-ethyl-amino)-piperidine-l-carboxylic acid benzyl ester

The title compound was prepared by reacting 2-[(3R,45)-3-ft'A'i-butoxycarbonylamino-4- (2,4,5-trinuoro-phenyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid (Preparation 92) with 4- ethylamino-piperidine-l -carboxylic acid benzyl ester employing a procedure similar to that outlined in Preparation 104: RT = 4.35 min; mlz (ES⁺) = 683.13 [M+ H]⁺ (LCMS Method - 1),

Preparation 192: [(3Λ,45)- 1 - |5-(Ethyl-piperidin-4-yl-carbamoyl)-pyrimidin-2-yl] -4-(2,4,5- trifluoro-phenyl)-pyrrolidin-3- -carbamic acid tert-butyl ester

To a solution of 10% Pd/C (24mg, 0.022mmol) in EtOH (15mL) was added 4-({2-[{3R,45)- 3-ter^butoxycarbonylarmno-4-(2,4,5 rifluoro-phenyl)-pyrrolidin -yl]-pyrimid

ethyl-amino)-piperidine- 1 -carboxylic acid benzyl ester (Preparation 191, 240mg, 0.35mmol) and the mixture placed under hydrogen for 1 h at room temperature. The mixture was then filtered through celite and the filtrate concentrated in vacuo, azeotroping with DCM, to afford the title compound: RT = 2.75 min; mlz (ES ) - 549.16 [M+ H]⁺ (LCMS Method - 1).

Preparation 193: [(3 ?,4^-l-(5-{[l-(5-Chloro-pyrimidin-2-yl)-piperidin-4-yl]-ethyl-carbamoyl}- pyrimidin-2-yl)-4-(2,4,5- id tert-butyl ester

To a solution of [(3i?,4S)-l -[5-(ethyl-piperidm-4-yl-carbamoyl)^yrimidin-2-yl]-4-(2,4,5- tritluoro-phenyl)-pyrrolidin-3-ylJ-carbamic acid tert-butyl ester (Preparation 192, 40mg, 0.07mmol) in DM SO (lmL) was added DIPEA (1 μL, O. l lmmol) and 2,5-dichloropyrimidine (16mg, 0.1 l mmol). The mixture was heated in the microwave at 150 °C for 1 h. The mixture was purified by preparative HPLC and the compound containing fractions concentrated in vacuo to afford the title compound: RT = 4,55 min; mlz (ES^÷) = 661.13 [ + I I] ' (LCMS Method - 1).

Preparation 194: 4-({2-[(3i?,45)-3-r£'rt-Butoxycarbonylamino-4-(2,5-difluoro-phenyl)- pyrrolidin-l-ylj-pyrimidine-5-carbon l}-ethyl-amino)-piperidine-l-carboxylic acid benzyl ester

The title compound was prepared by reacting 2-[(3R,4S)-3-terf-butoxycarbonylamino-4-(2,5- difluoro-phcnyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid (Preparation 90) with 4-ethylamino- piperidine-1 -carboxylic acid benzyl ester employing a procedure similar to that outlined in Preparation 105: RT = 1.33 min; mlz (ES ) = 665.51 [ + H]⁺ (LCMS Method - 2). Preparation 195: {(3/?,45)-4-(2,5-Difluo ro-phenyl)- 1- [5-(ethyl-piperidin-4-yl-carbamoyl)- pyrimidin-2-yl]-pyrrolidin-3- l}-carbamic acid feri-butyl ester

The title compound was prepared from 4-({2-[(3i?,4S)-3-teri-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin- 1 -yl] -pyrimidine-5 -carbonyl } -ethyl-amino)-piperidine- 1 -carboxylic acid benzyl ester (Preparation 194) employing a procedure similar to that outlined in Preparation 192: RT = 0.81 min: mlz (ES⁺) = 531.51 [Λ/ + Η] ^" (LCMS Method - 2).

Preparation 196: 4-({2-[(3if,4 )-3-tert-Butoxycarbonylamino-4-(2,5-difluoro-phenyl)- pyrrolidin-l-yl)-pyrimidine-5-carbonyl}-ethyl-amino)-piperidine-l-carboxylic acid 1-mcthyl- cyclopropyi ester

To a stirred solution of {(3i?,45)-4-(2,5-difluoro-phenyl)-l-[5-(ethyl-piperidin-4-yl- carbamoyl)-pyrimidin-2-yl]-pyrrolidin-3-yl} -carbamic acid terf-butyl ester (Preparation 195, 200mg, 0.3mmol) and triethylamine (72.5μΤ, 0.520mmol) in DCM (7mL) was added 1- methylcyclopropyl 4-nitrophenyl carbonate (82.3mg, 0.347mmol) followed by 4- dimethylaminopyridinc (4.24mg, 0.0347mmol) and the solution stirred at r.t. for 6 h. The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium carbonate solution, 1M HCl solution, water and finally brine. The organics were dried (magnesium sulfate), filtered and concentrated in vacuo. Purification by column chromatography (97:3 DCM;MeOH) afforded the title compound: RT = 1.25 min; mlz (ES⁺) = 629.51 [ + H] ^' (LCMS Method - 2). Preparation 197: [{3^,45)-l-{5-l(l-Cyano-piperidin-4-yl)-ethyI-carbamoyI]-pyrimidin-2-yl}-4- (2,5-difluoro-phenyl)-pyrrolidin-3- l|-carbaniic acid fert-butyl ester

The title compound was prepared from {(3i?,45)-4-(2,5-difl oro-phenyl)-l-[5-(ethyl- piperidiri-4-yl-carbamoyl)-pyrimidin-2-yl]-pyrrolidin-3-yl} -carbamic acid tert-butyl ester (Preparation 1 5) employing a procedure similar to that outline in Preparation 21 : RT = 1 ,12 min; mlz (ES⁺) = 556.49 [Λ + Η] ^! (LCMS Method - 2),

Preparation 198: [(3/?,4J)-4-(2,5-Ditliioro-pheny])-l-(5-{ethyl-|l-(2H-tetrazol-5-yI)-piper!din-4- yI)-carbamoyl}-pyrimidin-2- l)-pyrrolidin-3-yl]-carbamic acid teri-butyl ester

To a solution of [(3i?,45)-l~{5-[(l -cyano-piperidin-4-yl)-ethyl-carbamoyl]-pyrimidin-2-yl} - 4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid teri-butyl ester (Preparation 197, 0.180g, 0.324mmol) in DMF (2.5mL) was added ammonium chloride (26mg, 0.486mmol) and sodium azide (31 .6mg, 0.486mmol). The mixture was heated at 100 °C for 18 h. The reaction mixture was diluted with water and extracted with EtOAc, then EtOAc:MeOH (95:5), The combined organic extracts were washed with brine, filtered through a hydrophobic frit and concentrated in vacuo. Purification by column chromatography (95:5 DCM:MeOH) afforded the title compound: RT = 1.01 min; mlz (ES⁺) = 599.46 [M+ H]⁺ (LCMS Method - 2).

Preparation 199: [(3 ?,45)- -(2,5-Difluoro-phenyl)-l-(5-{ethyl-[l-(2-ethyl-2II-tetrazoI-5-yl)- piperidin-4-yl]-carbanioyl -pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid icrt-butyl ester

To a solution of [(3R,4¾-4-(2,5-difluoro-phenyl)-l -(5-{ethyl-[l-(2H etrazol-5-yl)-piperidin- 4-yl]-carbamoyl }-pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-b tyl ester (Preparation 198, 60mg, O. lOmmol) in acetone (3mL) was added potassium carbonate (42mg, 0.30mmol) followed by the drop wise addition of iodoethane ( Ι Ομί, 0.13mmol). The mixture was then heated at 45 °C for 2.5 h then concentrated in vacuo. The residue was partitioned between EtOAc and water, the organic phase washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Purification by preparative HPLC (Standard Method) afforded the title compound: RT = 1.20 min; mlz (ES^*) = 627.54 [ + H]^" (LCMS Method - 2).

Preparation 200: l-(2,5-Difluoro-phenyl -2-nitro-ethanol

Nitromethane (227mL, 4.22mol) was added in one portion to a solution of 2,5- difluorobenzaldehyde (500g, 3.52mol) in MeOI I (5L) in a 10 L jacketed vessel The solution was cooled to 4 °C (jacket -10 °C ) and a solution of NaOH (169g, 4.22mol) in water (500mL) was added over 40 min causing a 6 °C exothcrm. The solution was stirred for 60 min (jacket 0 °C) after which time a thick white precipitate formed. Ice water ( L) was added (jacket 5 °C) followed by NH₄C1 (sat. aq., 3.5 L) and the solution extracted with DCM ( x 2 L). The combined organics were evaporated then taken up into DCM (1L), dried over MgS0₄ and evaporated to dryness to afford the title compound. H NMR δ_Η (300MHz, CDC1₃): 7.35 (m, 1H), 7.05 (m, 2H), 5.70 (m, 1H), 4.60 (m, 2H), 3.10 (m, 1H).

Preparation 201; l,4-Difluor ne

Acetic anhydride (665mL, 7.05mol) was added in one portion to 1 -(2,5-difluoro-phenyl)-2- nitro-ethanol (Preparation 200, 672g, 3.31mol) at 0 °C under argon. DMAP (28.3g, 0.23mol) was added and the solution darkened in colour. The reaction was warmed to r.t. over 18 h. The reaction mixture was cautiously poured into NaHCCh (sat. aq., 3.5L) and stirred to form a yellow solid. The slurry was stirred for 30 min at r.t. before filtering. The solid was washed with NaHC0₃ (sat. aq., 2L) then water (2L). The solid was dissolved in DCM (1 .5L) and washed with saturated NalICO, (sat. aq., 4 x 1L), dried over MgS0₄ and evaporated to afford a yellow / orange oil which solidified to give a yellow solid. This was purified by dry flash chromatography eluting with DCM to afford the title compound. Ή NMR δ_Η (300MHz, CDC1₃): 8.05 (d, I H), 7.70 (d, 1H), 7.20 (ni, 3H).

Preparation 202: 1 -Benzyl-3-(2,5- difluoro-p cnyl)-4-nitro-pyrrolidine

l,4-Difluoro-2-((£)-2-nitro-vinyl)-benzene (Preparation 201, 120g, 0.65mol) was dissolved in analytical grade DCM (1.2L) and dried over MgS0 . The solution was filtered and split into two portions (60g, 0.32mol). N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (lOOmL, ().39mol) was added to each portion under argon. The yellow solutions were then cooled to -5 °C and TFA (2.7mL, 0.04mol) added. After 5 min the temperature rapidly increased to 30 °C then cooled back to -5 °C. The resulting paler yellow solution was stirred at -10 °C for 1 h before quenching cautiously with NaHCOs (sat. aq., 1 L). The two batches were combined and the layers partitioned. The DCM layer was washed with water (2L) then brine (2L), dried over MgS0₄ and evaporated to give 209g of an orange oil. The material was purified by dry flash chromatography eluting with DCM to afford the title compound. Ή NMR δ„ (300MHz, CDCI₃): 7.40 - 7.20 (m, 5H), 7.00 (m, 3H), 4,95 (m, I II), 4.20 (m, 1H), 3.70 (m, 2H), 3.40 (m, IH), 3.20 (m, 2H), 2.70 (m, 1H).

Preparation 203: l-Benzyl-4-(2,5-diflu -ylamine

l -Benzy!-3-(2,5-difluoro-phenyl)-4-nitro-pyrrolidine (Preparation 202, 340g, l ,07mol) was dissolved in IMS (5L) and charged into a 7.8L autoclave. RaNi (20g) was added (without washing). The autoclave was sealed and charged with ¾ (50 bar) and stirred at r.t. for 18 h (10 °C exothcrm). The reaction mixture was filtered through celite, the pad washed with IMS and the filtrate evaporated to dryness. The brown oil was dissolved in DCM (1.5L), extracted with HC1 (1M, aq. 2.5L) and washed with DCM (3 x IL) to remove the colour from the aqueous layer. The aqueous layer was basified to pH 14 with NaOH (2M, aq. 3L) and extracted into DCM (5 x IL) then the organics were combined, dried over MgSO.₍ and evaporated to afford the title compound. ^]H NMR δ_Η (300MHz, CDCI₃): 7.40 - 7.20 (m, 5H), 7.10 (m, IH), 6.95 (m, IH), 6.85 (m, IH), 3.70 (tn, 2H), 3.50 (m, IH), 3.25 (m, 111), 3.05 (m, 211), 2.65 (m, H I), 2.45 (m, IH), 1.50 (br s, 211). Preparation 204: l-Benzyl-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl-carbamic acid ierf-butyl ester

Triethylamine (244mL, 1.75mol) was added to a solution of 1 -benzyl -4-(2,5-difluoro- phenyl)-pyrrolidin-3-ylaminc (Preparation 203, 252g, 0.87mol) in THF (3.8L) and the cloudy light brown solution was cooled to 0 °C. Di-ieri-butyldicarbonate (229g, l .OSmol) was added in one portion and the suspension wanned to room temperature over 18 h. The THF was removed by evaporation and the off-white slurry taken up into EtOAc (2.5L). The solution was washed with water (3 x IL), brine (1L), dried over MgSO,, then evaporated to give a pale yellow oil. Heptane (0.5L) was added and evaporated to give an off white solid, which was triturated with heptane. This was filtered and the solid washed with heptane then dried at 40 °C for 18 h to afford the title compound. Ή NMR δ„ (300MHz, CDC¾): 7.40 - 7.20 (m, 5H), 7.05 (m, 1H), 6.95 (m, 1H), 6.85 (m, 1H), 4.95 (m, 1H), 4.20 (m, 1H), 3.60 (s, 211), 3.30 (m, 1H), 3.10 (m, 1H), 2.95 (m, 1H), 2.65 (m, 1H), 2.45 (m, I II), 1.40 (s, 9H).

Preparation 205: f(3 ?,4- l-Benzyi-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yIj-carbamic acid tert- butyl ester

The title compound was afforded via chiral HPLC separation of 1 -bcnzyl-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl-carbarnic acid ferf-butyl ester (Preparation 204): III: 1PA:DEA 96:4:0.1 , 15ml/min, 270nm, RT = 10.9 min.

Preparation 206: [(3/?,45)-4-(2,5-Difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

10% Pd C (20g) was added as a paste in toluene to a solution of [(3R,45)-l -benzyl-4-(2_s5- difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid teri-butyl ester (Preparation 205, 212g, O.55mol) in IMS (61.) in a 7.8L autoclave. The autoclave was sealed, charged with ¾ (50 bar) and heated to 60 °C for 6 h then r.t. for 72 h. The Pd/C was removed by filtration through cclite, the pad washed with IMS and the filtrate evaporated to dryness. The reaction was repeated (200g, 0.52mol) and the two batches combined to give 288g of an off-white solid. This was triturated with heptane, filtered, washed with heptane and dried at 40 °C for 18 h to afford the title compound. Ή NMR δ_Μ (300MHz, CDClj): 7.00 (m, 2H), 6.85 (m, 1H) 4.75 (br s, 1H), 4.15 (m, 1H), 3.45 (m, 2H), 3.25 (m, 1H), 2.90 (m, 2H), 1.90 (s, 1H), 1.35 (s, 911).

Preparation 207; 2-Nitro-l-(2,4,5-trifluoro-phenyl)-ethaiioI

Nitromethane (274mL, 5.10mol) was added in one portion to a solution of 2,4,5- trifluorobenzaldehyde (680g, 4.25mol) in MeOH (7.2L) in a 10 L jacketed vessel. The solution was cooled to 0 °C (jacket -10 °C) and a solution of NaOH (204g, 5.10mol) in water (680mL) was added over 30 min. A 5 °C exothcrm was observed. The solution was stirred for 30 min (jacket 0 °C) after which time a white precipitate had formed. Half of the material was transferred to a second vessel and both slurries stirred for a further 30 min becoming very thick. Ice water (2L) and NH₄CI (sat. aq., 2.5L) was added to each to afford a solution. The solutions were extracted with DCM (5 x 1.5L) and the organics from both batches combined and evaporated then dissolved in DCM (IL), dried over MgS0₄ and evaporated to dryness to afford the title compound. 'li NMR δ_Η (300MHz, CDCI₃): 7.45 (m, 1H), 6.95 (m, 1H), 5.70 (m, 1H), 4.55 (m, 2H), 3.10 (d, 1H).

Preparation 208: l,2,4-Trifluoro-5-((£^')- -nitro-vinyl)-benzene

Acetic anhydride (849mL, 8.99mol) was added to 2-nitro- 1 -(2,4,5-trifluoro-phenyl)-ethanol (Preparation 207, 935g, 4.22mol) at 0 °C under argon. ΌΜΑΡ (36g, 0.30mol) was added in one portion and the solution darkened in colour. The temperature reached 50 °C over 20 min before cooling back to 0 °C. The solution was allowed to warm to r.t. over 18 h. The reaction mixture was cautiously poured into NaHC0₃ (sat. aq., 6L) and stirred to form a yellow solid. The slurry was stirred for 30 min at r.t. before filtering and washing with NaHCOj (sat. aq., 3L) then water (3L). The solid was dissolved in DCM (2L) and washed with saturated NaHC0₃ (sat, aq., 2 x 1.5L) then the organics dried over MgS0 and evaporated to give 795g of an orange / brown oil which solidified to give an orange solid. Purification by dry flash chromatography eluting with DCM afforded the title compound. Ή NMR δ„ (300MHz, CDClj): 7.95 (d, I II), 7.65 (d, 1 H), 7.35 (m, 1H), 7.05 (m, 1H).

Preparation 209: l-Benzyl-3-nitro-4-(2 -trifluoro-phenyl)-pyrrolidine

l,2,4-Trifluoro-5-((£)-2-nitro-vinyl)-benzene (Preparation 208, 375g, 1.85mol) was dissolved into analytical grade DCM (3.75L) and dried over MgSO,₍. The solution was filtered and split into five batches (75g, 0.37mol). N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1 1 mL, 0.44mol) was added to each under argon and the orange solutions were then cooled to -10 °C. TFA (3mL, 40.6mmol) was added to each in one portion and after 5 min the temperature rapidly increased to 30 °C then cooled back to -10 °C. The resulting paler yellow / orange solutions were stirred at -10 °C for 1 h before quenching cautiously with NaHCO_¾ (sat. aq., 1L). The layers were partitioned and the DCM layer washed with water (1L), brine ( IL). dried over MgS0₄ and evaporated. The crude batches were combined and purified by dry flash chromatography eluting with DCM to afford the title compound. Ή NMR δ„ (300MHz, CDClj): 7.40 - 7.20 (m, 6H), 6.90 (m, 1H), 4.95 (m, 1H), 4.20 (m, 1H), 3.70 (m, 211), 3.35 (m, 1H), 3.20 (m, 2H), 2.70 (m, 1H).

Preparation 210: l-Benzyl-4-(2 -3-ylamine

l -Benzyl-3-nitro-4-(2,4,5-tritluoro-phenyl)-pyrrolidine (Preparation 209, 62 l g, 923mol) was run as two batches, each dissolved into IMS (51.) and charged into a 7.8L autoclave. RaNi (20g) was added (without washing) and the autoclave charged with H₂ (50 bar) and stirred at r.t. for 18 h (10 °C exo therm). The mixtures were filtered through celite and both batches combined and evaporated to dryness. The resulting brown oil was dissolved in DCM (1.51.) and extracted with HCl (1M, aq. 2.5L) and washed with DCM (3 x IL) to remove the colour from the aqueous layer. The aqueous layer was basified to pH 14 with NaOIl (2M, aq. 3L) and extracted with DCM (5 x IL), combined, dried over MgS0₄ and evaporated to afford the title compound. Ή NMR δ_Η (300MHz, CDClj): 7.40 - 7,20 (m, 6H), 6.85 (m, I II), 3.70 (m, 2H), 3.45 (m, 1H), 3.20 (m, 1H), 3.10 (m, 2H), 2.65 (m, I II), 2.45 (m, 1H), 2.20 (br s, 211). Preparation 211: l-Benzyl-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl-carbamic acid fcrt-butyl ester

Triethylamine (210mL, 1.51 mol) was added to l -bcnzyl-4-(2,4,5-trifluoro-phcnyl)- pyrrolidin-3-ylamine (Preparation 210, 23 I g, 0.75mol) in TI IF (1.8L) and the light brown cloudy solution was cooled to 0 °C. Di-ferf-butyldicarbonate (198g, 0.91 mol) was added in one portion and the suspension warmed to room temperature over 18 h. The suspension was concentrated and the off- white slurry dissolved into EtOAc (2.5L). The solution was washed with water (3 x 1L) and brine (IL) then dried over MgS0₄ and evaporated to give a pale yellow oil. Heptane (0.5 L) was added and evaporated to give an off white solid. This was combined with a second batch (from 218g, 0.71 mol starting material) and triturated with heptane, filtered, washed with heptane and dried at 40 °C for 18 h to afford the title compound. Ή NMR δ„ (300MHz, CDClj); 7.40 - 7.20 (m, 6H), 6,85 (m, 111), 4.85 (m, 1 H), 4.20 (m, 1H), 3.60 (s, 2H), 3.30 (m, 1 H), 3.00 (m, 2H), 2.60 (m, 1 H), 2.45 (m, 1 H), 1.40 (s, 9H).

Preparation 212: 4-(2,4,5-Trifluoro-ph carbamic acid fert-butyl ester

l -Benzyl-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (Preparation 211, 612g. 1 .51 mol) was run in two batches each being suspended in EtOAc (0.5L) and IMS (4L) and charged into a 7.8L autoclave. 10% Pd/C (20g) was added to each as a paste in toluene. The autoclave was sealed and charged with ¾ (50 bar) then heated to 55 °C for 6 h, 20 °C for 18 h then 55 °C for 6 h. The reaction mixtures were filtered through celite and the pad washed with IMS before, evaporating to dryness. The resulting off-white solids were triturated with heptane, filtered, washed with heptane then dried at 40 °C for 18 h before the two batches were combined to afford the title compound. Ή NMR δ_Η (300MHz, CDCI₃): 7.10 (m, 1 H), 6.90 (m, 1H) 4.70 (br s, 1H), 4.15 (m, 1H), 3.45 (m, 2H), 3.20 (m, 1H), 2.85 (m, 2H), 1.75 (br s, I H), 1.40 (s, 9H),

Preparation 212: [(3/?,45)-4-(2,4,5-Trifluoro-phenyl)-pyrrolidin-3-ylJ-carbamic acid iert-butyl ester

4-(2,4,5-Trifluorophenyl)pyrrolidin-3-yl]carbamic acid ferf-butyl ester (Preparation 212, 30.0g, 95mmol) was suspended in EtOH (lOOmL) and heated to 70°C. To the suspension was added a warm solution o ($)-( · )-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 IM NaOH, brine, then dried (MgS0₄), and the solvent was removed in vacuo.

A second portion of [(/raw.v)-4-(2,4,5-trilluorophenyl)pyrrolidin-3-yl]carbamic acid te/ -butyl ester (Preparation 212, 29.5g, 93mmol), suspended in EtOH (lOOmL), was heated to 70°C. Treatment with a warm solution of (_lS)-(+)-naproxen (10.6g, 46mmoI) in EtOH (WOmL), 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 (S)-(+)-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: Ή NMR 6_H (400MHz , CD₃OD): 7.38 - 7.25 (m, 1 H), 7.14 - 7.01 (m, I I I), 4.20 - 4.09 (m, l H), 3.30 - 3.21 (m, 3H), 2.90 - 2.81 (m, I I I), 2.77 - 2.68 (m, 1H), 1.34 (br. s., 911).

Preparation 213: {l-[5-(l,l -Difluoro-ethyl)- [ 1,2,4] oxadiazoI-3-ylJ -piperidin-4-yl}-methyl- carbamic acid terf-butyl ester

To a solution of ( 1 -cyano-piperidin-4-yl)-methyl-carbamic acid ierf -butyl ester (Preparation 21, l .OOg, 4.18mmol) in EtOH (lOmL) was added 50% hydroxylaminc in water (0.26mL, 4.2mmol) and the mixture heated at 70°C for 1 h. The reaction was cooled to r.t. and concentrated under reduced pressure. The resulting solid was dissolved in DMF (6.47mL, 83.6mmol) and HOBt (0.064()g, 0.418mmol), EDCI (0.961 g, S.O l mmol) and 2,2-difluoropropionic acid (0. 52g, S.Olmmol) added. The reaction mixture was stirred at r.t. over 60 h, after which time it was diluted with EtOAc (I SOmL) and washed with a saturated solution of sodium bicarbonate (2 x 1 OOmL), 1 M citric acid solution (l OOmL) then brine (lOOmL). The organics were concentrated under reduced pressure, and the residue dissolved in toluene (SmL) then heated at reflux for 13 h. The reaction was cooled to r.t. and concentrated under reduced pressure. Purification by column chromatography (7:3 EtOAc:IH) afforded the title compound: RT = 1.33 min; mlz (ES⁺) = 347.4 [M + H]⁺ (LCMS Method - 2). Preparation 214: { 1- [5-( 1 , 1 -Ditluoro- 3-yl] -piperidin-4-ylJ-methyl-amine

{ 1 -[5 -(1 , 1 -Difluoro-ethyl)-[l ,2,4]oxadiazol-3 -yl] -piperidin-4-yl } -methyl-carbamic acid tert- butyl ester (Preparation 213, 1.1 g, 3.2mmol) was dissolved in DCM (l OmL, 200mmol) and TEA (2mL, 20mmol) added. The reaction was stirred at r.t. for 1 h before being loaded directly onto an SCX cartridge. Elution with MeOH followed by 7N ammonia in MeOH solution and concentration in vacuo afforded the title compound: RT - 0.52 min, m/z (ES⁺) = 247.3 [ + H]⁺ (LCMS Method - 2).

Preparation 215: [(3^,4S)-l-[S^{1 5-(1 -Difluoro-ethyi)-[l,2,4]oxadiazol-3-yl]-piperidin-4-yI}- methyl-carbamoyl)-pyrimidin-2-yl] -4-(2,5-difluoro-phcnyl)-pyrrolidin-3-yl] -carbamic acid tert- butyl ester

The title compound was synthesized from 2-[(3R.4S)-3-it'rf-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidm-l -yl]-pyrimidine-5-carboxylic acid (Preparation 90, 430mg, l .Ommol) and { 1 - [5 -( 1 , 1 -diiluoro-ethyl)- [ 1 ,2,4] oxadiazol-3 -yl] -piperidin-4-yl} -methyl -amine (Preparation

214, 250rng, l .OlSmmol) employing a procedure similar to that outlined in Preparation 105: RT 1 . 1 min; mlz (ES ) = 649.6 [M + H] ^' . Preparation 216 : C clopropyl- {l-[5-(l -methoxy-l-methyl-ethyl)- [ 1 ,2,4 j oxadiazoI-3-yl] - piperidin-4-yl}-carbamic acid terf-but l ester

The title compound was synthesized from ( 1 -cyano-piperidin-4-yl)-cyclopropyl-carbamic acid tert-butyl ester (Preparation 26, 621 mg, 2.34mmol) and 2-methoxy-2-methyl-propionic acid (351mL, 2.82mmol) employing a procedure similar to that outlined in Preparation 213: RT = 1.34 min; mlz (ES⁺) = 381.5 [M+ H]⁺.

Preparation 217: Cyclopropyl-{l -[5-(l-methoxy-l-methyl-ethyl)-[ 1 ,2,4]oxadiazol-3-yl]- piperidin-4-yl}-amine

The title compound was synthesized from cyclopropyl- { 1 -[5-( 1 -methoxy-1 -methyl-ethyl)- [ l ,2,4]oxadiazol-3-yl]-piperidin-4-yl} -carbarnic acid ieri-butyl ester (Preparation 216, 590mg, 1.55mmol) employing a procedure similar to that outlined in Preparation 214: RT = 0.51 min; mlz (ES⁺) = 281.4 [ + H]^÷.

Preparation 218: [(3ii,45)-l-[5-(CycJopropyl-{l-[5-(l-methoxy-l-methyl-ethyI)- [l,2,41oxadiazol-3-ylj-piperidin-4-yl}-carbamoyl)-pyrimidin-2-yl)-4-(2,5-difluoro-phcnyl)- pyrrolidin-3-yl]-carbamic acid to-/-but l ester

The title compound was synthesized from 2-[(3R,4.S)-3-to-/-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5-carboxylic acid (Preparation 90, 277mg, 0.66mmol) and cyclopropyl- { 1 -[5-( 1 -methoxy-1 -mcthyl-cthyl)-[ 1 ,2,4]oxadiazol-3-yl]-pipcridin-4-yl } -amine (Preparation 217, 185mg, 0.66mmol) employing a procedure similar to that outlined in Preparation 105: RT = 1.33 min; mlz (ES⁺) = 683.7 [M + H]⁺. Preparation 21 : [(3/?,4S)- 1 - {5- [(l-Carbamoyl-piperidin-4-yl)-cyclopropyl-carbamoylj - pyrimidin-2-yI}-4-(2,5-difluoro- henyl)-pyrrolidin-3-yl]-carbamic acid fert-butyl ester

To a stirred solution of (l -cyano-piperidin-4-yl)-cyclopropyl-carban ic acid /eri-butyl ester (Preparation 26, 1.09g, 4,12mmol) in DCM (20mL) at 0°C was added TFA (4mL, 50mmol). The solution was allowed to warm to r.t. and stirred for 4 h. The reaction mixture was passed through a SCX cartridge and the free base eluted with a 3.5M solution of ammonia in MeOH. The mixture was concentrated in vacuo and the residue dissolved in DCM (60mL). To this was added 2-[(3R,45)-3- ferr-butoxycarbonylamino -4-(2, 5 -difluoro-phenyl)-pyrrolidin- 1 -yl] -pyrimidine-5 -carboxylic acid (Preparation 90, 1.73g, 4.12mmol), triethylamine (2.29mL, 16.5mmol) and PPA (50% w/w in EtOAc, 4.90mL, 8.23mmol) and the reaction stirred at r.t. for 18 h. The mixture was quenched with MeOH and concentrated under reduced pressure. The residue was dissolved in MeOH and loaded directly onto a SCX cartridge and eluted with MeOH, then 7N ammonia in MeOH solution and concentrated in vacuo. Purification of the residue by column chromatography (7:3 EtOAc:IH) afforded the title compound: RT = 0.99 min, m/z (ES⁺) = 586.6 [M+ H]⁺ (LCMS Method - 2).

Preparation 220 : [(3J?,45 -1- {5- [( 1 -Cyano-piperidin-4-yI)-cyclopropyl-carbamoyl] -pyrimidin-2- yl}-4-(2,5-difluoro-phenyl)- rrolidin-3-yI]-carbamic acid feif-bwtyl ester

[(3R,45)- 1 - { 5-[( 1 -Carbamoyl -piperidin-4-yl)-cyclopropyl-carbamoyl] -pyrimidin-2-yl} -4-

(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid ferf-butyl ester (Preparation 219, ().70()g, 1 ,20mmol) and MeCN (20rnL) were combined under an argo atmosphere. Methanesulfonyl chloride (0.139mL, ! .79mmol) followed by pyridine (0,242mL, 2.99mmol) were added via syringe. The resulting suspension was stirred for 5 min prior to being heated to 50 °C for 18 h. The solvent was removed under reduced pressure and water (50mL) added to the resulting residue. The mixture was extracted with EtOAc (3 x 150mL), the organics combined and dried (magnesium sulfate) before concentration under reduced pressure afford the title compound: RT = 1.15 min, m/z (ES⁺) = 568.8 [ + H (LCMS Method -2). Preparation 221 : [(3 ?,4 )-l-(5-{Cyclopropyl-[ l-(A-hydroxycarbaminiidoyl)-piperidin-4-yl]- carbamoyl}-pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl] -carbamic acid fcrt-butyl ester

f(3R,4.S)-l -{5-f(l -Cyano-piperidin-4-yl)-cyclopropyl-carbamoyl]-pyrimidin-2-yl} -4-(2,5- difluoro-phenyl)-pyrrolidin-3-yl] -carbamic acid feri-butyl ester (Preparation 220, 500mg, 0.881 mniol) was dissolved in EtOH (lOrnL) and 50% hydroxylamine in water (0.1 ImL, l .Smmol) added via syringe. The reaction mixture was stirred overnight at r.t. The mixture was then concentrated under reduced pressure and further azeotroped with toluene to afford the title compound: RT = 0.84 min, m/z (ES⁺) = 601.6 [M+ H]⁺.

Preparation 222: [(3J?,4 )-l-[5-(Cyclopropyl-{l-[5-(l,l-difluoro-ethyl)-[l,2,4]oxadiazoI-3-yl)- piperidin-4-yI}-carbamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid iert-butyl ester

[(3R,4S)-l-(5-{Cyclopropyl-[l -(N-hydroxycarbaminiidoyl)-piperidin-4-yl]-carbamoyl}- pyrimidin-2-yl)-4-(2,5-difluoro-phenyl)-pyiTolidin-3-yl]-carbamic acid iert-butyl ester (Preparation 221 , 230mg, 0.383mmol), 2,2-dif uoropropionic acid (50.6mg, 0.459mmol), EDCI (88.1mg, 0.459mmol) and triethylamine (0.1 17mL, 0.842mmol) were combined in DCM (20mL) and HOBt (0.8mg, 0.005mmol) added. The reaction was stirred at r.t. for 1 h before quenching with MeOH and concentrating under reduced pressure, azeotroping with toluene. Purification of the residue by preparative HPLC afforded the title compound: RT - 4.32 min, m/z (ES⁺) = 675.9 [M + I I] ^' (LCMS Method -1). Preparation 223: [(3fl,4^-l-[5-(C clopropyl-{l-[(^

3-yl]-piperidin-4-yl}-carbamoyl)-pyrimidin-2-yl]^^

carbamic acid iert-butyl ester

The title compound was synthesized from [(3i?,4S) -(5-{cyclopropyl-[l -(N- hydroxycarbamimidoyl) -piperidin-4 -yl] -carbamoyl} -pyrimidin-2 -yl) -4-(2, 5 -di fluoro-phenyl)- pyrrolidin-3-yl] -carbamic acid fert-butyl ester (Preparation 221) and (R)-tetrahydro-furan-3- carboxylic acid employing a procedure similar to that outlined in Preparation 222: RT = 1.22 min, m/z (ES⁺) = 681.6 [ + H] ^' (LCMS Method - 2).

Preparation 224: (/f)-Tetrahydro-furan-3-carboxylic acid amide

To a solution of (R)-tetrahydro-furan-3-carboxylic acid (500mg, 4.31 mmol) in DCM (5mL) at 0 °C under inert atmosphere was added oxalyl chloride (444pL, 5.17mmol) followed by DMF (50μΙ_·, 0.65mmol). The reaction mixture was stirred for 1 h then allowed to warm to room temperature and stirred for further 2 h. After cooling to 0 °C, N¾ in MeOH solution (7N, 50mL) was added and the mixture stirred overnight. The solvents were then removed in vacuo, azcotroping with DCM to dryness to afford the title compound: ¾ NMR δ,, (300MHz, CDCU): 5.80-5.30 (bs, 2H), 3.90 (m, 4H), 2.90 (m, 1H), 2.20 (m, 2H).

Preparation 225: (5 Tctrahydro-furan-3- e

To a solution of (7?)-tetrahydro-furan-3-carboxylic acid amide (Preparation 224, 435mg, 3.78mmol) in THF ( lOmL) was added pyridine (2.3 ImL, 28.61mmol) and the reaction cooled to 0 °C. Trifluoroacetic anhydride (2.70mL, 28.61mmol) was added and the mixture stirred for 1 h. The mixture was partitioned between saturated aqueous sodium bicarbonate solution and DCM; the aqueous layer was back-extracted with further DCM. The combined organics were washed with brine and dried with magnesium sulfate before concentrating in vacuo. Purification of the residue by column chromatography (EtOAc) afforded the title compound: Ή NMR δ_Η (300MHz, CDCI ): 4.05 (t, 1 H), 3.90 (m, 3H), 3.05 (m, 1H), 2.3 (m, 2H).

Preparation 226: (5)-JV-Hydroxy~tetra arboxarnidine

To a solution of (S)-tetrahydrofuran-3-carbonitrile (Preparation 225, 280mg, 2.89mmol) in IMS (2mL) was added hydroxylamine (50% in water, 229μΙ_, 3.46mmol) and the reaction was heated to 70 °C for 18 h. On cooling, the solvent was removed in vacuo, azeotroping with toluene. The residue was triturated with toluene then DCM. Purification by column chromatography (DCM:MeOH, 90: 10) afforded the title compound: Tl NMR δ_Η (3G0MHz, CDC1,): 4.70 (bs, 2H), 4.05 (m, 211), 3.70 (m, 2H), 2.9 (m, 1H), 2.25 (m, 111), 2.00 (m, lH).

Preparation 227: Cyciopropyl-{l-[(5 -3-(tetrahydro-furan-3-yl)-[l,2,4]oxadiazoi-5-ylj- piperidin-4-yl}-amine

The title compound was synthesized from ( 1 -cyano-piperidin-4-yl)-cyclopropyl-carbamic acid tert- butyl ester (Preparation 26) and (S)-N-hydroxy-tetrahydro-furan-3-carboxamidine (Preparation 226) employing a procedure similar to that outlined in Preparation 35: RT = 0.46 min; m/'z (ES ^') = 279.37 [ · I I]^' (LCMS Method - 2).

Preparation 228: [(3 ?,4₁S l-[5-(Cyclopropyl-{l-[(>S>3-(tetrahydro-furan-3-yl)-[l,2,4joxadiazol- 5-yl] -piperidin-4-yl}-carbamoyl)-pyrimidin-2-yl] -4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl] - carbamic acid tert-butyl ester

The title compound was synthesized from 2-[(3R,45)-3-ieri-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5-carboxylic acid (Preparation 90) and cyclopropyl- {l-[(5)-3-(tetrahydro-furan-3-yl)-[l ,2,4]oxadiazol-5-yl]-piperidin-4-yl}-amine (Preparation 227) employing a procedure similar to that outlined in Preparation 105: RT = 1 .17 min; mlz (ES' ) = 681.56 [ + Hf.

Preparation 229: 2-Chloro-pyrimidine-5-sulfonic acid {l-[3-(l,l-difluoro-ethyl)- [l,2,4)oxadia/ol-5-yl]-piperidin-4- -inethyl-amide

{ 1 -[3-(l , 1 -Difluoro-ethyl)-[l ,2,4]oxadiazol-5-ylJ-piperidin-4-yl} -methyl-amine

(Preparation 44, 0.150g, 0.609mmol), triethylamine (0.102ml., 0.730mmol) and DCM (4ml .) were combined and 2-chloropyrirnidi ne-5 -sul fonyl chloride (0.130g, 0.609mmol) added. The reaction was stirred at r.t. for 10 min. Water (20mL) and DCM (50mL) were added and the organic layer separated and washed with 1M HCI solution (50mL) before concentrating under reduced pressure. Purification of the residue by column chromatography ( 1 : 1 EtQAc.TH) afforded the title compound: RT = 1.17 min, m/z (ES ) = 423.4 [M+ H]⁺.

Preparation 230: [(3fi,4,S)-l-[5-({l-[3-(l,l-Difluoro-ethyl)-[l,2,4]oxadiazol-5-yl]-piperidin-4-yl}- methyl-sulfamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-pyi olidin-3-yll-carbamic acid tert- butyl ester

2-Chloro-pyrimidine-5 -sulfonic acid { 1 -[3 -( 1 , 1 -difluoro-ethyl)-[l ,2,4]oxadiazol-5-yl]- piperidin-4-yl} -methyl-amide (Preparation 229, 103mg, 0.244mmol), triethylamine (0.0407mL, 0.292mmol) and TI IF (5 mL) were combined and [(3R,4S)-4-(2,5-difluoro-phenyl)-pyrrolidin-3-ylJ- carbamic acid iert-butyl ester (Preparation 206, 72.7mg, 0.244mmol) added. The reaction was stirred at 50 °C for 2 h. The reaction was cooled to r.t. and the TIIF removed under reduced pressure. The residue was dissolved in DCM (50mL) and the organic layer washed with I M HCI solution (2 x 1 OOmL) and saturated sodium bicarbonate solution (lOOmL), The organics were dried (magnesium sulfate) before being concentrated under reduced pressure. Purification by column chromatography (3.5:6.5 EtOAc:IH) afforded the title compound: RT = 1.38 min, m/z (ES⁺) = 685.6 [ + H] \ Preparation 231 : ( l-Cyclopropanesulfon l-piperidin-4-yl)-cyclopropyl-amine

Cyclopropyl-piperidin-4-yl-carbamic acid fcrf-butyl ester (Preparation 19, 0.200g, ⁽⁾.832mmol) was dissolved in DCM (lO.OmL, 156mmol) and D1PEA (0.362mL, 2.08mmol) added followed by cyclopropylsulfonylchloride (0!02mL, 0.998mmol). The reaction mixture was stirred at r.t, for 18 h. The mixture was diluted with DCM and washed with water followed by brine, filtered through a hydrophobic frit and then concentrated in vacuo. The residue was passed through a SCX cartridge and eluted with MeOH before concentrating in vacuo. The residue was dissolved in DCM (iOr L) and cooled to 0 °C before the dropwise addition of I F A (l .OmL, 13mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was then passed through a SCX cartridge and eluted with 10% ammonia in MeOH and concentrated in vacuo. Purification by column chromatography (8:92 McOHrDCM) afforded the title compound: Ή NMR δ„ (301 MHz , CTX¾): 3.44 - 3.37 (rn, 2H), 2.67 - 2.56 (m, 2H), 2.38 - 2.27 (m, 1H), 1.99 -1.89 (m, 1H), 1.84 - 1.78 (m, 1H), 1.73 - 1.64 (m, 2H), 1.29 - 1.10(m, 4H), 0.89 - 0.81 (m, 2H), 0.68 - 0.61 (m, 2H), 0.19 - 0.12 (m, 2H), 0.09 - 0.00 (m, 2H).

Preparation 232: [(3/?, S - 1 - {5- [( l-Cyclopropanesulfonyl-piperidin-4-yl)-cyclopropyl- carbamoyl]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyI)-pyrroIidin-3-yi]-carbamic acid tert-butyl ester

The title compound was synthesized from 2-[(3R,4S)-3-teri-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l -yl]-pyrimidine-5-earboxylic acid (Preparation 90) and ( 1 - cyclopropanesuli nyl-piperidin-4-yl)-cyclopropyl-amine (Preparation 231) employing a procedure similar to that outlined in Preparation 105: RT = 1.21 min; m/z (ES⁺) = 647.61 [M + H] ^' (LCMS

Method - 2). Preparation 233: Cyclopropyl-(l-(2H-tetrazol-5-yl)-piperi(lin-4-yl]-carbamic acid fert-butyl ester

(l-Cyano-piperidin-4-yl)-cyclopropyl-carbarnic acid teri-butyl ester (Preparation 26, 0.5 4g, 1 ,94mmol) was dissolved in DMF (l .OmL) and ammonium chloride (0.207g, 3.87mmol) was added followed by sodium azide (0.252g, 3.87mmol). The reaction mixture was heated at 100 °C for 18 h before the addition of water (15mL), then brine. The aqueous layer was extracted with EtOAc (3 x) and the combined organic extracts were filtered through a hydrophobic frit: and concentrated in vacuo. Purification of the residue by column chromatography (6:94 MeOH:DCM) afforded the title compound: RT = 0.9min; m/z (ES⁺) = 309.40 [M + H] ^' (LCMS Method - 2).

Preparation 234: Cyclopropyl-|l-(2-ethyl-2H-tetrazol-5-yl)-piperidin-4-yl]-carbamic acid tert- butyl ester

Cyclopropyl-[l -(2II-tetrazol-5-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (Preparation 233, 0.166g, 0.538mmol) was dissolved in acetone () 6mL) and potassium carbonate (0.22g, 1.6mmol) added followed by the dropwise addition of iodoethanc (0.056mL, OJOmmol). The reaction mixture was then heated at 45 °C for 5 h before concentrating in vacuo. The residue was partitioned between EtOAc (50mL) and water (25mL). The organic phase was separated and washed with brine, filtered through a hydrophobic frit and concentrated in vacuo. Purification by column chromatography (3:7 EtOAciIH) afforded the title compound: RT = 1.22 min; 337.44m/z (ES ) - [M + H] ^" (LCMS Method - 2).

Preparation 235: CycIopropyl-[l-{2-eth l-2H-tetrazol-5-yI)-piperidin-4-ylJ-amine

Cyclopropyl-[l -(2-cthyl-2I I-tetrazol-5-yl)-piperidin-4-yl]-carbamic acid teri-butyl ester (Preparation 234, 0.135g, 0.401mmol) was dissolved in DCM (8.0mL) and cooled to 0 °C. TEA (l .OmL, 13mmol) was added drop wise. Once addition was complete, the reaction was stirred at room temperature for 2 h. The reaction mixture was passed through a SCX cartridge and eluted with 10% ammonia in MeOH solution to obtain the title compound: RT = 0.49min; rn/z (ES⁺) = 237.35 [ + I If (LCMS Method - 2).

Preparation 236: [(3/?,45 -l-(5-{Cyclopropyl-[l-(2-ethyl-2H-tetrazol-5-j )-piperi(lin-4-yll- carbamoyl}-pyrimidin-2-yI)-4-(2,5-difluoro-pheny!)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

The title compound was synthesized from 2-[(3R,4S)-3-ieri-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5-carboxylic acid (Preparation 90) and cyclopropyl- [l-(2-ethyl-2H-tetrazol-5-yl)-piperidin-4-yl] -amine (Preparation 235) employing a procedure similar to that outlined in Preparation 105: RT = 1.24min; rn/z (ES⁺) = 639.64 [M + H]⁺ (LCMS Method - 2).

Preparation 237: Cyclopropyl-{l-i3-(tetrahydro-pyran-4-yl)-[l,2,4]oxadiazol-5-yl]-piperidin-4- yl} -amine

The title compound was synthesized from ( 1 -cyano-piperidin-4-yl)-cyclopropyl-carbamic acid e i-butyl ester (Preparation 26) and N-hydroxy-tetrahydro-pyran-4-carboxamidine employing a procedure similar to that outlined in Preparation 35: RT - 0.50min; m/z (ES^') = 293.41 [M + H] (LCMS Method - 2),

Preparation 238: [(3/?, S -l-[5-(Cyclopropyl-{l-[3-(tetrahydro-pyran-4-yl)-|l,2,4joxadia/.oI-5- yI]-piperidin-4-yl}-carbamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-

The title compound was synthesized from 2-[(3R,4S)-3- eri-butoxycarbonylamino-4-(2,5- difluoro-phcnyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid (Preparation 90) and cyclopropyl- { 1 - [3 -(tctrahydro-pyran-4-yl) -[1,2,4] oxadiazol-5-yl] -piperidin-4-yl } -amine (Prcpa ration 237) employing a procedure similar to that outlined in Preparation 105: RT = 1.19min; m/z (ES⁺) = 695.65 [ . H] ^' (LCMS Method - 2).

Preparation 239: 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 (ImL) 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 Nal lCO.i solution (2 x 20mL). The combined NaHC0₃ extracts were adjusted 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 (EtOAc Jll; 1 :9 to 3: 10) afforded the title compound: RT = 0.94 min; m/z (RS ) = 223.18 [M - H]\

Preparation 240: 4-Fluoro-benzoic acid 1-carbamoyl-cyclopropyl ester

To a solution of 4-fluoro-benzoic acid 1 -carboxy-cyclopropyl ester (Preparation 239, 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-dioxanc (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 NaHCO.i solution and brine, dried (MgS0₄), filtered and concentrated in vacuo: RT = 0.82 min; mlz (ES ) = 224.19 [M + H] ' .

Preparation 241 : 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 240, 0.290g, 1.30mmol) in THF (lOmL) at 0°C was added triethylamine (0.54mL, 3.9mmol)

followed by trifluoroacetic anhydride (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, 87.6μΕ, 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), pcrchloroacetic 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 (EtOAc:IH; 5:95) to afford the title compound: RT = 1.42 min; mlz (ES ) = 365.07 [Af +H]⁺.

Preparation 242: 4-FIuoro-benzoic acid l-{5-[4-(feff-butoxycarbonyl-cycJopropyI-amiflo)- piperidin- 1 -yl] - [1 ,2,4] oxadiazol-3- I} -cyclopropyl ester

Cyclopropyl-piperidin-4-yl-carba ic acid feri-butyl ester (Preparation 19, 0.038g, 0.16mmol) and 4-fluoro-benzoic acid 1 -(5-trichloromethyl-[l ,2,4]oxadiazol-3-yl)-cyclopropyl ester (Preparation 241, 0.034g, O.093mmol) were combined in dimethyl sulfoxide (0.2mL) and the mixture stirred at room temperature for 16 h. The reaction mixture was diluted with water ( 15mL) and then extracted with EtOAc (3 x 50mL). The combined organic extracts were washed with brine and passed through a hydrophobic frit then concentrated in vacuo. Purification by preparative HPLC (standard method) afforded the title compound: RT = 1.45min; m/z (ES⁺) - 4S7.44 [M + H]⁺ (LCMS

Method - 2). Preparation 243 : Cyclopropyl- {l-[3-(l -hydroxy-cyclopropyl)- [1,2,4] oxadiazol-5-yl] -piperidin-4- yl}-carbamic acid teri-butyl ester

4-FIuoro-benzoic acid 1 - {5-[4-(fert-butoxycarbonyl-cyclopropyl-amino)-piperidin-l -yl]- [ 1 ,2,4]oxadiazol-3 -yl } -cyclopropyl ester (Preparation 242, 0,034g, 0.070mmol) was dissolved in THF (2.0 mL), MeOH (1.0 mL), water (1.0 mL), lithium hydroxide monohydrate (0.012g, 0.28mmol) added and the mixture stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (2 x). The combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo to afford the title compound: RT - 1.04 min ; m/z (ES⁺) = 369.39 [M+ II]^' (LCMS Method - 2).

Preparation 24 ; Cyclopropyl- { 1 - [3-(l-methoxy-cyclopropyl)- [1,2, J oxadiazol-5-yl]-piperidin-

4-yl}-amine

Cyclopropyl- { 1 -[3 -( 1 -hydro xy-cyclopropyl)-[ 1 ,2,4]oxadiazol-5 -yl]-piperidin-4-yl} -carbamic acid teri-butyl ester (Preparation 243, 0.082g, 0.22mmol) was dissolved in THF (6.0inL) and cooled to 0.°C. NaH (60% dispersion in mineral oil, 0.012g, 0.29mmol) was added and the mixture stirred at 0°C for 20 min followed by stirring at room temperature for 10 min. Methyl iodide (0.018mL, was added and stirred at r.t. for 2 h. The reaction mixture was diluted with water (30mL) and extracted with EtOAc (3 50niL). The combined organic extracts were washed with brine, filtered through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in DCM (lOmL) and cooled to 0°C. TFA (1.5mL, 19mmol) was added and stirred for 2 h. The mixture was passed through a SCX cartridge eluting with 10% ammonia in MeOH solution to afford the title compound: RT = 0.53 min; m/z (ES⁺) = 279.49 [M+ H] ^' (LCMS Method - 2). Preparation 245: |(3 ?,45}-1-[5-(Cyclopropyl-{l-|3-(l-methoxy-cj'clopropyl)-[l,2,4Joxadiazol-5- yl)-piperidin-4-yl}-carbamoyl)-pyrimidin-2-yI|-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl|- carbamic acid fert-butyl ester

The title compound was synthesized from 2-[(3R,4S)-3-ieri-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l-yl]-pyriraidine-5-carboxylic acid (Preparation 90) and cyclopropyl- { 1 -[3-( 1 -methoxy-cyclopropyl)-[l ,2,4]oxadiazol-5 -yl] -piperidin-4-yl } -amine (Preparation 244) employing a procedure similar to that outlined in Preparation 105: RT = 1.27 min; m/z (ES ') = 681.57 [M+ H]⁺ (LCMS Method - 2).

Prep aration 246 : Cyclopropyl-{ 1- [(5)-3-(tetrahydro-fur an-2-yl)- [1 ,2,4 J oxadiazol-5-yI ] - piperidin-4-yl}-amine

The title compound was synthesized from (l -cyano-piperidin-4-yl)-cycIopropyl-carbamic acid tert-butyl ester (Preparation 26) and (5 -N-hydroxytetrahydrofiiran-2-carboxamidine (Preparation 34) employing a procedure similar to that outlined in Preparation 35: RT = 0.48min; m/z (ES⁺) = 279.35 [M+ H]⁺ (LCMS Method - 2).

Preparation 247: l(3 ?,4₁S -l-[5-(Cyclopropyl-{l-l(5)-3-(tetrahydro-furan-2-yl)-[l,2,4]oxadiazol- 5-yll-piperidin-^yl}-carbamoyl)-pyriniidin-2-yl|-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester

The title compound was synthesized from 2-[(3i?,4S)-3-teri-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l -yl]-pyrimidine-5-carboxylic acid (Preparation 90) and cyclopropyl- { l-[(5)-3-(tetrahydro-furan-2-yl)-[l ,2,4]oxadiazol-5-yl]-piperidin-4-yl} -amine (Preparation 246) employing a procedure similar to that outlined in Preparation 105: RT = 1.19 rniri; m/z (ES^*) = 681.54 [M + H]⁺ (LCMS Method - 2).

Preparation 248: (i-)-iV-Hydroxytetrahyd rboxamidine

The title compound was synthesized from (R)-tetrahydrofuran-2-carbonitrile employing a procedure similar to that outlined in Preparation 34; Ή NMR δ_Η (300MHz, CDC1₃): 4.85 (bs, 2H), 4.44 - 4.32 (m, I H), 4.00 - 3.74 (m, 211), 2.20 - 1.80 (m, 4H).

Preparation 249: Cyclopropyl-{l-|(i¾)-3-(tetrahydro-furan-2-yl)-[l,2,4]oxadiazol-5-yl]- piperidin-4-yl}-amine

The title compound was synthesized from ( 1 -cyano-pipcridin-4-yl)-cyclopropyl-carbamic acid terf-butyl ester (Preparation 26) and (i?)-N-hydroxytetrahydroraran-2-carboxarmdine (Preparation 248) employing a procedure similar to that outlined in Preparation 35: RT = 0.48min; m/z (ES⁺) = 279.34 [M + Hf (LCMS Method - 2).

Preparation 250: [(3/f,4S 1 - [5-(Cyclopropyl- { 1- [( ?)-3-(tetrahydro-f uran-2-yl)- [ 1 ,2,4] oxadiazol- 5-yl]-piperidin-4-y!}-carbamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro-p enyl)-pyrrolidin-3-yl]- carbamic acid tert-butyl ester

The title compound was synthesized from 2-[(3R,4S)-3-ier/-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5-carboxylic acid (Preparation 90) and cyclopropyl- { 1 -[(R)-3-(tetrahydro-furan-2-yl)-Ll ,2,4]oxadiazol-5-yl]-piperidin-4-yl} -amine (Preparation 249) employing a procedure similar to that outlined in Preparation 105: RT = 1.19 min; m/z (ES^*) = 681 .54 [ + H]⁺ (LCMS Method - 2). Preparation 251 : 5-((3/f,4_k )-3-/t'«-Butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrazine-2-carboxylic acid meth l ester

To a solution of 2-chloro-pyrizine-5-carboxylic acid methyl ester (2.55g, 14.75mmol) and triethylaminc (4.2ml, 26.82mmol) in anhydrous THF (240mL) was added [(3R,45)-4-(2,5- difluorophenyl)pyrrolidin-3-yl]carbamic acid lert-butyl ester (Preparation 206, 6.6g, 22.12mmol) and the resulting reaction mixture was stirred at 50°C for 4 h. The reaction mixture was concentrated in vacuo and the remainder was purified by chromatography on Si0₂ gel using F.tOAc first then DCM/MeOH/NHj as eluents to afford the title compound: RT = 0.82 min; mlz (ES⁺) = 435.12 [M + H]⁺.

Preparation 252: 5-[(3i?,45')-3-½ri-Butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-pyrazine-2-carboxylic acid

The title compound was synthesized from 5-[(3 ?,45)-3-/e^, /-butoxycarbonylamino-4-(2,5- ditluoro-phenyl)-pyrrolidin-l -yl]-pyrazine-2-carboxylic acid methyl ester (Preparation 251) employing a procedure similar to that outlined in Preparation 90: RT = 1 .54 min; mlz (ES⁺) = 421.14 [ + H]\

Preparation 253; [(3 i,4-y)-l-[5-({l-[3-(l,l-Difliioro-ethyl)-[l,2,41oxadiazol-5-yl]-piperidin-4-yl}- methyl-carbamoyl)-pyrazin-2-yl]-4-(2,5-difluoro-phenyI)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester

The title compound was synthesized from 5-[(3R,45)-3-teri-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l -yl]-pyrazine-2-carboxylic acid (Preparation 252) and { l -[3-( l , l - dilluoro-ethyl)-[l ,2,4]oxadiazol-5-yI]-piperidin-4-yl}-methyl-amine (Preparation 44) employing a procedure similar to that outlined in Preparation 105: RT = 1 .27min; m z (ES ) = 649.65 [M + H] (LCMS Method - 2).

Preparation 254: 6-[(3if,45)-3-tert-Butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- yl]-nicotinic acid methyl ester

To a solution of 2-chloro-pyridine-5-carboxylic acid methyl ester (0.5g, 2.91mmol) and [(3i?,45)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (Preparation 206, 0.96g, 3.21mmol) in DMF ( lOmL) was added potassium carbonate (0.8 l g, 5.83mmol) and the resulting reaction mixture was stirred at 50°C for 16 h. The reaction mixture was diluted with DCM (5()mL), washed with brine (20mL), dried (MgS0₄), filtered and concentrated in vacuo. The remainder was purified by chromatography on Si0₂ gel using EtOAc/hexane as eluents; the resulting product was triturated with Et₂0 to afford the title compound: Ή MR δ_Η (300MHz, CDC1₃): 8.81 (m, 1H), 8.02 (d, 1H), 7.10-6.90 (m, 3H), 6.35 (d, 1H), 4.46 (m, 1H), 4.10 (m, 2H), 3.85 (s, 311), 3.60 (m , 2H), 3.35 (t, 111), 1.40 (s, 9H).

Preparation 255: 6-[(3 i,45)-3-½rt-Butoxycarbonylamino-4-(2,5-difluoro-phenyl)-pyrrolidin-l- ylj-nicotinic acid

The title compound was synthesized from 6-[(3i?,4S)-3-teri-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidm-l-yi] -nicotinic acid methyl ester (Preparation 254) employing a procedure similar to that outlined in Preparation 90: RT = 0.60 min; m/z (ES⁺) = 420.48 [M+ H] ^' . Preparation 256: [(3Λ,4£)-1- [5-({ 1- [3-(l ,1-Difluoro-ethyl)- [1,2,4) oxadiazol-5-yl] -piperidin-4-yl}- methyl-carbamoyl)-pyridin-2-yl]-4-(2,5-difluoro-phenyI)-pyrrolidin-3-yl]-carbamic acid tert- butyl ester

The title compound was synthesized from 6-[(3R,45)-3-½r/-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l-yl] -nicotinic acid (Preparation 255) and { 1 1 , 1 -difluoro-ethyl)- [l ,2,4]oxadiazol-5-yl]-pipcridin-4-yI} -methyl-amine (Preparation 44) employing a procedure similar to that outlined in Preparation 105: RT = 1.11 min; m/z (ES⁺) = 648.62 [M + H]⁺ (LCMS Method - 2).

Preparation 257: 6- f(3^, S^-3-½«-ButoxycarbonyIamino-4-(2,5-difluoro-phenyI)-pyrroIidin-l- yl]-5-cyano-nicotinic acid methyl ester

To a solution of 2-hydroxy-3-cyano-pyridine-5-carboxylic acid methyl ester (0.5g,

2.81 mmol) and [(3R,4S)-4-(2,5-difluorophenyl)pyrrolidin-3-yl]carbamic acid teri-butyl ester (Preparation 206, l .Og, 3.37mmol) in MeCN (lOmL) was added BOP (1 .86g„ 4.21 mmol) and DBU (0.63ml, 4.21 mmol); the resulting reaction mixture was stirred at r.t. for 16 h. The reaction mixture was diluted with EtOAc (50mL) and water (20mL); aqueous layer was back-extracted with more EtOAc, then the organics were combined, washed with brine (20ml.), dried (MgSCXj), filtered and concentrated in vacuo. The remainder was purified by chromatography on S1O₂ gel using EtOAc/Hexane as eluents to afford the title compound: Ή NMR δ_Η (300MHz, CDCU): 8.85 (s, 1H), 8.34 (s, 1H), 7.10-6.90 (m, 3H), 4.44 (m, 1H), 3.90 (s, 3H), 3.75 (t, 1H), 3.65 (m, 1H), 1.40 (s, 9H). Preparation 258: 6-[(3/?,4i')-3-ii?r/-Butoxycarbonylamino-4-(2,5-difluoro-phenyI)-pyrroJidin-l- ylj-5-cyano-nicotinic acid

The title compound was synthesized from 6-[(3R,4S)-3-ieri-butoxycarbonylamino-4-(2,5- difluoro-phenyl)-pyrrolidin-l -ylj-5-cyano-nicotinic acid methyl ester (Preparation 257) employing a procedure similar to that outlined in Preparation 90: RT = 0.63 min; m/z (ES⁺) = 445.20 [M + H]⁺.

Prep aration 25 : [(3R,4S)-l- [3-Cyano-5-({l-[3-(l, l-difluoro-ethyl)-[l ,2,4] oxadiazol-5-yl] - piperidin-4-yl}-methyl-carbamoyl)-pyridin-2-yl]-4-(2,5-difluoro-phenyl)-pyrroiidin-3-yl]- carbamic acid tert-but l ester

The title compound was synthesized from 6-[(3R,4.S)-3-ieri-butoxycarbonylamino-4-(2₎5- difluoro-phenyl)-pyrrolidin-l -yl]-5-cyano-nicotinic acid (Preparation 258) and {l-[3-(l ,l-difluoro- ethyl)-[l ,2,4]oxadiazol-5-yl]-piperidin-4-yl}-methyl-amine (Preparation 44) employing a procedure similar to that outlined in Preparation 105: RT = 1 ,32 min; m/z (ES⁺) = 673.56 [M + H]⁺ (LCMS Method - 2).

Example 1: 2-[(3/?, S -3-Amino-4-(2,4,5-trifluoro-phcnyl)-pyrrolidin-l-yi]-pyrimidine-5- carboxylic acid cyclopropyl- [ 1 -(3-isopropyl- [ 1 ,2,41 oxadiazol-5-yl)-piperidin-4-yl] -amide hydrochloride

To a solution of [(3i?,45)-l-{5-[(l-cyano-piperidin-4-yl)-cyclopropyl-carbamoyl]-pyrimidin- 2-yl} -4-(2,4,5-trifluoiO-phcnyl)-pyrrolidin-3-ylJ-carbarmc acid iert-butyl ester (Preparation 103, 61mg, ΙΟΟμηιοΙ) and N-hydroxy-isobutyramidine (13mg, ] 20^imol) in EtOH (4mL) was added dropwise zinc dichloride in Et₂0 (1M, 120μΕ, 120mmol) and the resulting reaction mixture was stirred at r.t, for 80 min. HC1 in 1 ,4-dioxane (4M, 130 L, 521 μιηο1) was added and the reaction mixture was heated at 60 °C for 16 h. Upon cooling, the reaction mixture was diluted with MeOH and loaded onto an SCX cartridge cluting with MeOH followed by N¾ in MeOH (7M). The basic fraction was concentrated in vacuo and purified by preparative HPLC. The product containing fractions were concentrated in vacuo and the remainder dissolved in MeOH, added to an SCX cartridge and eluted with MeOH followed by N¾ in MeOH (7M). The basic fraction was concentrated in vacuo, dissolved in MeCN:McOH (1 :2) and HCl in 1 ,4-dioxane (4M, 19 Ι.) was added. The resulting mixture was stirred at r.t. for 10 min and the solvent removed in vacuo to afford the title compound: RT = 0.81 min; mlz (ES⁺) = 571.52 [M + R† (LCMS Method - 2).

Example 2: 2-[(3/?,45)-3-Amino-4-(2,5-difluoro-phcnyl)-pyrrolidin-l- l]-pyrimidine-5- carboxylic acid [ 1 -(3-isopropyI- [ 1 ,2,4] oxadiazol-5-yl)-piperidin-4-yl] -methyl-amide

To a solution of [(3R_!4S)-4-(2,5-difluoro-phenyl)-l-(5-{[l-(3-isopropyl-[l ,2,4]oxadiazol-5- yl)-piperidin-4-yl] -methyl -carbamoyl } -pyrimidin-2-yl)-pyrrolidin-3 -yl] -carbamic ester teri-butyl ester (Preparation 104, 143mg, 228_tumol) in DCM (2.9mL) was added TFA (352μί, 4.56mmol) and the resulting reaction mixture was stirred at r.t. for 1 h. Further TFA (320uL, 4.15mmol) was added and the reaction mixture stirred at r.t. for 1.5 h. The reaction mixture was added to an SCX cartridge and eluted with MeOH followed by N¾ in MeOH (7M). The basic fraction was concentrated in vacuo to afford the title compound: RT - 2.50 min; mlz (ES⁺) = 527.29 [M + H] ^' .

Example 3: 2-|(3/i,45')-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid ethyl- [ 1 -(3-iso ropyl- [1,2,4] oxadiazol-5-yl)-piperidin-4-yl] -amide hydrochloride

To a solution of [(3R,45)-4-(2,5-difluoro-phenyl)-l -(5- {ethyl-[l -(3-isopropyl- [l ,2,4Joxadiazol-5-yl)-piperidin-4-yl]-carbarnoyl} -pyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid ierf -butyl ester (Preparation 106, 95mg, 150μmol) in DCM (2.3mL) was added TFA (485μΙ-, 6.30mmoi) and the resulting reaction mixture stirred at r.t. for 1.5 h. The reaction mixture was added to an SCX cartridge and eluted with MeOH followed by ¾ in MeOH (7M). The basic fraction was concentrated in vacuo, dissolved in MeOH (5mL) and HCl in Et₂0 (2M, 380μΤ) was added. The mixture was stirred at r.t. for 15 min, then concentrated in vacuo to afford the title compound: RT = 0.78 min; mlz (F.S ) = 541 .52 [M + H]⁺ (LCMS Method - 2).

Example 4: 2-[(3if,45}-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid {l-[3-(l-fluoro-l-methyl-cthyl)-[l,2,4|oxadiazol-5-yl]-piperidin-4-yl}-methyl- 5 amide hydrochloride

To a solution of {(3i?,4S)-4-(2,5-difJuoro-phenyl)-l-[5-({l-[3-(l-fluoro-l-methyl-ethyl)- [ l ,2,4]oxadiazol-5-yl]-piperidin-4-yl}-methyl-carbamoy

acid teri-butyl ester (Preparation 105, 85 mg, 130μηιο1) in MeOH (3mL) under argon was added HCl in Et₂0 (2M, 660μί) at 0°C. The reaction mixture was allowed to warm to r.t. and stirred for 18 h. The mixture was concentrated in vacuo to afford the title compound: RT = 0.77 min; mlz (ES ) = 545.42 [M + H] ^' (LCMS Method - 2).

The following compounds were prepared from the appropriate tert-butoxy carbonyl protected amino 5 intermediate employing a procedure similar to that outlined in Example 2:

The following compounds were prepared from the appropriate fcrr-butoxy carbonyl protected amino intermediate employing a procedure similar to that outlined in Example 3:

hl id

hydrochloride

-

+ -

-

-

hydrochloride -

-

-

h

-

-

- y roc or e

The following compounds were prepared from the appropriate fert-butoxy carbonyl protected amino intermediate employing a procedure similar to that outlined in Example 4:

4-yl } -ethyl -amide hydrochloride

Ill -

l -

-

-y -et y -am e y roc or e - - - +

-

-

-

-

[124] di l5 l] -

hy roc or e

-

-

Example 87: 2-((3 Z,4i)-3-Amino-4-(2,4,5-trifluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid [ 1 -(3 -amide hydrochloride

To a solution of [(3ii,4S)-l-(5-{[l -(3-ethyl-[l ,2,4]oxadiazol-5-yl)-piperidin-4-yl]-methyl- carbamoyl} -pyrinndin-2-yl)-4-(2,4,5-trifluoro-phcnyl)-pyrrolidin-3-yl]-carbamic acid fcrf-butyl ester

(Preparation 131, 115mg, 182μιηο1) in 1 ,4-dioaxne (5mL) was added HCl in 1 ,4-dioxane (4M, 182μί, 729μηιο1) and the resulting reaction mixture was stirred at r.t. for 75 min. Further HCl in 1 ,4- dioxane (4M, 1.5mL, 6mmol) was added and stirring at r.t. continued for 16 h. The solvent was removed in vacuo and the remainder purified by preparative HPLC. The product containing fractions were loaded onto an SCX cartridge and eluted with MeOH followed by NH₃ in MeOH (7M). The basic fraction was concentrated in vacuo, then the remainder was dissolved in 1 ,4-dioxane and HC1 i 1 ,4-dioxanc (4M, 0.2mL) was added. The resulting mixture was stirred at r.t. for 1 h and concentrated in vacuo to afford the title compound: RT = 0.71 min; m/z (ES ) = 531.5 [M + I I] ^' (LCMS Method - 2).

Example 88 : 2- [(3/?,45^-3-Amino-4-(2-fluoro-5-methyI-phenyl)-pyrroIidin-l-yl] -pyrimidine-5- carboxylic acid [l-(3-ethyl- l,2,4]oxadiazol-5-yl)-pipcridin-4-yl)-methyl-amide hydrochloride

To a solution of [(3/?,4.S 1 -(5- { [ 1 -(3-ethyl-[l ,2,4]oxadiazol-5-yl)-piperidin-4-yl]-mcthyl- carbamoyl } -pyrirm^in-2-yl)-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-3-yl]-carbamic acid feri-butyl ester (Preparation 154, 109mg, 179μηιο1) in Et₂0 (5mL) at 0°C was added IIC1 in 1 ,4-dioxanc (4M, 1 mL, 4mmol) and the resulting reaction mixture was stirred at r.t. for 4 h. The solvent was removed in vacuo and the remainder was dissolved in the minimum amount of hot EtOH and allowed to cool to r.t. Et₂0 was added dropwise until a white precipitate formed, then the yellow solution was decanted off and the solid dried in vacuo to afford the title compound: RT = 2.48 min; m/z (ES ) = 509.18 [M I ll] ^' .

Example 89: 2- [(3/?,45)-3-Amino-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin- 1 -yl) -pyrimidine-5- carboxylic acid [ l-(3-isopropyl- [1,2,4] oxadiazol-5-yl)-piperidin-4-yl] -methyl-amide hydrochloride

The title compound was synthesized from [(3/?,4-S 4-(2-fluoro-5-mcthyl-pheny

(3-isopropyl-[l ,2,4]oxadiazol-5-yl)-piperidin-4-yl]-methyl-carbamoyl} -pyrimidin-2-yl)-pyrrolidi yl]-carbamic acid tert-butyl ester (Preparation 152, 1 80mg, 290μιηο1) employing a procedure similar to that outlined in Example 88: RT = 2.70 min; m/z (ES⁺) = 523.19 [ + H]⁺.

Example 90: 2-[(3 ?,45)-3-Amino-4-(2-fluoro-5-methyl-phenyl)-pyrrolidin-l-yl]-pyrimidinc-5- carboxylic acid ethyl-[l-(3-iso ropyl-[l,2,41oxadiazol-5-yl)-piperidin-4-yl]-amide hydrochloride

To a solution of [(3/?,4S)- 1 -(5- {ethyl-[ 1 -(3-isopropyl-[ 1 ,2,4]oxadiazol-5-yl)-piperidin-4-ylJ- carbamoyl} -pyrimidin-2-yl)-4-(2-fluoro-5 -methyl -phenyl)-pyrrolidin-3-yI] -carbamic acid /e/V-butyl ester (Preparation 153, 210mg, 330,umol) in Et₂0 (5mL) and DCM (2.5mL) at 0°C was added HC1 in 1 ,4-dioxane (4M, 2.0mL, S.Ommol) and the resulting reaction mixture was stirred at r.t. for 16 h. The solvent was removed in vacuo, then the remainder dissolved in EtOAc, washed with aqueous NaOH solution (2M), dried (MgS()₄), filtered and concentrated in vacuo. The remainder was purified by preparative HPLC (basic method) and the product dissolved in MeOH prior to the addition of HC1 in Et.O (2M, 2.0mL). The solvents were removed in vacuo to afford the title compound: RT = 2.72 min; mlz (ES⁺) = 537.25 [M+ H] ' .

Example 91 : 2-[(3R,45 -3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid { 1- [5-(l , 1 -difluoro-cthyl)- f 1 ,2,4]oxadiazol-3-yl] -piperidin-4-yl}-methyl-amide hydrochloride

The title compound was synthesized from [(3R,45)-1 -[5-( { 1 -[5-( 1 , 1 -ditluoro-ethyl)- [l ,2,4]oxadiazol-3-yl]-piperidin-4-yl}-methyl-carbamoyl)-pyrirnidin-2-yl]-4-(2,5-difluoro-phenyl)- pyrrolidin-3-yl] -carbamic acid terf-butyl ester (Preparation 215, 357mg, 0.55mmol) employing a procedure similar to that outlined in Example 4: RT = 0.81 min; mlz (ES⁺) = 549,51 [M+ H]⁺.

Example 92: 2-[(3 f,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yI]-pyrimidine-5- carboxylie acid cyclopropyl- { 1- [5-(l-methoxy- 1-methyl-ethyl)- [1 ,2,4] oxadiazol-3-yl] -piperidin- 4-yl}-amide hydrochloride

The title compound was synthesized from [(3R,4S)-1 -[5-(cyclopropyl- { 1 -[5-(l -mcthoxy-1 - mcthyl-ethyl)-[l ,2,4]oxadiazol-3-yl]-piperidii>4-yl} -carbamoyl)-pyriniidin-2-yl]-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl] -carbamic acid iert-butyl ester (Preparation 218, 1 mg, 0.13mmol) employing a procedure similar to that outlined in Example 3: RT - 0.81 min; mlz (ES ) = 583.6 [M+ H] . Example 93: 2-[(3 ?,4A')-3-Ammo-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimicline-5- carboxylic acid cyclopropyl-{l-[5-(l,l-difluoro-ethyl)-[l,2,4Joxadiazol-3-yI]-piperidin-4-yl}- amide hydrochloride

The title compound was synthesized from [(3i?,45)-l-[5-(cyclopropyl-{ l-[5-(l ,l-difluoro- ethyl)-[l,2,4]oxadiazol-3-yl]-piperidin-4-yl}-carbamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid tot-butyl ester (Preparation 222, 31 mg, 0.046mmol) employing a procedure similar to that outlined in Example 4: RT = 0.81 min; mlz (ES ) = 583.6 [M + H]⁺.

Example 94: 2- [(3/?,45 -3-Amino-4-(2,5-difluoro-phenyl)-pyrroiidin-l-yll-pyrimidine-5- carboxylic acid cyclopropyl-{l-[( ?)-S-(tetrahydro-furan-3-yl)-| l,2,4]oxadiazol-3-yl]-piperidin- 4-yI}-amide hydrochloride

The title compound was synthesized from [(3R,45')-1 -[5-(cyclopropyl- { 1 -[(R)-5-(tetrahydro- furan-3-yl)-[l ,2,4]oxadiazol-3-yl]-piperidin-4-yl} -carbamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid fert-butyl ester (Preparation 223, 36mg, O.053mmol) employing a procedure similar to that outlined in Example 4: RT = 0.72 min; mlz (ES-) = 581.6 [M + H (LCMS Method - 2).

Example 95: 2-[(3-?,4.S)-3-Aniino-4-(2,5-difluoro-phenyl)-pyrroIidin-l-yl]-pyriinidine-5- carboxylic acid cyclopropyl-{ 1- ((5)-3-(tetrahydro-furan-3-yl)- [ 1 ,2,4] oxadiazol-5-yl j -pipcridin- 4-yl}-amide hydrochlori

The title compound was synthesized from [(3R,4S)-l -[5-(cyclopropyl-{ l -[(S)-3-(tetrahydro- furan-3 -yl)-[ 1 ,2,4] oxadiazol-5 -yl] -piperidin-4-yl } -carbamoyl)-pyrimidin-2-yl] -4-(2,5 -difluoro- phenyl)-pyrrolidin-3-yl]-carbamicacid teri-butyl ester (Preparation 228) employing a procedure similar to that outlined in Example 4: RT = 0.74 min; mlz (ES^*) = 581.46 [M + Hf (LCMS Method - 2).

Example 96: 2-[(3/?,4 )-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5-sulfonic acid {l -f3-(l,l-difluoro-ethyl)-[l,2,4]oxadiazol-5-ylJ-piperidin-4-yl}-methyl-amide hydrochloride

The title compound was synthesized from [(3R,45)-l-[5-({l-[3-(l,l -difluoro-ethyl) [l ,2,4]oxadia2»l-5-yl]-piperidin-4-yl}-meth^

pyrrolidin-3-y]]-carbamic acid tert-butyl ester (Preparation 230) employing a procedure similar to that outlined in Example 3: LCMS: RT = 0.84 min, m/z (US^') = 585,5 [ + H] .

Example 97: 2-[(3 ?,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l -yl] -pyrimidine-5 carboxylic acid (l-cycloprop amide hydrochloride

The title compound was synthesized from [(3R, S 1 -{5-[(l -cyclopropanesulfonyl-piperidin-4- yl)-cyclopropyI-carbamoyl]-pyrimidin-2-yl}-4-(2,5-difluoro-phenyl)-pyrrolidin-3-yl]-carbami acid tert-butyl ester (Preparation 232) employing a procedure similar to that outlined in Example 3; RT = 0.73 min; m/z (ES ') = 547.51 [M+ H]⁺ (LCMS Method - 2).

Example 98: 2- [(3/i,45)-3-Amino-4-(2 ,5-difluoro-phenyl)-pyrro!idin- 1 -yl] -pyriniidine-: carboxylic acid cycloprop - [ 1 -(2-ethyl-2H-tetrazol-5-yl)-piperidin-4-yl] -amide hydrochloride

The title compound was synthesized from [(3i?,4S}-l-(5-{cyclopropyl-[l-(2-ethyl-2H-tetrazol- 5-yl)^iperidin-4-yl] -carbamoyl } -pyrirm^m

acid tert-butyl ester (Preparation 236) employing a procedure similar to that outlined in Example 4: RT - 0.75min; m/z (ES⁺) = 539.57 [ + H]⁺ (LCMS Method - 2). Example 99: 2-[(3i?,4-^-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- carboxylic acid cyclopropyl-{l - [3-(tetrahydro-pyra n-4-yI)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin-4- yl}-amidc hydrochlorid

The title compound was synthesized from [(3R,4S)-1 -[ 5-(cyclopropyl- { 1 -[3-(tetrahydro-pyran- 4-yl)-[ l ,2,4]oxadiazol-5-yl]-piperidin-4-yl } -carbamoyl

pyiTo]idin-3-yl]-carbamic acid ferf-butyi ester (Preparation 238) employing a procedure similar to that outlined in Example 3: RT = 0.73 min; m/z (ES⁺) = 595.62 [M + H]~ (LCMS Method - 2).

Example 100: 2-[(3 ?,45)-3-Amino-4-(2,5-difluoro-phenyI)-pyrrolidin-l-yl)-pyrimidine-5- carboxylic acid cyclopropyl- { 1 - [3-( 1-methoxy-cyclopropyl)- [ 1 ,2,4] oxadiazol-5-yl] -piperidin-4- yl}-amide hydrochloride

The title compound was synthesized from [(3R,45)-l -[5-(cyclopropyl-{l -[3-(l -methoxy- cyclopropyl) 1,2,4]oxadiazol-5-yl]-piperidir 4-yl} -carbamoyl)-pyrimidin-2-yl]-4-(2,5-difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid ter/-butyl ester (Preparation 245) employing a procedure similar to that outlined in Example 3: RT = 0.76min; m/z (tiS ) = 581 .57 [ + H] ' (LCMS Method - 2).

Example 101 : 2- f(3S,45 3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin- 1-ylJ -pyrimidine-5- carboxylic acid cyclopropyl- {l-[(5)-3-(tetrahydro-furan-2-yl)- [ 1,2,4] oxadiazol-5-yl] -piperidin- 4-yl}-amide hydrochloride

The title compound was synthesized from [(3ii₃4S)-l-[5-(cyclopropyl- { l -[(S)-3-(tetrahydro- fwan-2-yl)-[l ,2,4]oxadiazol-5-yl]-piperidin-4-yl} -carbamoyl)-pyrmiidin-2-yl]-4- phenyl)-pyrrolidin-3-yl]-carbamic acid teri-butyl ester (Preparation 247) employing a procedure similar to that outlined in Example 3: RT = 0.75min; m/z (ES⁺) = 581 .51 [M + H]⁺ (LCMS Method -

2).

Example 102: 2-[(3iZ,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrimidine-5- car boxylic acid cyclopropyl- { 1- [{R )-3-(tetrahyd o-f uran-2-yl)- f 1 ,2,4] oxadiazol-5-yl] -piperidin- 4-yI}-amide hydrochloride

The title compound was synthesized from [(3i?,45)-l-[5-(cyclopropyl-{ l -[(R)-3-(tetrahydro- furan-2-yl)-[ 1 ,2,4]oxadiazol-5 -yl] -piperidin-4-yl} -carbamoyi)-pyrimidin-2-yl] -4-(2,5 -difluoro- phenyl)-pyrrolidin-3-yl]-carbamic acid ieri-butyl ester (Preparation 250) employing a procedure similar to that outlined in Example 3: RT = 0.75 min; m/z (ES⁺) = 581.46 [M + I I] ^' (LCMS Method -

Example 103: 5-[(3 ?,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-pyrazinc-2- carboxylic acid {l-[3-(l,l-difluoro-ethyI)-(l,2,4]oxadiazol-5-yI]-piperidin-4-yl}-methyl-amide hydrochloride

The title compound was synthesized from [(3RAS -1 -[5-( { 1 -[3-(l ,l -difluoro-cthyl)- [1 ,2,4] oxadiazol- -yl] -pipcridin-4-yl } -methyl-carbamoyl)-pyrazin-2-yl] -4-(2,5 -difluoro-phenyl)- pyrrolidin-3 -yl] -carbamic acid teri-butyl ester (Preparation 253) employing a procedure similar to that outlined in Example 4: RT = 0.79min; m/z (ES⁺) = 549.55 [ + H] ' (LCMS Method - 2). Example 104: e-KS^^^-S-Amino^-il^-dmuoro-phen lJ-p rroHdin-l-yll-^-il-ia-il,!- difluoro-ethyl)-[ 1,2,4] oxadi ide hydrochloride

The title compound was synthesized from [(3i?,45)-l-[5-({ i-[3-(l,l-difluoro-ethyl)- [l ,2,4]oxadiazol-5-yl]-piperidin-4-yl}-methyl-carbamoyl)-pyridin-2-yl]-4-(2,5-difluoro-phenyl)- pyrrolidin-3-ylJ-carbamic acid fcrt-butyl ester (Preparation 256) employing a procedure similar to that outlined in Example 3: RT = 0.74min; m/z (ES⁺) = 548.60 [M + H (LCMS Method - 2).

Example 105: 6-[(3 i,45)-3-Amino-4-(2,5-difluoro-phenyl)-pyrrolidin-l-yl]-5-cyano-A'-{l-[3- ( 1 ,1 -difluoro-ethyl)- [1 ,2,4] oxa diazol-5- l] -piperidin-4-yl}-A-methyl-nicotinamide hydrochloride

The title compound was synthesized from [(3R,4S)-l -[3-cyano-5-({l-[3-(l ,l -difluoro-ethyl)- [l,2,4]oxadiazol-5-yl]-piperidin-4-yl}-methyl-carbamoyl)-pyridin-2-yl]-4-(2,5-difluoro-phenyl)- pyrrolidin-3-yl]-carbamic acid fe/ -butyl ester (Preparation 259) employing a procedure similar to that outlined in Example 3: RT = 0.79min; m/z (ES⁺) = 573.54 [AT + H] ^" (LCMS Method - 2).

The biological activity of the compounds of the invention may be tested in the following assay systems: GPR119 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 <1 () 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-weIl plates (Black OptiPlate-96F) in a total volume of 100 μΐ, per well consisting of 50 inM Tris pH 7.6, 100 μΜ GP-AMC, 10-25 μΐ) recombinant human DPP-IV and a range of inhibitor dilutions in a final concentration of 1% DM SO. 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 105 above were tested and found to show activity in this assay having an ICso of <20 μΜ. Some of the examples were found to have a DPP-IV EC₅₀ value of less than ΙμΜ; others an EC₅₀ value of less than 20 μΜ.

Activities of a representative group of compounds that were tested in the cAMP assay and the DPP-IV assay are shown in Table 1 below:

Table 1.

Anti-diabetic effects of compounds of the invention in an in-vitro model of pancreatic beta cells (H1T-T15)

Cell Culture

I IIT-T15 cells (passage 60) were obtained from ATCC, and were cultured in RPMI1640 medium supplemented with 10% fetal calf serum and 30 nM sodium selemte. 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 mL well and cultured for 24 h and the medium was then discarded. Cells were incubated for 15 min at room temperature with 1 ΟΟμΙ 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 rpin 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 μL· sample, 5 μΕ 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 1 0 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 n.Vl) 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 1 19 raM NaCl, 4.74 mM Cl, 2.54 mM CaCl,, 1 .19 mM MgS0₄, 1.19 mM ΚΙΙ,ΡΟ,, 25 mM NaHCOj, 10 mM HEPES at pi I 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 1 ml 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 /j-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 1 0 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 ' .

The effects of compounds of the invention on oral glucose (Glc) tolerance were evaluated in male C57B1/6 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 μΐ .) 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

or 25% aqueous Gelucire 44/14) 30 min before the removal of an additional blood sample (20 μΙ .) and treatment with the Glc load (2-5 g kg^"1 p.o.). Blood samples (20 μί) were then taken 25, 50, 80, 120, and 180 min after Glc administration. The 20 μΐ_^ 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 μL· of haemolysis reagent. Duplicate 20 μί, aliquots of the diluted hacmolysed blood were then added to 180 ΐ, 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 ' , for example at a dose of 30 mg kg^"1 the compound of Example 7 showed a > 40% reduction in the Glc excursion

Claims

1.

wherein A is a para-linked phenyl, pyridinyl, pyrimidinyl, pyrazinyl or triazinyl;

R1 is hydrogen, halo, cyano, C^alkyl, C ^haloalkyl, C^alkoxy or C2_6alkoxyalkyl;

R2 is selected from the group consisting of:

(a) phenyl optionally substituted by one or more halo, methyl or halomethyJ groups,

(b) pyridyl optionally substituted by one or more halo, methyl or halomethyl groups and (c) N-pyridonyl optionally substituted by one or more halo, methyl or halomethyl groups

R3 is methyl, C^.^cycloalkyl, 4 to 6 membered saturated heterocyclyl (comprising 1 or 2 ring heteroatoms selected from N, O and S) or C2.4 alkyl wherein the C^.gcycloalkyl and C^^alkyl are optionally substituted by fluoro, cyano, hydroxy or C \ _ alkyloxy;

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

Z is selected from the group consisting of:

(a) C(0)OR\

(b) C(0)R\

(c) S(0)₂R⁴,

(d) 5- or 6-membered N-containing heteroaryl ring optionally

containing 1 to 3 additional heteroatoms selected from N, O and S, or a 8 to 10 membered fused bicyclic system optionally containing 1 to 3 heteroatoms selected from N, O and S, wherein the heteroaryl ring or fused bicyclic system is optionally substituted by one or two groups independently selected from halo, cyano, Ci _4 alkyl, Ci _4 haloalkyl, Cj _4 alkoxy, C2.4 alkoxyalkyl, heterocyclyl (a 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from N , O and S), heterocyclyl C j _4 alkyl (wherein the heterocyclyl is a 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from N, O and S) and C3.5 cycloalkyl optionally substituted by C 1.4 alkyl alkoxy or halo; and (e) -CH j-phenyl, wherein the phenyl is optionally substituted by one or two groups independently selected from C \ .4 alkyl, C ^haloalkyl and halo;

and when Z is optionally substituted -CH₂-phenyl then p and q are both 0 or 1 ;

R⁴ is selected from the group consisting of:

a) Cj .galkyl,

b) phenyl,

c) C-2-6alkoxyalkyl,

d) C3_C_jCycloalkyl optionally substituted by C\ .4 alkyl,

e) C3_gcycloalkylCi ^alkyl optionally substituted by C .4 alkyl,

fj 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from N, O and S, and

g) 5 or 6 membered heteroaryl ring containing 1 to 4 heteroatoms selected from N, O and S optionally substituted by one or two groups selected from halo, cyano, C _j ^alkyl, C^haloalkyl, Cj .

4alkoxy, C2_4alkoxyalkyl, a 4 to 6 membered saturated heterocycle comprising 1 or 2 ring heteroatoms selected from N, O and S and C^.gcycloalkyl wherein the cycloalkyl is optionally substituted by ( .4 alkyl or halo;

X is selected from C(0) or S(0)₂ with the proviso that when X is S(0)₂ then is methyl, p and q are both 1 and Z is a 5 to 6 membered heteroaryl ring;

each of R⁵ and R⁶ is independently hydrogen, halo, C_j ^alkyl, Cj ^haloalkyl or

Cj _3 alkoxy; alternatively R⁵ and R⁶ can be joined to form an azabicyclo[3.3.1 Jnonane, a 3-oxa-7- azabicyclo[3.3.1 Jnonane or an azabicyclo [3.2.1] octane;

R⁷ is hydrogen, halo, Ci_-2alkyl, C].₂haloalkyl or C^alkoxy;

s is 0, 2 or 3

and when and R^ are both hydrogen then s is 0, 2 or 3,

and when at least one of R⁵ and R⁶ is halo, CI.2 alkyl, Cj .4 haloalkyl or Ci .4 alkoxy then s is 0 and pharmaceutically acceptable salts thereof.

2. A compound as claimed in Claim 1 wherein said compound has the stereochemistry:

wherein R² is as defined in claim 1.

3. A compound as claim 1 or claim 2 wherein X is C(O).

4. A compound as claimed in Claim 1 or Claim 2 wherein is hydrogen.

5. A compound as claimed in any one of Claims 1 to 4 wherein is methyl, C3.gcycloalkyl or C2_4alkyl, wherein the C3_gcycloalkyl and C2_4alkyl arc optionally substituted by fluoro, cyano, hydroxy or C _j _2alkyloxy.

6. A compound as claimed in any one of claims 1 to 5 wherein p and q are the same.

7. A compound as claimed in any one of claims 1 to 6 wherein A is pyridine, pyrimidine or pyrazinc.

8. A compound as claimed in any of claims 1 to 7 wherein Z is a hcteroaryl group optionally be substituted by one or two groups selected from halo, C\ _4 alkyl, j ^haloalkyl, Cj ^alkoxy, C?.

4alkoxyalkyl, heterocyclyl, heterocyclylC] ^alkyl and C^.gcycloalkyl, wherein the cycloalkyl is optionally substituted by C\ .4 alkyl, Ci_₄ alkoxy or halo.

9. A compound as claimed in claim 8 wherein the heteroaryl group is oxadiazole, pyrimidine, pyridazine, thiazole, tetrazole, benzothiazole or thiadiazole.

10. A compound as claimed in claim 9 wherein Z comprises optionally substituted 1 ,2,4-oxadiazol-3- yl, l,2,4-oxadiazol-5-yl or pyrimidin-2-yl.

1 1 . A compound as claimed in any preceding claim wherein Z is -C(0)QR4.

12. A compound as claimed in any preceding claim wherein R^ is alkyl, C4.5 alkoxyalkyl, cycloalkyl or cycloalkylalkyl, wherein the cycloalkylalkyl is optionally substituted by C \ .4 alkyl.

13. A compound as claimed in claim 1 1 wherein R^ is propyl, preferably isopropyl.

14. A compound as claimed in any preceding claim wherein is substituted phenyl or pyridyl.

15. A compound as claimed in any preceding claim, wherein R^ is phenyl substituted by one, two or three halo or methyl groups.

16. A compound as claimed in any preceding claim, wherein R- is phenyl substituted by two or three halo groups.

17. A compound according to any of Examples 1 to 105 or a pharmaceutically acceptable salt thereof.

18. A compound as claimed in any preceding claim for use in a method of treatment of a metabolic disorder, including type II diabetes.

19. A pharmaceutical formulation or composition comprising a compound as claimed in any of claims 1 to 19 and a pharmaceutically acceptable carrier therefor.

20. A method for the treatment or prevention of diabetes, including type II diabetes, or 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 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical formulation or composition as claimed in claim 19.